U.S. patent application number 16/828119 was filed with the patent office on 2020-12-24 for compositions, methods, and systems for the synthesis and use of imaging agents.
This patent application is currently assigned to Lantheus Medical Imaging, Inc.. The applicant listed for this patent is Lantheus Medical Imaging, Inc.. Invention is credited to Matthias Broekema, David S. Casebier, Richard R. Cesati, Thomas D. Harris, Carol Hui Hu, David C. Onthank, Ajay Purohit, Heike S. Radeke, Simon P. Robinson, Ming Yu.
Application Number | 20200397927 16/828119 |
Document ID | / |
Family ID | 1000005064669 |
Filed Date | 2020-12-24 |
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United States Patent
Application |
20200397927 |
Kind Code |
A1 |
Radeke; Heike S. ; et
al. |
December 24, 2020 |
COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USE OF
IMAGING AGENTS
Abstract
The present invention relates to systems, compositions, and
methods for the synthesis and use of imaging agents, or precursors
thereof. An imaging agent precursor may be converted to an imaging
agent using the methods described herein. In some cases, the
imaging agent is enriched in .sup.18F. In some cases, an imaging
agent may be used to image an area of interest in a subject,
including, but not limited to, the heart, cardiovascular system,
cardiac vessels, brain, and other organs. In some embodiments,
methods and compositions for assessing perfusion and innervation
mismatch in a portion of a subject are provided.
Inventors: |
Radeke; Heike S.; (South
Grafton, MA) ; Cesati; Richard R.; (Pepperell,
MA) ; Purohit; Ajay; (Sudbury, MA) ; Harris;
Thomas D.; (Salem, NH) ; Robinson; Simon P.;
(Stow, MA) ; Yu; Ming; (Chelmsford, MA) ;
Casebier; David S.; (Carlisle, MA) ; Hu; Carol
Hui; (New Hope, PA) ; Broekema; Matthias; (New
Hope, PA) ; Onthank; David C.; (Groton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lantheus Medical Imaging, Inc. |
North Billerica |
MA |
US |
|
|
Assignee: |
Lantheus Medical Imaging,
Inc.
North Billerica
MA
|
Family ID: |
1000005064669 |
Appl. No.: |
16/828119 |
Filed: |
March 24, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15364678 |
Nov 30, 2016 |
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16828119 |
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14343627 |
Jun 30, 2014 |
9550000 |
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PCT/US2012/054309 |
Sep 7, 2012 |
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15364678 |
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61656489 |
Jun 6, 2012 |
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61656492 |
Jun 6, 2012 |
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61533133 |
Sep 9, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 51/04 20130101;
C07C 279/12 20130101; C07C 281/18 20130101; A61K 51/0459 20130101;
C07C 279/14 20130101; A61K 51/041 20130101; A61K 51/0497 20130101;
C07C 257/14 20130101; A61K 51/0453 20130101; C07C 279/08 20130101;
C07C 279/06 20130101; C07C 279/04 20130101; C07B 2200/05 20130101;
C07D 209/14 20130101; C07D 233/46 20130101; C07C 217/70
20130101 |
International
Class: |
A61K 51/04 20060101
A61K051/04; C07C 279/04 20060101 C07C279/04; C07D 233/46 20060101
C07D233/46; C07D 209/14 20060101 C07D209/14; C07C 257/14 20060101
C07C257/14; C07C 279/06 20060101 C07C279/06; C07C 279/08 20060101
C07C279/08; C07C 279/12 20060101 C07C279/12; C07C 279/14 20060101
C07C279/14; C07C 281/18 20060101 C07C281/18; C07C 217/70 20060101
C07C217/70 |
Claims
1-373. (canceled)
374. A compound of the formula: ##STR00401## or a salt thereof,
wherein: ##STR00402## L is selected from --OCH.sub.2CH.sub.2--,
--NH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.N--, R.sup.1 is:
##STR00403## wherein each occurrence of R.sup.B is independently
hydrogen, substituted or unsubstituted alkyl, or a
nitrogen-protecting group, provided at least two R.sup.B are
hydrogen; R.sup.2 and R.sup.6 are hydrogen; each of R.sup.3,
R.sup.4 and R.sup.5 is independently hydrogen, halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2,
--SR.sup.A1, --C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1,
--C(.dbd.O)SR.sup.A1, --C(.dbd.O)N(R.sup.A2).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or any two
adjacent R.sup.3, R.sup.4 and R.sup.5 are joined to form an
optionally substituted or unsubstituted carbocyclic, heterocyclic,
aryl, or heteroaryl ring; each occurrence of R.sup.A1 is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl;
and each occurrence of R.sup.A2 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, or an amino protecting group, or
two R.sup.A2 groups are joined to form an optionally substituted
heterocyclic ring; and wherein R.sup.4 is substituted with an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, and .sup.124I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is .sup.124I.
375. The compound of claim 374, wherein R.sup.1 is ##STR00404##
376. The compound of claim 374, wherein R.sup.4 is alkyl
substituted with the imaging moiety.
377. The compound of claim 374, wherein R.sup.4 is alkoxy
substituted with the imaging moiety.
378. The compound of claim 377, wherein R.sup.4 is substituted with
.sup.18F.
379. The compound of claim 377, wherein R.sup.4 is --OCH.sub.2F,
--OCH.sub.2CH.sub.2F, --OCH.sub.2CH.sub.2CH.sub.2F, or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F, wherein F is isotopically
enriched with .sup.18F.
380. The compound of claim 374, wherein R.sup.4 is of the formula:
##STR00405## wherein n is an integer between 0 and 6, inclusive;
and m is an integer between 0 and 6, inclusive.
381. The compound of claim 380, where R.sup.4 is ##STR00406##
382. The compound of claim 374, wherein R.sup.5 is hydrogen.
383. The compound of claim 374, wherein R.sup.3 and R.sup.5 are
hydrogen.
384. The compound of claim 374, wherein R.sup.3 is hydrogen.
385. The compound of claim 374, wherein R.sup.3 is halogen.
386. The compound of claim 374, selected from: ##STR00407## and
salts thereof, wherein each F is enriched with .sup.18F.
387. A pharmaceutical composition comprising a compound of claim
374, or a salt thereof, and optionally a pharmaceutically
acceptable excipient.
388. A method of imaging cardiac innervation, comprising
administering an effective amount of a compound of claim 374, or a
salt thereof, to a subject, and detecting radiation emitted by the
compound; and forming an image therefrom.
389. A method of imaging a subject, comprising administering a
compound of claim 374 or a salt thereof, to the subject, and
acquiring at least one image of a portion of the subject.
390. A method of detecting norepinephrine transporter (NET) in a
portion of a subject, comprising administering a compound of claim
374, or a salt thereof, to the subject, and acquiring at least one
image of the portion of the subject, wherein the image detects NET
in the subject.
391. A method of selecting an antiarrhythmic agent and/or
determining the dose of an antiarrhythmic agent for administration
to a subject, the method comprising administering to a subject the
compound of claim 374, or a salt thereof, acquiring at least one
image of a portion of the subject; and selecting the antiarrhythmic
agent and/or determining the dose of an antiarrhythmic agent for
administration to a subject based on the at least one first
image.
392. The method of claim 391, wherein a reduced dose of an
antiarrhythmic agent that induces electrophysiological changes in a
subject's heart is prescribed based on the at least one first image
indicating presence of cardiac denervation.
393. A method comprising administering to a subject the compound of
claim 374, or a salt thereof, acquiring at least one image of a
portion of the subject; and identifying (i) a subject to be treated
with an antiarrhythmic agent that does not induce
electrophysiological changes in the heart of the subject based on
presence of cardiac denervation in the image; (ii) a subject to be
treated with a reduced dose of an antiarrhythmic agent that induces
electrophysiological changes in the heart of the subject based on
presence of cardiac denervation in the image; and/or (iii) a
subject in need of a dose reduction of an antiarrhythmic agent that
induces electrophysiological changes in the heart of the subject
based on presence of cardiac denervation in the image.
Description
RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/364,678, filed Nov. 30, 2016, entitled
"COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USE OF
IMAGING AGENTS", which is a continuation of U.S. application Ser.
No. 14/343,627, filed Jun. 30, 2014, entitled "COMPOSITIONS,
METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USE OF IMAGING AGENTS",
which is a U.S. National Stage application of International Patent
Application Serial No. PCT/US2012/054309, filed Sep. 7, 2012,
entitled "COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND
USE OF IMAGING AGENTS", which claims priority under 35 U.S.C.
.sctn. 119(e) to U.S. Provisional Application Ser. No. 61/533,133,
filed Sep. 9, 2011, entitled "COMPOSITIONS, METHODS, AND SYSTEMS
FOR THE SYNTHESIS AND USE OF IMAGING AGENTS"; U.S. Provisional
Application Ser. No. 61/656,489, filed Jun. 6, 2012, entitled
"COMPOSITIONS, METHODS, AND SYSTEMS FOR THE SYNTHESIS AND USE OF
IMAGING AGENTS"; and U.S. Provisional Application Ser. No.
61/656,492, filed Jun. 6, 2012, entitled "METHODS AND COMPOSITIONS
FOR ASSESSING PERFUSION AND INNERVATION MISMATCH", the entire
contents of each of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful as imaging
agents, compositions thereof, methods for the synthesis and use
thereof, and precursors thereto. In some embodiments, the compounds
may be used to image perfusion (e.g., cardiac perfusion). In other
embodiments, the compounds may be used to image innervation. The
present invention also provides methods and compositions for
assessing perfusion and innervation mismatch in a subject, for
example, a human subject.
BACKGROUND OF THE INVENTION
[0003] Heart failure (HF) is defined as the inability of the heart
to supply peripheral organs with sufficient blood flow. It may be
characterized by a hyperadrenergic state whereby increased systemic
levels of norepinephrine (NE) and increased local spillover of
catecholamines occur. The condition afflicts increasingly more
people each year and is a common end-stage of many cardiac diseases
and conditions including myocardial infarction, pressure/volume
overload, viral myocarditis, toxic cardiomyopathy, valve failure,
and other abnormalities. The resultant myocardial damage, in
conjunction with neurohormonal and cytokine activation, stimulates
chamber remodeling which is the initial phase of heart failure.
This remodeling process results in decreased overall myocardial
efficiency and eventual progression to clinical HF. To date,
however, no cure for the condition exists, thus early diagnosis is
a key factor in its management and long-term prognosis. An imaging
agent that identifies subjects in early HF would thus enable
treatment and life-style improvements for patients living with the
condition.
[0004] Myocardial damage may also occur following tissue insult
(e.g., a myocardial infarction), whereby innervation and perfusion
defects may form in a portion of the subject (i.e. a portion of the
heart). In certain cases, the size of the defect areas, as detected
by imaging, could be different (e.g., regional mismatch) and may be
associated with an increased probability for cardiac arrhythmia as
well as other conditions.
[0005] Accordingly, improved compositions, methods, systems, and
apparatuses are needed for the synthesis and administration of
imaging agents (e.g., for imaging the heart).
SUMMARY OF THE INVENTION
[0006] The present invention provides, in a broad sense, compounds
and compositions thereof (including salt forms) that are useful as
imaging agents or imaging agent precursors, methods of use thereof,
and methods for synthesizing provided compounds. In some
embodiments, the imaging agents may be used for imaging perfusion.
In some embodiments, the imaging agents may be used for imaging a
portion of the subject, for example, a portion of the heart. In
some embodiments, method of imaging are provided. In some
embodiments, methods and compositions for assessing perfusion and
innervation mismatch in a portion of a subject are provided.
[0007] In some embodiments, a compound is provided having
formula:
R.sup.0--Ar-L-R.sup.1
wherein
[0008] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0009] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0010] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety; and
[0011] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0012] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0013] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
[0014] In some embodiments, a compound is provided having
formula:
##STR00001##
wherein
[0015] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0016] R.sup.1 is selected from the group consisting of:
##STR00002##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen;
[0017] R.sup.2 and R.sup.6 are hydrogen;
[0018] each of R.sup.3, R.sup.4 and R.sup.5 is independently
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or any two
adjacent R.sup.3, R.sup.4 and R.sup.5 are joined to form an
optionally substituted or unsubstituted carbocyclic, heterocyclic,
aryl, or heteroaryl ring;
[0019] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0020] wherein R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br, and
.sup.124I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is .sup.124I;
[0021] or a salt thereof
[0022] with the proviso that if one of R.sup.3 or R.sup.5 is Cl,
Br, or CF.sub.3, then the other of R.sup.3 or R.sup.5 is not H.
[0023] In some embodiments, a compound is provided having
formula:
##STR00003##
wherein
[0024] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0025] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0026] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0027] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0028] each occurrence of R.sup.4 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0029] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
[0030] at least one R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
[0031] In some embodiments, a compound is provided having
formula:
##STR00004##
wherein
[0032] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0033] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0034] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0035] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A1)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0036] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0037] R.sup.4 is substituted with an imaging moiety selected from
the group consisting of .sup.18F, .sup.76Br, .sup.124I, an
.sup.113I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I;
[0038] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0039] In some embodiments, a compound is provided having
formula:
##STR00005##
wherein
[0040] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0041] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0042] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0043] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0044] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0045] R.sup.4 is substituted with an imaging moiety selected from
the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.113I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I;
[0046] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0047] In some embodiments, a compound is provided having
formula:
##STR00006##
wherein
[0048] R.sup.9 and R.sup.10 are independently selected from the
group consisting of H, --OR.sup.11, F, Cl, Br, I, --CF.sub.3,
alkyl(C.sub.1-C.sub.4), and imaging moiety (I.sub.m);
[0049] R.sup.11, R.sup.12 and R.sup.13 are selected from the group
consisting of H, alkyl, and aryl; and
[0050] W and X are independently selected from the group consisting
of H, --OR.sub.4, --N(R.sup.11).sub.2, F, Cl, Br, --CF.sub.3,
I.sub.m, aryl, and heteroaryl; [0051] wherein A) Y and Z are
independently selected from the group consisting of --CH--,
--CH.sub.2--, --O--, --N--, --NR.sup.11--, and --CH.dbd.CH-- when a
linking group Q between Y and Z is present or absent, wherein Q is
selected from the group consisting of --CH--, --CH.sub.2--,
--CR.sup.11--, --N--, --NH--, --NR.sup.11--, --O--, and --S--;
or
[0052] B) Y and Z are independently selected from the group
consisting of H, --OR.sub.4, --N(R.sup.11).sub.2, F, Cl, Br,
--CF.sub.3, I.sub.m, aryl, and heteroaryl when linking group Q is
absent;
[0053] wherein I.sub.m is selected from the group consisting of
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I, and is present in
either W-Z or R.sup.9-R.sup.13, or a salt thereof.
[0054] In some embodiments, a compound is provided having
formula:
##STR00007##
[0055] wherein R.sup.9 is independently selected from the group
consisting of H, --CF.sub.3, and alkyl(C.sub.1-C.sub.4);
[0056] W, Y and Z are independently selected from the group
consisting of H, --OR.sup.11, --N(R.sup.11).sub.2, F, Cl, Br,
--CF.sub.3, I.sub.m, aryl and heteroaryl; and
[0057] R.sup.11 is selected from the group consisting of H, alkyl,
and aryl;
[0058] wherein I.sub.m is selected from the group consisting of
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I, and is present in
either W, Y, Z, R.sup.9, or R.sup.11; or a salt thereof.
[0059] In some embodiments, a compound is provided having
formula:
##STR00008##
[0060] wherein W and Y are independently selected from the group
consisting of H, --OR.sup.11, F, Cl, Br, --CF.sub.3, and I.sub.m;
and
[0061] R.sup.11 is alkyl,
[0062] wherein I.sub.m is selected from the group consisting of
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I, and is present in
either W, Y, or R.sup.11; or a salt thereof.
[0063] In some embodiments, a compound is provided having
formula:
##STR00009## ##STR00010## ##STR00011## ##STR00012##
##STR00013##
[0064] In one aspect, the present invention provides pharmaceutical
compositions comprising an inventive compound. The pharmaceutical
composition typically includes an amount of the inventive compound
sufficient to image a subject or a portion of the subject.
Pharmaceutical compositions of the present invention may optionally
include a pharmaceutically acceptable excipient. Any mode of
administration including oral and parenteral administration of an
inventive compound or pharmaceutical composition thereof may be
used.
[0065] In another aspect, the present invention provides methods of
imaging a subject comprising administering an inventive compound to
a subject; and acquiring an image of the subject or a portion of
the subject. Compounds of the invention or pharmaceutical
compositions thereof may be used to image an area of interest in a
subject, including, but not limited to, the heart, a portion of the
heart, the cardiovascular system, cardiac vessels, brain, and other
organs. In certain embodiments, methods of the invention include a
method of imaging cardiac innervation and a method of detecting
norepinephrine transporter. In certain embodiments, the area of the
subject being imaged is imaged by positron emission tomography
(PET). A kit comprising an inventive compound or composition and
instructions for use is also provided by the present invention.
[0066] In another aspect, the present invention provides methods
for synthesizing an imaging agent by reacting an imaging agent
precursor with an imaging moiety or source thereof to form an
imaging agent. For example, in certain embodiments, fluorination of
an imaging agent precursor comprising a leaving group (e.g.,
sulfonate leaving group) is performed with a fully deprotected form
of the precursor eliminating the need for a subsequent deprotection
step.
[0067] In another aspect, the present invention provides methods of
selecting an antiarrhythmic agent and/or determining the dose of an
antiarrhythmic agent for administration to a subject, the method
comprising:
[0068] administering to the subject a compound as described herein
or a salt thereof, or a compound of the formula:
R.sup.0--Ar-L-R.sup.1
wherein
[0069] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0070] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0071] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety; and
[0072] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
SO.sub.2R.sup.A1, NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0073] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0074] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof;
[0075] acquiring at least one image of a portion of the
subject;
[0076] selecting the antiarrhythmic agent and/or determining the
dose of an antiarrhythmic agent for administration to a subject
based on the image. In some embodiments, wherein the imaging agent
is:
##STR00014##
or a pharmaceutically acceptable salt thereof. In some embodiments,
the antiarrhythmic agent is an agent which is known to induce
electrophysiological changes in a subject's heart. In some
embodiments, the antiarrhythmic agent is an agent which does not
induce electrophysiological changes in a subject's heart. In some
embodiments, the electrophysiological changes comprise QT
prolongation. In some embodiments, an antiarrhythmic agent that
does not induce electrophysiological changes in a subject's heart
is selected based on the image indicating the presence of cardiac
denervation. In some embodiments, a reduced dose of an
antiarrhythmic agent that induces electrophysiological changes in a
subject's heart is prescribed based on the image indicating the
presence of cardiac denervation.
[0077] In another aspect, the present invention provides methods
comprising administering to the subject a compound described herein
or a salt thereof, or a compound of the formula:
R.sup.0--Ar-L-R.sup.1
wherein
[0078] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0079] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0080] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety; and
[0081] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A1)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0082] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring; and
[0083] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof;
[0084] acquiring at least one image of a portion of the subject;
and
[0085] identifying:
[0086] (i) a subject to be treated with an antiarrhythmic agent
that does not induce electrophysiological changes in the heart of
the subject based on presence of cardiac denervation in the
image,
[0087] (ii) a subject to be treated with a reduced dose of an
antiarrhythmic agent that induces electrophysiological changes in
the heart of the subject based on presence of cardiac denervation
in the image, and/or
[0088] (iii) a subject in need of a dose reduction of an
antiarrhythmic agent that induces electrophysiological changes in
the heart of the subject based on presence of cardiac denervation
in the image. In some embodiments, the antiarrhythmic agent that
induces electrophysiological changes in the heart of the subject is
a sodium channel blocker, a potassium channel blocker, or a calcium
channel blocker. In some embodiments, the antiarrhythmic agent that
induces electrophysiological changes in the heart of the subject is
a calcium channel blocker. In some embodiments, the antiarrhythmic
agent that induces electrophysiological changes in the heart of the
subject is quinidine, procainamide, disopyramide, lidocaine,
phenytoin, mexiletine, tocainade, amiodarone, sotalol, ibutilide,
dofetilide, dronedarone, E-4031, verapamil, or ditiazem. In some
embodiments, the antiarrhythmic agent that does not induce
electrophysiological changes in the heart of the subject is a
beta-blocker. In some embodiments, the antiarrhythmic agent that
does not induce electrophysiological changes in the heart of the
subject is propranolol, esmolol, timolol, metoprolol, atenolol, or
bisoprolol.
[0089] In some embodiments, a compound (e.g., an imaging agent
precursor) is provided having formula:
R.sup.0--Ar-L-R.sup.1
wherein
[0090] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0091] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0092] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --N(R.sup.A2).sub.3.sup.+,
--SR.sup.A1, --C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1,
--C(.dbd.O)SR.sup.A1, --C(.dbd.O)N(R.sup.A2).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --OSO.sub.2R.sup.A1, --Si(R.sup.A1).sub.3,
--Sn(R.sup.A1).sub.3, --B(OR.sup.A1).sub.2,
--NR.sup.A2SO.sub.2R.sup.A1, --NO.sub.2,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.22; and
R.sup.0 is substituted with a leaving group or is a leaving group;
and
[0093] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0094] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0095] In some embodiments, a method is provided comprising
reacting a compound of formula:
R.sup.0--Ar-L-R.sup.1
wherein
[0096] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0097] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0098] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; and
R.sup.0 is substituted with a leaving group or is a leaving
group;
[0099] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0100] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring;
[0101] or a salt, free base, or combination thereof;
[0102] with a fluorinating reagent under suitable conditions to
form a compound of formula:
R.sup.0--Ar-L-R.sup.1
[0103] wherein R.sup.0 is substituted with a fluorine.
[0104] In some embodiments, a method of determining perfusion and
innervation mismatch in a portion of a human subject is provided
comprising:
[0105] administering to the subject a first imaging agent and
acquiring at least one first image of a portion of the subject,
wherein the first imaging agent is employed to image perfusion;
[0106] administering to the subject a second imaging agent and
acquiring at least one second image of the portion of the subject,
wherein the second imaging agent is employed to image innervation;
and
[0107] determining regional mismatch of innervation and perfusion
areas in the portion of the subject based at least in part on the
at least one first image and the at least one second image, wherein
the first imaging agent has the structure:
##STR00015##
wherein
[0108] J is selected from the group consisting of N(R.sup.28), S,
O, C(.dbd.O), C(.dbd.O)O, NHCH.sub.2CH.sub.2O, a bond, and
C(.dbd.O)N(R.sup.27);
[0109] when present, K is selected from the group consisting of
hydrogen, alkoxyalkyl optionally substituted with an imaging
moiety, alkyloxy optionally substituted with an imaging moiety,
aryl optionally substituted with an imaging moiety, C.sub.1-C.sub.6
alkyl optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety;
[0110] when present, L is selected from the group consisting of
hydrogen, alkoxyalkyl optionally substituted with an imaging
moiety, alkyloxy optionally substituted with an imaging moiety,
aryl optionally substituted with an imaging moiety, C.sub.1-C.sub.6
alkyl optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety;
[0111] M is selected from the group consisting of hydrogen,
alkoxyalkyl optionally substituted with an imaging moiety, alkyloxy
optionally substituted with an imaging moiety, aryl optionally
substituted with an imaging moiety, C.sub.1-C.sub.6 alkyl
optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety; or
[0112] L and M, together with the atom to which they are attached,
may form a three- or four-membered carbocyclic ring;
[0113] Q is halo or haloalkyl;
[0114] n is 0, 1, 2, or 3;
[0115] R.sup.21, R.sup.22, R.sup.27, and R.sup.28 are independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with an imaging moiety, and an imaging moiety;
[0116] R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
selected from hydrogen, halogen, hydroxyl, alkyloxy,
C.sub.1-C.sub.6 alkyl optionally substituted with an imaging
moiety, and an imaging moiety; R.sup.29 is C.sub.1-C.sub.6 alkyl
optionally substituted with an imaging moiety; and Y
[0117] is selected from the group consisting of a bond, carbon, and
oxygen; provided that when Y is a bond, K and L are absent, and M
is selected from the group consisting of aryl optionally
substituted with an imaging moiety and heteroaryl optionally
substituted with an imaging moiety; and provided that when Y is
oxygen, K and L are absent, and M is selected from hydrogen,
alkoxyalkyl optionally substituted with an imaging moiety, aryl
optionally substituted with an imaging moiety, C.sub.1-C.sub.6
alkyl optionally substituted with an imaging moiety, and heteroaryl
optionally substituted with an imaging moiety; or a salt thereof,
provided that at least one imaging moiety is present.
[0118] In some embodiments, a method of assessing perfusion and
innervation mismatch in a portion of a human subject is provided
comprising:
[0119] administering to a subject a first imaging agent and
acquiring at least one first image of a portion of a subject,
wherein the first imaging agent employed to image perfusion;
[0120] administering to a subject a second imaging agent and
acquiring at least one second image of the portion of the subject,
wherein the second imaging agent is employed to image innervation;
and
[0121] determining regional mismatch of innervation and perfusion
areas in the portion of the subject based at least in part on the
at least one first image and the at least one second image, wherein
the second imaging agent has the structure:
R.sup.0--Ar-L-R.sup.1
wherein
[0122] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0123] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0124] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety; and R.sup.0 is halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2,
--SR.sup.A1, --C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1,
--C(.dbd.O)SR.sup.A1, --C(.dbd.O)N(R.sup.A2).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0125] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring; and
[0126] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0127] FIG. 1 depicts non-limiting examples of imaging agents.
[0128] FIGS. 2 through 8 show images derived using non-limiting
examples of imaging agents.
[0129] FIG. 9 shows a plot of percent cell uptakes for non-limiting
examples of imaging agents.
[0130] FIG. 10 shows dose-response curves of a non-limiting imaging
agent in non-limiting cell lines.
[0131] FIGS. 11 and 12 shows representative cardiac images and
polar maps of a non-limiting imaging agent and a myocardial
perfusion imaging agent.
[0132] FIG. 13A-FIG. 13C show representative time-activity curves
derived from a non-limiting imaging agent and a myocardial
perfusion imaging agent.
[0133] FIG. 14 shows image quantification to assess non-defect left
ventricular areas in rabbits at varying time points according to
some embodiments.
[0134] FIG. 15A shows examples of ECG tracings in rabbits before
and during dofetilide infusion.
[0135] FIG. 15B and FIG. 15C show changes in heart rate (HR) and
QT.sub.cf interval in rabbits, according to some embodiments.
[0136] FIG. 16A-FIG. 16C show images obtained using either Imaging
Agent-1 or Imaging Agent-2, for a control rabbit, a rabbit having
global denervation, and a rabbit having regional denervation.
[0137] FIG. 17 shows images obtained using either Imaging Agent-1
or Imaging Agent-2, and corresponding polar maps for a control
rabbit.
[0138] FIG. 18A-FIG. 18C show images obtained using either Imaging
Agent-1 or Imaging Agent-2, and corresponding polar maps for a
rabbit having regional denervation at 4 weeks, 13 weeks, and 46
weeks post-surgery.
[0139] FIG. 18D shows a plot of the % LV defect versus time for the
images shown in FIG. 18A-FIG. 18C.
[0140] Other aspects, embodiments, and features of the invention
will become apparent from the following detailed description when
considered in conjunction with the accompanying drawings. The
accompanying figures are schematic and are not intended to be drawn
to scale. For purposes of clarity, not every component is labeled
in every figure, nor is every component of each embodiment of the
invention shown where illustration is not necessary to allow those
of ordinary skill in the art to understand the invention. All
patent applications and patents incorporated herein by reference
are incorporated by reference in their entirety. In case of
conflict, the present specification, including definitions,
controls.
DETAILED DESCRIPTION OF THE INVENTION
[0141] The present invention provides compounds, compositions
thereof, systems comprising such compounds, reagents, cassettes,
methods, kits, and apparatuses for the synthesis and/or use of
imaging agents and precursors thereof. In some aspects, the
invention generally relates to an imaging agent of Formula
(Ia)-(Id), (IIa)-(IIb), (III), (IV), (Va)-(Vd), (VI), or (VII). The
imaging agents of the invention may be used to image an area of
interest in a subject, including, but not limited to, the heart, a
portion of the heart, the cardiovascular system, cardiac vessels,
brain, and other organs. In certain embodiments, the area of the
subject being imaged is imaged by positron emission tomography
(PET). The present invention also provides methods for synthesizing
an imaging agent by reacting an imaging agent precursor with an
imaging moiety or source thereof to form an imaging agent.
[0142] In some embodiments, methods and compositions for assessing
perfusion and innervation mismatch in a portion in a subject, for
example, a human subject, are provided. In some embodiments, the
methods and compositions may be employed for assessing perfusion
and innervation mismatch in a subject following a tissue insult. In
some embodiments, the tissue insult is a cardiac insult, for
example, a myocardial infarction. In some embodiments, the portion
of the subject is the heart or a portion of the heart.
A. Imaging Agents
[0143] In one aspect, the invention provides compounds useful as
imaging agents for imaging a subject or an area of interest of a
subject. In certain embodiments, the imaging agent is labeled with
.sup.18F and is useful in PET imaging.
[0144] In some embodiments, a compound is provided comprising
Formula (Ia):
R.sup.0--Ar-L-R.sup.1 (Ia)
wherein
[0145] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0146] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0147] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety; and
[0148] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0149] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring; and
[0150] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
[0151] In certain embodiments, the compound of Formula (Ia) is not
of the formula:
##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020##
[0152] In some embodiments, a compound is provided comprising
Formula (M):
R.sup.0--Ar-L-R.sup.1 (Ib)
wherein
[0153] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0154] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0155] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0156] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0157] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0158] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br, and
.sup.124I, or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator, or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, and .sup.124I; or
a salt thereof;
[0159] provided that when Ar is phenyl, when L is --CH.sub.2--,
when R.sup.1 is
##STR00021##
and when R.sup.0 is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, and .sup.124I, then Ar is
substituted with substituents other than --R.sup.0 and
-L-R.sup.1.
[0160] In some embodiments, a compound of Formula (Ib) is not of
the formula:
##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026##
[0161] In some embodiments, a compound is provided comprising
Formula (Ic):
R.sup.0--Ar-L-R.sup.1 (Ic)
wherein
[0162] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0163] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0164] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0165] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0166] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0167] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br, and
.sup.124I, or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator, or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, and .sup.124I; or
a salt thereof;
[0168] provided that when Ar is phenyl, then R.sup.0 is not
.sup.18F; and
[0169] further provided that when Ar is phenyl, when L is
--CH.sub.2--, when R.sup.1 is
##STR00027##
and when R.sup.0 is an imaging moiety selected from the group
consisting of .sup.76Br and .sup.124I, then Ar is substituted with
substituents other than --R.sup.0 and -L-R.sup.1.
[0170] In some embodiments, a compound of Formula (Ic) is not of
the formula:
##STR00028## ##STR00029## ##STR00030## ##STR00031##
[0171] In some embodiments, a compound is provided comprising
Formula (Id):
R.sup.0--Ar-L-R.sup.1 (Id)
wherein
[0172] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0173] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0174] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0175] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0176] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0177] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br, and
.sup.124I, or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator, or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, and .sup.124I; or
a salt thereof;
[0178] provided that when Ar is phenyl, then R.sup.0 is not
.sup.18F;
[0179] further provided that when Ar is phenyl, when L is
--CH.sub.2--, when R.sup.1 is
##STR00032##
and when R.sup.0 is an imaging moiety selected from the group
consisting of .sup.76Br and .sup.124I, then Ar is substituted with
substituents other than --R.sup.0 and -L-R.sup.1; and further
provided that when Ar is phenyl, then Ar is not substituted with
--OH.
[0180] In some embodiments, a compound of Formula (Id) is not of
the formula:
##STR00033## ##STR00034## ##STR00035## ##STR00036##
[0181] In certain embodiments, a compound of Formula (Ia), (Ib),
(Ic), or (Id) is any suitable salt, as described herein. In certain
embodiments, a compound of Formula (Ia), (Ib), (Ic), or (Id) is a
pharmaceutically acceptable salt. Non-limiting examples of salts
include mesylate (i.e., methanesulfonate), phosphate, sulfate,
acetate, formate, benzoate, chloride, iodide, bromide, ascorbate,
trifluoroacetate, or tosylate salt of a compound of Formula (Ia),
(Ib), (Ic), or (Id).
[0182] As described above, in some embodiments for a compound of
Formula (Ia), R.sup.0 or R.sup.1 is substituted with an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124 and .sup.131I. In certain embodiments, the imaging moiety
is .sup.18F. In certain embodiments, the imaging moiety is
.sup.76Br. In certain embodiments, the imaging moiety is .sup.124I.
In certain embodiments, the imaging moiety is .sup.131I. In some
cases, the imaging moiety is not .sup.131I. In some cases, the
imaging moiety is .sup.18F, .sup.76Br, or .sup.124I. In some cases,
the imaging moiety is .sup.18F or .sup.76Br. In some embodiments,
the imaging moiety is not directly bound to Ar. In certain
embodiments, R.sup.0 is substituted with an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is an imaging moiety selected
from the group consisting of and .sup.18F, .sup.76Br, .sup.124I,
and .sup.131I. In certain embodiments, R.sup.0 is substituted with
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124, and .sup.131I. In certain embodiments, R.sup.0
is associated with an imaging moiety selected from the group
consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and .sup.111In
through a chelator. In certain embodiments, R.sup.0 is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I. In some embodiments, R.sup.1 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or is
associated with an imaging moiety selected from the group
consisting of .sup.46Cu, .sup.89Zr, .sup.99mTc, and .sup.111In
through a chelator; or is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I. In
some cases, R.sup.1 is substituted with an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I. In some cases, R.sup.1 is substituted with .sup.18F.
[0183] As described above, in some embodiments for a compound of
Formula (Ib), (Ic), or (Id), R.sup.0 or R.sup.1 is substituted with
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, and .sup.124I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
and .sup.124I. In certain embodiments, the imaging moiety is
.sup.18F. In certain embodiments, the imaging moiety is .sup.76Br.
In certain embodiments, the imaging moiety is .sup.124I. In certain
embodiments, the imaging moiety is .sup.131I. In certain
embodiments, the imaging moiety is not .sup.131I. In some cases,
the imaging moiety is not .sup.131I. In some cases, the imaging
moiety is .sup.18F, .sup.76Br, or .sup.124I. In some cases, the
imaging moiety is .sup.18F or .sup.76Br. In some embodiments, the
imaging moiety is not directly bound to Ar. In certain embodiments,
R.sup.0 is substituted with an imaging moiety selected from the
group consisting of .sup.18F, .sup.76Br, and .sup.124I; or is
associated with an imaging moiety selected from the group
consisting of .sup.64Cu, .sup.99mTc, and .sup.111In through a
chelator; or is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, and .sup.124I. In certain
embodiments, R.sup.0 is substituted with an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, and .sup.124I. In
certain embodiments, R.sup.0 is associated with an imaging moiety
selected from the group consisting of .sup.46Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator. In certain
embodiments, R.sup.0 is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, and .sup.124I. In certain
embodiments, the imaging moiety is .sup.18F. In some embodiments,
R.sup.1 is substituted with an imaging moiety selected from the
group consisting of .sup.18F, .sup.76Br, and .sup.124I; or is
associated with an imaging moiety selected from the group
consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and .sup.111In
through a chelator; or is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, and .sup.124I. In some cases,
R.sup.1 is substituted with an imaging moiety selected from the
group consisting of .sup.18F, .sup.76Br, and .sup.124I. In some
cases, R.sup.1 is substituted with .sup.18F.
[0184] As described above, in some embodiments for a compound of
Formula (Ia), (Ib), (Ic), or (Id), Ar may be substituted or
unsubstituted, monocyclic or bicyclic aryl; or substituted or
unsubstituted, monocyclic or bicyclic heteroaryl. As described
above, in some embodiments, the imaging moiety is not directly
bound to Ar. In certain embodiments, when .sup.18F is the imaging
moiety, then .sup.18F is not bound directly to Ar. In certain
embodiments, when .sup.18F is the imaging moiety and Ar is phenyl
then .sup.18F is not bound directly to Ar. In other embodiments,
when .sup.76Br is the imaging moiety, then .sup.76Br is not bound
directly to Ar. In other embodiments, when .sup.76Br is the imaging
moiety and Ar is phenyl then .sup.76Br is not bound directly to Ar.
In other embodiments, when .sup.124I is the imaging moiety then
.sup.124I is not bound directly to Ar. In other embodiments, when
.sup.124I is the imaging moiety and Ar is phenyl then .sup.124I is
not bound directly to Ar. In other embodiments, when .sup.131I is
the imaging moiety, then .sup.131I is not bound directly to Ar. In
other embodiments, when .sup.131I is the imaging moiety and Ar is
phenyl then .sup.131I is not bound directly to Ar. However, in
other embodiments, the imaging moiety is directly bound to Ar. In
some embodiments, when Ar is phenyl then the imaging moiety is not
present in R.sup.0. In some embodiments, when Ar is phenyl then the
imaging moiety is not present in R.sup.0 when R.sup.0 is OR.sup.A1
and R.sup.A1 is alkyl. In some embodiments, when Ar is phenyl then
the imaging moiety is not present in R.sup.0, when R.sup.0 is
alkyl.
[0185] In certain embodiments, for a compound of Formula (Ia),
(Ib), (Ic), or (Id), Ar is selected from the group consisting of
substituted or unsubstituted phenyl, substituted or unsubstituted
naphthyl, substituted or unsubstituted biphenyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted monocyclic
heteroaryl, substituted or unsubstituted bicyclic heteroaryl,
substituted or unsubstituted benzoxazolyl, substituted or
unsubstituted benzimidazoly, substituted or unsubstituted
benzthiazolyl, substituted or unsubstituted indolyl, substituted or
unsubstituted quinolinyl, substituted or unsubstituted
isoquinolinyl, substituted or unsubstituted chromanyl, substituted
or unsubstituted chromenyl, substituted or unsubstituted
benzofuranyl, or substituted or unsubstituted benzpyrazolyl. In
certain embodiments, Ar is substituted or unsubstituted aryl. In
some embodiments, Ar is substituted or unsubstituted phenyl. In
other embodiments, Ar is not phenyl. In some embodiments, Ar is
substituted or unsubstituted naphthyl. In some embodiments, Ar is
substituted or unsubstituted biphenyl. In some embodiments, Ar is
substituted or unsubstituted heteroaryl. In some embodiments, Ar is
substituted or unsubstituted monocyclic heteroaryl. In some
embodiments, Ar is substituted or unsubstituted bicyclic
heteroaryl. In certain embodiments, Ar is substituted or
unsubstituted, 10-membered heteroaryl. In certain, embodiments, Ar
is substituted or unsubstituted, 9-membered heteroaryl. In certain
embodiments, Ar is substituted or unsubstituted 8-membered
heteroaryl. In some embodiments, Ar is substituted or unsubstituted
benzoxazolyl. In some embodiments, Ar is substituted or
unsubstituted benzimidazolyl. In some embodiments, Ar is
substituted or unsubstituted benzthiazolyl. In some embodiments, Ar
is substituted or unsubstituted indolyl. In some embodiments, Ar is
substituted or unsubstituted quinolinyl. In some embodiments, Ar is
substituted or unsubstituted isoquinolinyl. In some embodiments, Ar
is substituted or unsubstituted chromanyl. In some embodiments, Ar
is substituted or unsubstituted chromenyl. In some embodiments, Ar
is substituted or unsubstituted benzofuranyl. In some embodiments,
Ar is substituted or unsubstituted benzpyrazolyl. In some
embodiments, Ar is substituted or unsubstituted indazolyl. In some
embodiments, Ar is substituted or unsubstituted benztriazolyl.
[0186] As described above, in some embodiments for a compound of
Formula (Ia), (Ib), (Ic), or (Id), L may be a bond; substituted or
unsubstituted, cyclic or acyclic alkylene; substituted or
unsubstituted, cyclic or acyclic alkenylene; substituted or
unsubstituted, cyclic or acyclic alkynylene; or substituted or
unsubstituted, cyclic or acyclic heteroaliphatic. L may be of any
suitable length. In some cases, L ranges from 0 to 6 atoms in
length, from 0 to 3 atoms in length, or from 0 to 2 atoms in
length. In certain embodiments, L is 0, 1, 2, 3, 4, 5, or 6 atoms
in length. The length of L may be determined by determining the
number of atoms in the shortest distance from Ar to R.sup.1,
wherein R.sup.1 begins at the first atom of R.sup.1 or N. In some
cases, when determining the length of L, the substituents are not
considered.
[0187] In some embodiments, L is selected from the group consisting
of a bond; substituted or unsubstituted, cyclic or acyclic
C.sub.1-6 alkylene; unsubstituted, acyclic C.sub.1-6alkylene;
acyclic C.sub.1-6 alkylene; substituted or unsubstituted, cyclic or
acyclic C.sub.1-6alkenylene; or substituted or unsubstituted, and
cyclic or acyclic heteroaliphatic.
[0188] In some embodiments, L is selected from the group consisting
of --CR'.sub.2--, --CR'.sub.2CR'.sub.2--,
--CR'.sub.2CR'.sub.2CR'.sub.2--, --CR'.dbd.CR'--,
--CR'.dbd.CR'CR'.sub.2--, --CR'.sub.2CR'.dbd.CR'--, --OC
R'.sub.2--, --CR'.sub.2O--, --OCR'.sub.2CR'.sub.2--,
--CR'.sub.2CR'.sub.2O--, --NR'CR'.sub.2--, --CR'.sub.2N R'--, --N
R'CR'.sub.2C R'.sub.2--, --CR'.sub.2C R'.sub.2NR'--, --CR'.dbd.N--,
--N.dbd.CR'--,
##STR00037##
wherein R' is independently hydrogen, halogen, --OH, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkoxy, or substituted or
unsubstituted alkoxyalkyl.
[0189] In some embodiments, L is a bond. In some embodiments, L is
selected from the group consisting of --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--CH.dbd.CHCH.sub.2--, --CH.sub.2CH.dbd.CH--, --OCH.sub.2--,
--CH.sub.2O--, --OCH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2O--,
--NHCH.sub.2--, --CH.sub.2NH--, --NHCH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2NH--, --CH.dbd.N--, --N.dbd.CH--,
##STR00038##
each optionally substituted.
[0190] In some embodiments, L is substituted or unsubstituted,
cyclic or acyclic alkylene. In some embodiments, L is substituted
or unsubstituted, cyclic or acyclic C.sub.1-6 alkylene. In some
embodiments, L is unsubstituted, acyclic C.sub.1-6 alkylene. In
some embodiments, L is substituted, acyclic C.sub.1-6 alkylene. In
some embodiments, L is --CH.sub.2--. In some embodiments, L is
--CH.sub.2CH.sub.2--. In some embodiments, L is
--CH.sub.2CH.sub.2CH.sub.2--. In some embodiments, L is
--CH.dbd.CH--. In some embodiments, L is substituted or
unsubstituted, cyclic or acyclic C.sub.1-6 alkenylene. In some
embodiments, L is substituted or unsubstituted, cyclic or acyclic
heteroaliphatic. In some embodiments, L is --OCH.sub.2--or
--CH.sub.2O--. In some embodiments, L is OCH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2O--. In some embodiments, L is --NHCH.sub.2-- or
--CH.sub.2NH--. In some embodiments, L is NHCH.sub.2CH.sub.2-- or
--CH.sub.2CH.sub.2NH--. In some embodiments, L is --CH.dbd.N-- or
--N.dbd.CH--. In some embodiments, L is
--CH.sub.2CH.sub.2CH.sub.2--. In some embodiments, L is:
##STR00039##
[0191] In some embodiments, L is:
##STR00040##
[0192] In some embodiments, L is:
##STR00041##
[0193] In some embodiments, L is:
##STR00042##
[0194] In some embodiments, L is:
##STR00043##
[0195] In some embodiments, L is:
##STR00044##
[0196] In some embodiments, L is:
##STR00045##
[0197] In some embodiments, L is:
##STR00046##
[0198] In some embodiments, L is:
##STR00047##
[0199] In some embodiments, L is:
##STR00048##
[0200] Each of the L groups described herein may be combined with
any suitable Ar, R.sup.1, and/or R.sup.0 group, or combinations
described herein.
[0201] As described above, in some embodiments for a compound of
Formula (Ia), (Ib), (Ic), or (Id), R.sup.1 is a substituted or
unsubstituted nitrogen-containing moiety. In some embodiments,
R.sup.1 is --N(R.sup.A).sub.2, heteroaryl, heterocyclic,
--C(.dbd.NH)NH.sub.2, --NHC(.dbd.NH)NH.sub.2,
--NR.sup.AC(.dbd.NR.sup.A)N(R.sup.A).sub.2,
--NHC(.dbd.NH)NHR.sup.A, or --NHC(.dbd.NH)N(R.sup.A).sub.2, wherein
each occurrence of R.sup.A is independently hydrogen, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted unsubstituted heterocyclyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl, or
two R.sup.A groups may be joined to form an optionally substituted
heterocyclic ring. In some embodiments, R.sup.1 is a non-aromatic,
cyclic, substituted or unsubstituted nitrogen-containing moiety. In
some embodiments, R.sup.1 is selected from the group consisting of
--NHC(.dbd.NH)NH.sub.2, --NH.sub.2, --NHR.sup.A (wherein R.sup.A is
as defined herein), --NHCH.sub.3, --NHCH.sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2CH.sub.3,
##STR00049##
each optionally substituted, wherein each occurrence of R.sup.B is
independently hydrogen, substituted or unsubstituted alkyl, or a
nitrogen-protecting group. In some cases, at least two R.sup.B are
hydrogen.
[0202] In some embodiments, R.sup.1 is --NHC(.dbd.NH)NH.sub.2. In
some embodiments, R.sup.1 is:
##STR00050##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
R.sup.1 is:
##STR00051##
wherein R.sup.B is hydrogen, substituted or unsubstituted alkyl, or
a nitrogen-protecting group.
[0203] However, in other embodiments, R.sup.1 is not
--NHC(.dbd.NH)NH.sub.2. In some embodiments, R.sup.1 is not:
##STR00052##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
R.sup.1 is not:
##STR00053##
wherein R.sup.B is hydrogen, substituted or unsubstituted alkyl, or
a nitrogen-protecting group. In certain embodiments, when L is
--CH.sub.2--, then R.sup.1 is not --NHC(.dbd.NH)NH.sub.2. In
certain embodiment, when L is --CH.sub.2--, and Ar is phenyl, then
R.sup.1 is not --NHC(.dbd.NH)NH.sub.2.
[0204] In some embodiments, R.sup.1 is --NH.sub.2. In some
embodiments, R.sup.1 is --NHR.sup.A. In some embodiments, R.sup.1
is --NHCH.sub.3, --NHCH.sub.2CH.sub.3, or
--NHCH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.1 is:
##STR00054##
[0205] In some embodiments, R.sup.1 is:
##STR00055##
[0206] In some embodiments, R.sup.1 is:
##STR00056##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
R.sup.1 is:
##STR00057##
wherein R.sup.B is hydrogen, substituted or unsubstituted alkyl, or
a nitrogen-protecting group. In some embodiments, R.sup.1 is:
##STR00058##
[0207] In some embodiments, R.sup.1 is:
##STR00059##
[0208] In some embodiments, R.sup.1 is:
##STR00060##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
R.sup.1 is:
##STR00061##
wherein R.sup.B is hydrogen, substituted or unsubstituted alkyl, or
a nitrogen-protecting group. In some embodiments, R.sup.1 is:
##STR00062##
[0209] In some embodiments, R.sup.1 is:
##STR00063##
[0210] In some embodiments, R.sup.1 is:
##STR00064##
[0211] In some embodiments, R.sup.1 is:
##STR00065##
[0212] In some embodiments, R.sup.1 is:
##STR00066##
[0213] In some embodiments, R.sup.1 is:
##STR00067##
[0214] In some embodiments, R.sup.1 is:
##STR00068##
[0215] In some embodiments, R.sup.1 is:
##STR00069##
[0216] In some embodiments, R.sup.1 is:
##STR00070##
[0217] In some embodiments, R.sup.1 is:
##STR00071##
[0218] In some embodiments, R.sup.1 is:
##STR00072##
[0219] In some embodiments, R.sup.1 is:
##STR00073##
[0220] In some embodiments, R.sup.1 is:
##STR00074##
[0221] In some embodiments, R.sup.1 is:
##STR00075##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
R.sup.1 is:
##STR00076##
wherein R.sup.B is hydrogen, substituted or unsubstituted alkyl, or
a nitrogen-protecting, group. In some embodiments, R.sup.1 is:
##STR00077##
[0222] In some embodiments, R.sup.1 is:
##STR00078##
[0223] In some embodiments, R.sup.1 is:
##STR00079##
[0224] In some embodiments, R.sup.1 is:
##STR00080##
[0225] In some embodiments, R.sup.1 is:
##STR00081##
[0226] In some embodiments, R.sup.1 is:
##STR00082##
[0227] In some embodiments, R.sup.1 is:
##STR00083##
[0228] In some embodiments, R.sup.1 is:
##STR00084##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
R.sup.1 is:
##STR00085##
wherein R.sup.B is hydrogen, substituted or unsubstituted alkyl, or
a nitrogen-protecting group.
[0229] In some embodiments, R.sup.1 is:
##STR00086##
[0230] In some embodiments, R.sup.1 is:
##STR00087##
[0231] In some embodiments, R.sup.1 is:
##STR00088##
[0232] In some embodiments, R.sup.1 is:
##STR00089##
[0233] In some embodiments, R.sup.1 is:
##STR00090##
[0234] In some embodiments, R.sup.1 is:
##STR00091##
[0235] In some embodiments, R.sup.1 is:
##STR00092##
[0236] Each of the R.sup.1 groups described herein may be combined
with any suitable Ar, R.sup.0, and/or L groups and combinations
described herein, for example, as described in connection with a
compound of Formula (Ia), (Ib), (Ic), or (Id). For example, in
certain embodiments, when L is a bond; R.sup.1 is:
##STR00093##
[0237] As another example, in certain embodiments, when L is a
bond; Ar is phenyl; and R.sup.1 is:
##STR00094##
then Ar is substituted with at least one other group besides
R.sup.0 and L-R.sup.1. As another example, in certain embodiments,
when L is a bond; Ar is not phenyl; and R.sup.1 is:
##STR00095##
then Ar is substituted with at least one other group besides
R.sup.0 and L-R.sup.1.
[0238] As yet another example, in certain embodiments, when L is
--CH.sub.2--; then R.sup.1 is --NHC(.dbd.NH)NH.sub.2. In some
embodiments, Ar is phenyl; L is --CH.sub.2--; and R.sup.1 is
--NHC(.dbd.NH)NH.sub.2. In some embodiments, Ar is not phenyl; L is
--CH.sub.2--; and R.sup.1 is --NHC(.dbd.NH)NH.sub.2.
[0239] In some embodiments, for a compound of Formula (Ia), (Ib),
(Ic), or (Id), when Ar is phenyl, Ar is not substituted with a
hydroxyl group. In some embodiments, when Ar is phenyl, Ar is not
substituted with a hydroxyl group or a halogen. In some
embodiments, when Ar is phenyl, and R.sup.0 is alkyl substituted
with an imaging moiety, then Ar is not substituted with a hydroxyl
group. In some embodiments, when Ar is phenyl, and R.sup.0 is
alkoxy substituted with an imaging moiety, then Ar is not
substituted with a hydroxyl group. In some embodiments, when Ar is
phenyl, and the imaging moiety is attached directly to the phenyl
ring, then the phenyl ring is not substituted with a hydroxyl group
or unsubstituted except with R.sup.0 and -L-R.sup.1.
[0240] In some embodiments, when Ar is phenyl, L is --CH.sub.2--,
R.sup.1 is:
##STR00096##
and R.sup.0 is alkoxy substituted with an imaging moiety, then Ar
is not substituted with a halogen. In some embodiments, when Ar is
phenyl, R.sup.0 is alkoxymethyl substituted with an imaging moiety,
and R.sup.1 is:
##STR00097##
then L is --CH.sub.2--. In some embodiments, when Ar is phenyl, L
is --CH.sub.2--, R.sup.1 is:
##STR00098##
and R.sup.0 is alkoxy substituted with an imaging moiety or alkyl
substituted with an imaging moiety, then Ar is not substituted with
a halogen or unsubstituted except with R.sup.0 and -L-R.sup.1. In
some embodiments, when Ar is phenyl, R.sup.1 is:
##STR00099##
and R.sup.0 is alkoxy substituted with an imaging moiety, then L is
not:
##STR00100##
[0241] In some embodiments, when Ar is phenyl, and L is a bond,
then R.sup.1 is not:
##STR00101##
[0242] In some embodiments, when Ar is phenyl, L is a bond, and
R.sup.1 is:
##STR00102##
then R.sup.0 is not an imaging moiety directly attached to the
phenyl ring, alkyl substituted with an imaging moiety, alkoxyalkyl
substituted with an imaging moiety, or alkoxy substituted with an
imaging moiety.
[0243] In some embodiments, one, two, three, four, or five of the
following a)-e) apply to a compound of Formula (Ia), (Ib), (Ic), or
(Id), where suitable: [0244] a) Ar is a substituted or
unsubstituted group selected from the group consisting of phenyl,
naphthyl, biphenyl, monocyclic heteroaryl, and bicyclic heteroaryl;
[0245] b) Ar is not phenyl; [0246] c) L is selected from the group
consisting of a bond; substituted or unsubstituted, cyclic or
acyclic C.sub.1-6 alkylene; unsubstituted, acyclic C.sub.1-6
alkylene; acyclic C.sub.1-6alkylene; substituted or unsubstituted,
cyclic or acyclic C.sub.1-6 alkenylene; and substituted or
unsubstituted, cyclic or acyclic heteroaliphatic; [0247] d) R.sup.1
is selected from the group consisting of --N(R.sup.A).sub.2,
heteroaryl, heterocyclic, --C(.dbd.NH)NH.sub.2,
--NHC(.dbd.NH)NH.sub.2, --NR.sup.AC(.dbd.NR.sup.A)N(R.sup.A).sub.2;
--NHC(.dbd.NH)NHR.sup.A, and --NHC(.dbd.NH)N(R.sup.A).sub.2,
wherein R.sup.A is as described herein; [0248] e) R.sup.0 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or is
associated with an imaging moiety selected from the group
consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and .sup.111In
through a chelator; or is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I.
[0249] In some embodiments, one, two, three, four, five, six, or
seven of the following a)-g) apply to a compound of Formula (Ia),
(Ib), (Ic), or (Id), where suitable: [0250] a) Ar is a substituted
or unsubstituted group selected from the group consisting of
phenyl, naphthyl, biphenyl, benzothiazolyl, indolyl, quinolinyl,
isoquinolinyl, chromanyl, chromenyl, benzofuranyl, and
benzpyrazolyl; [0251] b) Ar is not phenyl; [0252] c) L is selected
from the group consisting of a bond; --CH.sub.2--,
--CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--,
--OCH.sub.2--, --CH.sub.2O--, --OCH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2O--, --NHCH.sub.2--, --CH.sub.2NH--,
--NHCH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2NH--, --CH.dbd.N--,
--N.dbd.CH--, --CH.sub.2CH.sub.2CH.sub.2--,
[0252] ##STR00103## [0253] d) R.sup.1 is selected from the group
consisting of --NHC(.dbd.NH)NH.sub.2, --NH.sub.2, --NHR.sup.A,
--NHCH.sub.3, --NHCH.sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2CH.sub.3,
##STR00104## ##STR00105##
[0253] each optionally substituted, wherein each occurrence of
R.sup.B is independently hydrogen, substituted or unsubstituted
alkyl, or a nitrogen-protecting group, provided at least two
R.sup.B are hydrogen; [0254] e) R.sup.1 is not
--NHC(.dbd.NH)NH.sub.2; [0255] f) R.sup.1 is substituted with an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or is an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I and .sup.131I; [0256] g) R.sup.0 is substituted with an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or is an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I and .sup.131I.
[0257] In certain embodiments, a compound of Formula (Ia) comprises
Formula (IIa):
##STR00106##
wherein
[0258] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0259] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0260] each of R.sup.2-R.sup.6 is independently hydrogen, halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or any two
adjacent R.sup.2-R.sup.6 are joined to form an optionally
substituted or unsubstituted carbocyclic, heterocyclic, aryl, or
heteroaryl ring;
[0261] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0262] one or more of R.sup.1-R.sup.6 is substituted with an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or is associated with an
imaging moiety selected from the group consisting of .sup.64Cu,
.sup.89Zr, .sup.99mTc, and .sup.111In through a chelator; or is an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or a salt thereof.
[0263] As described above for a compound of Formula (IIa), one or
more of R.sup.1-R.sup.6 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I. In some embodiments, one of
R.sup.1-R.sup.6 is substituted with an imaging moiety selected from
the group consisting of .sup.18F, .sup.76Br, .sup.124I, an
.sup.131I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I. In certain embodiments, the imaging moiety is .sup.18F.
In certain embodiments, the imaging moiety is .sup.76Br. In certain
embodiments, the imaging moiety is .sup.124I. In certain
embodiments, the imaging moiety is .sup.131I. In some cases, the
imaging moiety is not .sup.131I. In some cases, the imaging moiety
is .sup.18F, .sup.76Br, or .sup.124I. In some cases, the imaging
moiety is .sup.18F or .sup.76Br.
[0264] In some cases, R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator;
[0265] or is an imaging moiety selected from the group consisting
of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I. In some
embodiments, R.sup.4 is substituted with an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I. In some embodiments, R.sup.4 is substituted with an
imaging moiety selected from the group consisting of .sup.18F.
[0266] In some embodiments, R.sup.4 is selected from the group
consisting of hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2.
[0267] In some embodiments, for a compound of Formula (IIa),
R.sup.4 is selected from the group consisting of C.sub.1-6 alkyl,
alkoxy, and alkoxyalkyl, each optionally substituted with an
imaging moiety, or any combination of R.sup.4 groups in this list.
In some cases, R.sup.4 is alkoxymethyl, optionally substituted with
the imaging moiety. In some cases, R.sup.4 is selected from the
group consisting of --CH.sub.2F, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2F,
--OCH.sub.2F, --OCH.sub.2CH.sub.2F, --OCH.sub.2CH.sub.2CH.sub.2F,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2OCH.sub.2F,
--CH.sub.2OCH.sub.2CH.sub.2F, --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2F,
and --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some cases,
the F is isotopically enriched with .sup.18F.
[0268] In some embodiments, R.sup.4 is C.sub.1-6 alkyl. In some
embodiments, R.sup.4 is alkyl substituted with an imaging moiety.
In some embodiments, R.sup.4 is --CH.sub.2F, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2CH.sub.2F, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some cases, the F is
isotopically enriched with .sup.18F. In some embodiments, R.sup.4
is alkoxy substituted with an imaging moiety. In some embodiments,
R.sup.4 is --OCH.sub.2F, --OCH.sub.2CH.sub.2F,
--OCH.sub.2CH.sub.2CH.sub.2F, or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some cases, the F is
isotopically enriched with .sup.18F. In some embodiments, R.sup.4
is alkoxyalkyl substituted with an imaging moiety. In some
embodiments, R.sup.4 is of the formula:
##STR00107##
wherein n is an integer between 0 and 6, inclusive; and m is an
integer between 0 and 6, inclusive. In some embodiments, R.sup.4 is
alkoxymethyl substituted with an imaging moiety. In some
embodiments, R.sup.4 is --CH.sub.2OCH.sub.2F,
--CH.sub.2OCH.sub.2CH.sub.2F, --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2F,
or --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some cases, the
F is isotopically enriched with .sup.18F.
[0269] Additional examples of R.sup.4 groups which may be used in
connection with a compound of Formula (IIa) are described herein,
for example, in connection with a compound of Formula (IV).
[0270] In some embodiments, R.sup.4 is selected from the group
consisting of halogen; alkoxy, optionally substituted; C.sub.1-6
alkyl, optionally substituted; --CN; and --OH. In some embodiments,
R.sup.3 is selected from the group consisting of fluorine,
chlorine, bromine, iodine, --CF.sub.3, OCH.sub.3, --OH, --CH.sub.3,
and CN.
[0271] In some embodiments, R.sup.4 is halogen. In some
embodiments, R.sup.4 is fluorine. In some embodiments, R.sup.4 is
isotopically enriched with .sup.18F. In some embodiments, R.sup.4
is chlorine. In some embodiments, R.sup.4 is bromine. In some
embodiments, R.sup.4 is iodine. In some embodiments, R.sup.4 is
--CF.sub.3. In some embodiments, R.sup.4 is alkoxy. In some
embodiments, R.sup.4 is substituted alkoxy. In some embodiments,
R.sup.3 is --OCH.sub.3. In some embodiments, R.sup.4 is --OH. In
some embodiments, R.sup.4 is C.sub.1-6 alkyl. In some embodiments,
R.sup.4 is --CH.sub.3. In some embodiments, R.sup.4 is --CN.
Additional examples of R.sup.4 groups which may be used in
connection with a compound of Formula (IIa) are described below in
connection with a compound of Formula (IV).
[0272] Furthermore, each of the R.sup.4 groups described herein in
connection with a compound of Formula (IIa) may be combined with
any suitable R.sup.1 and/or L group as described herein, for
example, in connection with a compound of Formula (Ia)-(Id).
[0273] In some cases, for a compound of Formula (IIa), R.sup.3 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or is
associated with an imaging moiety selected from the group
consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and .sup.111In
through a chelator; or is an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I. In
some embodiments, R.sup.3 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I. In some embodiments, R.sup.3 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F. In some embodiments, R.sup.3 is halogen. In
some embodiments, R.sup.3 is fluorine. In some embodiments, R.sup.3
is isotopically enriched with .sup.18F.
[0274] In some embodiments, for a compound of Formula (IIa),
R.sup.3 is selected from the group consisting of hydrogen, halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2.
[0275] In some embodiments, R.sup.3 is selected from the group
consisting of C.sub.1-6 alkyl, alkoxy, and alkoxyalkyl, each
optionally substituted with an imaging moiety, or any combination
of R.sup.3 groups in this list. In some cases, R.sup.3 is
alkoxymethyl, optionally substituted with the imaging moiety. In
some cases, R.sup.3 is selected from the group consisting of
--CH.sub.2F, --CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2F, --OCH.sub.2F,
--OCH.sub.2CH.sub.2F, --OCH.sub.2CH.sub.2CH.sub.2F,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F, --CH.sub.2OCH.sub.2F,
--CH.sub.2OCH.sub.2CH.sub.2F, --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2F,
and --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some cases,
the F is isotopically enriched in .sup.18F.
[0276] In some embodiments, R.sup.3 is C.sub.1-6 alkyl. In some
embodiments, R.sup.3 is alkyl substituted with an imaging moiety.
In some embodiments, R.sup.3 is --CH.sub.2F, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2CH.sub.2F, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some embodiments, R.sup.3
is alkoxy substituted with an imaging moiety. In some embodiments,
R.sup.3 is --OCH.sub.2F, --OCH.sub.2CH.sub.2F,
--OCH.sub.2CH.sub.2CH.sub.2F, or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F. In some embodiments, R.sup.3
is alkoxyalkyl substituted with an imaging moiety. In some
embodiments, R.sup.3 is of the formula:
##STR00108##
wherein n is an integer between 0 and 6, inclusive; and m is an
integer between 0 and 6, inclusive. In some embodiments, R.sup.3 is
alkoxymethyl substituted with an imaging moiety. In some
embodiments, R.sup.3 is --CH.sub.2OCH.sub.2F,
--CH.sub.2OCH.sub.2CH.sub.2F, --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2F,
or --CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2F.
[0277] In some embodiments, R.sup.3 is selected from the group
consisting of halogen; alkoxy, optionally substituted; C.sub.1-6
alkyl, optionally substituted; --CN; and --OH. In some embodiments,
R.sup.3 is selected from the group consisting of fluorine,
chlorine, bromine, iodine, --CF.sub.3, OCH.sub.3, --OH, --CH.sub.3,
and --CN.
[0278] In some embodiments, R.sup.3 is halogen. In some
embodiments, R.sup.3 is fluorine. In some embodiments, R.sup.3 is
chlorine. In some embodiments, R.sup.3 is bromine. In some
embodiments, R.sup.3 is iodine. In some embodiments, R.sup.3 is
--CF.sub.3. In some embodiments, R.sup.3 is alkoxy. In some
embodiments, R.sup.3 is substituted alkoxy. In some embodiments,
R.sup.3 is --OCH.sub.3. In some embodiments, R.sup.3 is --OH. In
some embodiments, R.sup.3 is C.sub.1-6alkyl. In some embodiments,
R.sup.3 is --CH.sub.3. In some embodiments, R.sup.3 is --CN.
Additional examples of R.sup.3 groups which may be used in
connection with a compound of Formula (IIa) are described below in
connection with a compound of Formula (IV).
[0279] Each of the R.sup.3 groups described herein in connection
with a compound of Formula (IIa) may be combined with any R.sup.4
group described herein, for example, in connection with a compound
of Formula (IIa) or (IV), and/or any suitable R.sup.1 and/or L
group as described herein, for example, in connection with a
compound of Formula (Ia)-(Id).
[0280] As described above, for a compound of Formula (IIa), each of
R.sup.2-R.sup.6 is independently hydrogen, halogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2,
--SR.sup.A1, --C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1,
--C(.dbd.O)SR.sup.A1, --C(.dbd.O)N(R.sup.A2).sub.2,
--OC(.dbd.O)R.sup.A1, --OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)NR.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2NR.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or any two
adjacent R.sup.2--R.sup.6 are joined to form an optionally
substituted or unsubstituted carbocyclic, heterocyclic, aryl, or
heteroaryl ring.
[0281] In some embodiments, each of R.sup.2, R.sup.3, R.sup.5, and
R.sup.6 are hydrogen. In some embodiments, R.sup.2, R.sup.5, and
R.sup.6 are all hydrogen. In some embodiments, R.sup.2 and R.sup.6
are both hydrogen. In some embodiments, R.sup.3 is hydrogen. In
some embodiments, at least one, two, three, or four of R.sup.2,
R.sup.3, R.sup.5, and R.sup.6 is not hydrogen. In some embodiments,
at least one of R.sup.2, R.sup.3, R.sup.5, and R.sup.6 is not
hydrogen. In some embodiments, at least two of R.sup.2, R.sup.3,
R.sup.5, and R.sup.6 are not hydrogen. In some embodiments, R.sup.2
and R.sup.6 are hydrogen, and at least one of R.sup.3, R.sup.4, and
R.sup.5 is not hydrogen. In some embodiments, R.sup.2, R.sup.5 and
R.sup.6 are hydrogen, and R.sup.3 and R.sup.4 are not hydrogen. In
some embodiments, R.sup.2, R.sup.5 and R.sup.6 are hydrogen,
R.sup.3 and R.sup.4 are not hydrogen, and at least one of R.sup.3
and R.sup.4 is substituted with an imaging moiety. In some
embodiments, R.sup.2, R.sup.5 and R.sup.6 are hydrogen, R.sup.3 and
R.sup.4 are not hydrogen, and at least one of R.sup.3 and R.sup.4
is an imaging moiety.
[0282] In some embodiments, one, two, three, four, five, six,
seven, or eight of the following a)-h) apply for a provided
compound of Formula (IIa), where suitable: [0283] a) R.sup.1 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I and .sup.131I; [0284] b) R.sup.4 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; [0285] c) L is selected from
the group consisting of a bond; substituted or unsubstituted,
cyclic or acyclic C.sub.1-6 alkylene; unsubstituted, acyclic
C.sub.1-6 alkylene; acyclic C.sub.1-6alkylene; substituted or
unsubstituted, cyclic or acyclic C.sub.1-6 alkenylene; and
substituted or unsubstituted, cyclic or acyclic heteroaliphatic;
[0286] d) R.sup.1 is selected from the group consisting of
--N(R.sup.A).sub.2, heteroaryl, heterocyclic, --C(.dbd.NH)NH.sub.2,
--NHC(.dbd.NH)NH.sub.2, --NR.sup.AC(.dbd.NR.sup.A)N(R.sup.A).sub.2;
--NHC(.dbd.NH)NHR.sup.A, and --NHC(.dbd.NH)N(R.sup.A).sub.2,
wherein R.sup.A is as described herein; [0287] e) R.sup.4 is
selected from the group consisting of C.sub.1-6 alkyl, alkoxy, and
alkoxyalkyl, each optionally substituted with an imaging moiety;
[0288] f) R.sup.3 is selected from the group consisting of halogen;
optionally substituted alkoxy; optionally substituted C.sub.1-6
alkyl; --CN; and --OH; [0289] g) R.sup.2 is hydrogen; [0290] h)
R.sup.6 is hydrogen or halogen.
[0291] In some embodiments, a compound is provided comprising
Formula (IIb):
##STR00109##
wherein
[0292] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0293] R.sup.1 is selected from the group consisting of:
##STR00110##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen;
[0294] R.sup.2 and R.sup.6 are hydrogen;
[0295] each of R.sup.3, R.sup.4 and R.sup.5 is independently
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)NR.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)NR.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or any two
adjacent R.sup.3, R.sup.4 and R.sup.5 are joined to form an
optionally substituted or unsubstituted carbocyclic, heterocyclic,
aryl, or heteroaryl ring;
[0296] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring; and
[0297] wherein R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br, and
.sup.124I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is .sup.124I; or a salt
thereof;
[0298] provided that if one of R.sup.3 or R.sup.5 is Cl, Br, or
CF.sub.3, then the other of R.sup.3 or R.sup.5 is not H. In some
embodiments, the compound is not of the formula:
##STR00111##
[0299] For a compound of Formula (IIb), any suitable R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and/or L groups as
described herein, for example, in connection with a compound of
Formula (IIa) may be employed. In some embodiments, for a compound
of Formula (IIb), R.sup.1 is:
##STR00112##
wherein each occurrence of R.sup.B is independently hydrogen,
substituted or unsubstituted alkyl, or a nitrogen-protecting group,
provided at least two R.sup.B are hydrogen. In some embodiments,
for a compound of Formula (IIb), R.sup.4 is:
##STR00113##
[0300] In some embodiments, a compound of Formula (IIa) comprises
Formula (III):
##STR00114##
wherein
[0301] L is a bond; substituted or unsubstituted alkylene;
substituted or unsubstituted alkenylene; or substituted or
unsubstituted heteroalkylene;
[0302] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0303] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2, or
--CN;
[0304] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R, or --CN;
[0305] each occurrence of R.sup.A1 is independently hydrogen, or
optionally substituted alkyl; and each occurrence of R.sup.A2 is
independently hydrogen or optionally substituted alkyl, or two
R.sup.A2 groups are joined to form an optionally substituted
heterocyclic ring; and
[0306] one or more of R.sup.3 and R.sup.4 and is substituted with
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or is associated with an
imaging moiety selected from the group consisting of .sup.64Cu,
.sup.89Zr, .sup.99mTc, and .sup.111In through a chelator; or is
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or a salt
thereof.
[0307] In some cases, R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. In some cases, R.sup.3 is
substituted with an imaging moiety selected from the group
consisting of .sup.18F, .sup.76Br, .sup.124I, and .sup.131I; or is
associated with an imaging moiety selected from the group
consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and .sup.111In
through a chelator; or is .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I.
[0308] The compound of Formula (III) may comprise any suitable
R.sup.3 and/or R.sup.4 group(s) as described herein, for example,
in connection with a compound of Formula (IIa) or (IV), and/or any
L and/or R.sup.1 group as described herein, for example, in
connection with a compound of Formula (Ia)-(Id).
[0309] In some embodiments, a compound of Formula (III) comprises
the structure:
##STR00115##
or salt thereof, wherein R.sup.4 and R.sup.3 may be any suitable
R.sup.4 and R.sup.3 group as described herein, for example, in
connection with a compound of Formula (IIa) or Formula (IV). In
some embodiments, a compound of Formula (III) comprises the
structure:
##STR00116##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. In some embodiments, a
compound of Formula (III) comprises the structure:
##STR00117##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. In some embodiments, a
compound of Formula (III) comprises the structure:
##STR00118##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. R.sup.3 and R.sup.4 may be any
suitable R.sup.3 and R.sup.4 as described herein, for example, in
connection with a compound of Formula (IIa) or Formula (IV). In
some embodiments, a compound of Formula (III) comprises the
structure:
##STR00119##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. R.sup.3 and R.sup.4 may be any
suitable R.sup.3 and R.sup.4 as described herein, for example, in
connection with a compound of Formula (IIa) or Formula (IV). In
some embodiments, a compound of Formula (III) comprises the
structure:
##STR00120##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. In some embodiments, a
compound of Formula (III) comprises the structure:
##STR00121##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. In some embodiments, a
compound of Formula (III) comprises the structure:
##STR00122##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. R.sup.1 may be any suitable
R.sup.1 as described herein, for example, in connection with a
compound of Formula (Ia)-(Id). In some embodiments, a compound of
Formula (III) comprises the structure:
##STR00123##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. R.sup.1 may be any suitable
R.sup.1 as described herein, for example, in connection with a
compound of Formula (Ia)-(Id). In some embodiments, a compound of
Formula (III) comprises the structure:
##STR00124##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. R.sup.1 may be any suitable
R.sup.1 as described herein, for example, in connection with a
compound of Formula (Ia)-(Id). In some embodiments, a compound of
Formula (III) comprises the structure:
##STR00125##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. R.sup.1 may be any suitable
R.sup.1 as described herein, for example, in connection with a
compound of Formula (Ia)-(Id). In some embodiments, a compound of
Formula (III) comprises the structure:
##STR00126##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I. L and/or R.sup.1 may be any
suitable L and/or R.sup.1 as described herein, for example, in
connection with a compound of Formula (Ia)-(Id). In some
embodiments, a compound of Formula (III) comprises the
structure:
##STR00127##
L and/or R.sup.1 may be any suitable L and/or R.sup.1 as described
in connection with a compound of Formula (Ia)-(Id) and/or R.sup.4
may be any suitable R.sup.4 as described herein, for example, in
connection with a compound of Formula (IIa) or Formula (IV). In
some embodiments, a compound of Formula (III) comprises the
structure:
##STR00128##
L and/or R.sup.1 may be any suitable L and/or R.sup.1 as described
herein, for example, in connection with a compound of Formula
(Ia)-(Id) and/or R.sup.4 may be any suitable R.sup.4 as described
in connection with a compound of Formula (IIa) or Formula (IV). In
some embodiments, a compound of Formula (III) comprises the
structure:
##STR00129##
L and/or R.sup.1 may be any suitable L and/or R.sup.1 as described
herein, for example, in connection with a compound of Formula
(Ia)-(Id) and/or R.sup.4 may be any suitable R.sup.4 as described
in connection with a compound of Formula (IIa) or Formula (IV).
[0310] In some embodiments, a compound of Formula (III) comprises
Formula (IV):
##STR00130##
wherein
[0311] L is a bond; substituted or unsubstituted alkylene;
substituted or unsubstituted alkenylene; or substituted or
unsubstituted heteroalkylene;
[0312] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0313] R.sup.3 is halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2, or
--CN;
[0314] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2, or
--CN;
[0315] R.sup.5 is halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2, or
--CN;
[0316] each occurrence of R.sup.A1 is independently hydrogen, or
optionally substituted alkyl; and each occurrence of R.sup.A2 is
independently hydrogen or optionally substituted alkyl, or two
R.sup.A2 groups are joined to form an optionally substituted
heterocyclic ring; and
[0317] one or more of R.sup.3 and R.sup.4 is substituted with an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or is associated with an
imaging moiety selected from the group consisting of .sup.64Cu,
.sup.89Zr, .sup.99mTc, and .sup.111In through a chelator; or is an
imaging moiety selected from the group consisting of .sup.18F,
.sup.76Br, .sup.124I, and .sup.131I; or a salt thereof.
[0318] The compound of Formula (IV) may comprise any suitable
R.sup.3 and/or R.sup.4 as described herein, for example, in
connection with a compound of Formula (IIa), and/or any L and/or
R.sup.1 group as described herein, for example, in connection with
a compound of Formula (Ia)-(Id). In certain embodiments, the
imaging moiety is .sup.18F. In certain embodiments, the imaging
moiety is .sup.76Br. In certain embodiments, the imaging moiety is
.sup.124I. In certain embodiments, the imaging moiety is .sup.131I.
In some cases, the imaging moiety is not .sup.131I. In some cases,
the imaging moiety is .sup.18F, .sup.76Br, or .sup.124I. In some
cases, the imaging moiety is .sup.18F or .sup.76Br.
[0319] In some embodiments, in a compound of Formula (IV), both
R.sup.3 and R.sup.5 are not --OH.
[0320] In some embodiments, L is a bond. In some embodiments, L is
--CH.sub.2--. In some embodiments, L is --CH.dbd.CH--. Other
suitable L groups are described in connection with a compound of
Formula (Ia)-(Id).
[0321] The following description of R.sup.3 groups may be used in
connection with a compound of Formula (IV), or as noted herein. In
some embodiments, R.sup.3 is halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2, or CN.
In some embodiments, R.sup.3 is hydrogen, halogen, optionally
substituted alkyl, --OR.sup.A1, or CN. In some embodiments, R.sup.3
is hydrogen, fluoro, bromo, chloro, iodo, trifluoromethyl, methoxy,
hydroxyl, or CN. In some embodiments, R.sup.3 is not hydroxyl. In
some embodiments, R.sup.3 is not iodo, bromo, chloro, or fluoro. In
some embodiments, R.sup.3 is fluoro. In some embodiments, R.sup.3
is .sup.18F. In some embodiments, R.sup.3 is alkyl substituted with
an imaging moiety. In some embodiments, R.sup.3 is alkoxyalkyl
substituted with an imaging moiety. In some embodiments, R.sup.3 is
alkoxymethyl substituted with an imaging moiety. In some
embodiments, R.sup.3 is alkoxyethyl substituted with an imaging
moiety. In some embodiments, R.sup.3 is alkoxypropyl substituted
with an imaging moiety.
[0322] In some embodiments, R.sup.3 is selected from the group
consisting of:
##STR00131##
wherein m and n is an integer between 1 and 6, inclusive; and
I.sub.m is an imaging moiety. In some embodiments, R.sup.3 is
selected from the group consisting of:
##STR00132##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is selected from the group consisting of:
##STR00133##
wherein m and n is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.3 is selected from the group consisting of:
##STR00134##
[0323] In some embodiments, R.sup.3 is:
##STR00135##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.3 is:
##STR00136##
wherein m is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.3 is:
##STR00137##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is:
##STR00138##
In some embodiments, R.sup.3 is:
##STR00139##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is:
##STR00140##
In some cases, R.sup.3 is --(CH.sub.2).sub.4I.sub.m,
--(CH.sub.2).sub.5I.sub.m, --(CH.sub.2).sub.6I.sub.m,
--(CH.sub.2).sub.7I.sub.m, --(CH.sub.2).sub.86,
--(CH.sub.2).sub.9I.sub.m, or --(CH.sub.2).sub.10I.sub.m. In some
cases, R.sup.3 is --(CH.sub.2).sub.4.sup.18F,
--(CH.sub.2).sub.5.sup.18F, --(CH.sub.2).sub.6.sup.18F,
--(CH.sub.2).sub.7.sup.18F, --(CH.sub.2).sub.8.sup.18F,
--(CH.sub.2).sub.9.sup.18F, or --(CH.sub.2).sub.10.sup.18F. In some
embodiments, R.sup.3 is:
##STR00141##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.3 is:
##STR00142##
wherein n is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.3 is:
##STR00143##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is:
##STR00144##
In some embodiments, R.sup.3 is:
##STR00145##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is:
##STR00146##
In some embodiments, R.sup.3 is:
##STR00147##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is:
##STR00148##
In some cases, R.sup.3 is --O(CH.sub.2).sub.5I.sub.m,
--O(CH.sub.2).sub.6I.sub.m, --O(CH.sub.2).sub.7I.sub.m,
--O(CH.sub.2).sub.8I.sub.m, --O(CH.sub.2).sub.9I.sub.m, or
--O(CH.sub.2).sub.10I.sub.m. In some cases, R.sup.3 is
--O(CH.sub.2).sub.5.sup.18F, --O(CH.sub.2).sub.6.sup.18F,
--O(CH.sub.2).sub.7.sup.18F, --O(CH.sub.2).sub.8.sup.18F,
--O(CH.sub.2).sub.9.sup.18F, or --O(CH.sub.2).sub.10.sup.18F. In
some embodiments, R.sup.3 is:
##STR00149##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.3 is:
##STR00150##
wherein n is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.3 is:
##STR00151##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.3
is:
##STR00152##
In some cases, R.sup.3 is --CH.sub.2O(CH.sub.2).sub.3I.sub.m,
--CH.sub.2O(CH.sub.2).sub.4I.sub.m,
--CH.sub.2O(CH.sub.2).sub.5I.sub.m,
--CH.sub.2O(CH.sub.2).sub.6I.sub.m,
--CH.sub.2O(CH.sub.2).sub.7I.sub.m,
--CH.sub.2O(CH.sub.2).sub.8I.sub.m,
--CH.sub.2O(CH.sub.2).sub.9I.sub.m, or
--CH.sub.2O(CH.sub.2).sub.10I.sub.m. In some cases, R.sup.3 is
--CH.sub.2O(CH.sub.2).sub.3.sup.18F,
--CH.sub.2O(CH.sub.2).sub.4.sup.18F,
--CH.sub.2O(CH.sub.2).sub.5.sup.18F,
--CH.sub.2O(CH.sub.2).sub.6.sup.18F,
--CH.sub.2O(CH.sub.2).sub.7.sup.18F,
--CH.sub.2O(CH.sub.2).sub.8.sup.18F,
CH.sub.2O(CH.sub.2).sub.9.sup.18F, or
CH.sub.2O(CH.sub.2).sub.10.sup.18F.
[0324] In the above embodiments wherein R.sup.3 is described in
connection with a compound of Formula (IV), the compound of Formula
(III) may comprise any suitable R.sup.4 group as described in
connection with a compound of Formula (IIa), and/or any L and/or
R.sup.1 group as described in connection with a compound of Formula
(Ia)-(Id).
[0325] The following description of R.sup.4 groups may be used in
connection with a compound of Formula (IV), or as noted herein. In
some embodiments, R.sup.4 is hydrogen, halogen, optionally
substituted alkyl, --OR.sup.A1, or --NR.sup.A2C(.dbd.O)R.sup.A2. In
some embodiments, R.sup.4 is fluoro. In some embodiments, R.sup.4
is .sup.18F. In some embodiments, R.sup.4 is alkyl substituted with
an imaging moiety. In some embodiments, R.sup.4 is alkoxy
substituted with an imaging moiety. In some embodiments, R.sup.4 is
alkoxyalkyl substituted with an imaging moiety. In some
embodiments, R.sup.4 is alkoxymethyl substituted with an imaging
moiety. In some embodiments, R.sup.4 is alkoxyethyl substituted
with an imaging moiety. In some embodiments, R.sup.4 is
alkoxypropyl substituted with an imaging moiety. In certain
embodiments, the imaging moiety is .sup.18F.
[0326] In some embodiments, R.sup.4 is selected from the group
consisting of:
##STR00153##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.4 is selected from
the group consisting of:
##STR00154##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is selected from the group consisting of:
##STR00155##
wherein m or n is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.4 is selected from the group consisting of:
##STR00156##
In some embodiments, R.sup.4 is:
##STR00157##
wherein m is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.4 is:
##STR00158##
wherein m is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.4 is:
##STR00159##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is:
##STR00160##
In some embodiments, R.sup.4 is:
##STR00161##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is:
##STR00162##
In some cases, R.sup.4 is --(CH.sub.2).sub.4I.sub.m,
--(CH.sub.2).sub.5I.sub.m, --(CH.sub.2).sub.6I.sub.m,
--(CH.sub.2).sub.7I.sub.m, --(CH.sub.2).sub.8I.sub.m,
--(CH.sub.2).sub.9I.sub.m, or --(CH.sub.2).sub.10I.sub.m. In some
cases, R.sup.4 is --(CH.sub.2).sub.4.sup.18F,
--(CH.sub.2).sub.5.sup.18F, --(CH.sub.2).sub.6.sup.18F,
--(CH.sub.2).sub.7.sup.18F, --(CH.sub.2).sub.8.sup.18F,
--(CH.sub.2).sub.9.sup.18F, or --(CH.sub.2).sub.10.sup.18F. In some
embodiments, R.sup.4 is:
##STR00163##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.4 is:
##STR00164##
wherein n is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.4 is:
##STR00165##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is:
##STR00166##
In some embodiments, R.sup.4 is:
##STR00167##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is:
##STR00168##
In some embodiments, R.sup.4 is:
##STR00169##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is:
##STR00170##
In some cases, R.sup.4 is --O(CH.sub.2).sub.5I.sub.m,
--O(CH.sub.2).sub.6I.sub.m, --O(CH.sub.2).sub.7I.sub.m,
--O(CH.sub.2).sub.8I.sub.m, --O(CH.sub.2).sub.9I.sub.m, or
--O(CH.sub.2).sub.10I.sub.m. In some cases, R.sup.4 is
--O(CH.sub.2).sub.5.sup.18F, --O(CH.sub.2).sub.6.sup.18F,
O(CH.sub.2).sub.7.sup.18F, --O(CH.sub.2).sub.8.sup.18F,
--O(CH.sub.2).sub.9.sup.18F, or --O(CH.sub.2).sub.10.sup.18F. In
some embodiments, R.sup.4 is:
##STR00171##
wherein n is an integer between 1 and 6, inclusive; and I.sub.m is
an imaging moiety. In some embodiments, R.sup.4 is:
##STR00172##
wherein n is an integer between 1 and 6, inclusive. In some
embodiments, R.sup.4 is:
##STR00173##
wherein I.sub.m is an imaging moiety. In some embodiments, R.sup.4
is:
##STR00174##
In some cases, R.sup.4 is --CH.sub.2O(CH.sub.2).sub.3I.sub.m,
--CH.sub.2O(CH.sub.2).sub.4I.sub.m,
--CH.sub.2O(CH.sub.2).sub.5I.sub.m,
--CH.sub.2O(CH.sub.2).sub.6I.sub.m,
--CH.sub.2O(CH.sub.2).sub.7I.sub.m,
--CH.sub.2O(CH.sub.2).sub.8I.sub.m CH.sub.2O(CH.sub.2).sub.9I.sub.m
or --CH.sub.2O(CH.sub.2).sub.10I.sub.m. In some cases, R.sup.4 is
--CH.sub.2O(CH.sub.2).sub.3.sup.18F,
--CH.sub.2O(CH.sub.2).sub.4.sup.18F,
--CH.sub.2O(CH.sub.2).sub.5.sup.18F,
--CH.sub.2O(CH.sub.2).sub.6.sup.18F,
--CH.sub.2O(CH.sub.2).sub.7.sup.18F,
--CH.sub.2O(CH.sub.2).sub.8.sup.18F,
CH.sub.2O(CH.sub.2).sub.9.sup.18F, or
CH.sub.2O(CH.sub.2).sub.10.sup.18F.
[0327] In the above embodiments wherein R.sup.4 is described in
connection with a compound of Formula (IV), the compound of Formula
(III) may comprise any suitable R.sup.3 as described herein, for
example, in connection with a compound of Formula (IIa) or (IV),
and/or any L and/or R.sup.1 group as described herein, for example,
in connection with a compound of Formula (Ia)-(Id).
[0328] The following description of R.sup.1 groups may be used in
connection with a compound of Formula (IV), or as noted herein. In
some embodiments, R.sup.1 is selected from the group consisting
of:
##STR00175##
--NH.sub.2, --NHCH.sub.3, --NHCH.sub.2CH.sub.3, and
--NHCH.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.1 is:
##STR00176##
In some embodiments, R.sup.1 is:
##STR00177##
In some embodiments, R.sup.1 is:
##STR00178##
In some embodiments, R.sup.1 is:
##STR00179##
In some embodiments, R.sup.1 is:
##STR00180##
In some embodiments, R.sup.1 is:
##STR00181##
In some embodiments, R.sup.1 is:
##STR00182##
In some embodiments, R.sup.1 is:
##STR00183##
In some embodiments, R.sup.1 is:
##STR00184##
In some embodiments, R.sup.1 is:
##STR00185##
In some embodiments, R.sup.1 is:
##STR00186##
In some embodiments, R.sup.1 is:
##STR00187##
In some embodiments, R.sup.1 is:
##STR00188##
In some embodiments, R.sup.1 is:
##STR00189##
In some embodiments, R.sup.1 is:
##STR00190##
In some embodiments, R.sup.1 is:
##STR00191##
In some embodiments, R.sup.1 is NH.sub.2, --NHCH.sub.3,
--NHCH.sub.2CH.sub.3, or --NHCH.sub.2CH.sub.2CH.sub.3. In some
embodiments, R.sup.3 is hydrogen, fluoro, bromo, chloro, iodo,
trifluoromethyl, methoxy, hydroxyl, or CN; and R.sup.4 is alkyl
substituted with an imaging moiety, alkoxy substituted with an
imaging moiety, or alkoxyalkyl substituted with an imaging
moiety.
[0329] In the above embodiments wherein R.sup.1 is described in
connection with a compound of Formula (IV), the compound of Formula
(III) may comprise any suitable R.sup.3 and/or R.sup.4 as described
herein, for example, in connection with a compound of Formula (IIa)
or (IV), and/or any L group as described herein, for example, in
connection with a compound of Formula (Ia)-(Id).
[0330] As noted above, for a compound of Formula (IV), any suitable
combination of R.sup.1, R.sup.3, R.sup.4, R.sup.5, and L groups may
be used as described herein. For example, wherein R.sup.1 is as
described in connection with a compound of Formula (IV) or
(Ia)-(Id), R.sup.3 and/or R.sup.4 is as described in connection
with a compound of Formula (IIa) or (IV), and/or L is as described
in connection with a compound of Formula (Ia)-(Id).
[0331] In some embodiments, for a compound of Formula (IV), L is
--CH.sub.2--, and R.sup.1 is:
##STR00192##
R.sup.3 is halogen; and R.sup.4 is alkoxyalkyl substituted with an
imaging moiety.
[0332] In some embodiments, a compound is provided comprising
Formula (Va)-(Vd):
##STR00193##
wherein
[0333] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0334] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0335] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0336] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0337] each occurrence of R.sup.4 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0338] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of R is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, or
an amino protecting group, or two R.sup.A2 groups are joined to
form an optionally substituted heterocyclic ring;
[0339] p is 0, 1, or 2; and
[0340] r is 0, 1, 2, 3, or 4;
[0341] at least one R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
[0342] In some embodiments, a compound is provided comprising
Formula (Va)-(Vd):
##STR00194##
wherein
[0343] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0344] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0345] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0346] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0347] each occurrence of R.sup.4 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0348] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring;
[0349] at least one R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
[0350] For a compound of Formula (Va)-(Vd), any suitable
combination of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L groups may
be used as described herein. For example, wherein R.sup.1 is as
described in connection with a compound of Formula (IV) or
(Ia)-(Id), R.sup.3 and/or R.sup.4 is as described in connection
with a compound of Formula (IIa) or (IV), and/or L is as described
in connection with a compound of Formula (Ia)-(Id). In certain
embodiments, the imaging moiety is .sup.18F. In certain
embodiments, the imaging moiety is .sup.76Br. In certain
embodiments, the imaging moiety is .sup.124I. In certain
embodiments, the imaging moiety is .sup.131I. In some cases, the
imaging moiety is not .sup.131I. In some cases, the imaging moiety
is .sup.18F, .sup.76Br, or .sup.124I. In some cases, the imaging
moiety is .sup.18F or .sup.76Br.
[0351] In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00195##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L are as described
herein. For example, wherein R.sup.1 is as described in connection
with a compound of Formula (IV) or (Ia)-(Id), R.sup.3 and/or
R.sup.4 is as described in connection with a compound of Formula
(IIa) or (IV), and/or L is as described in connection with a
compound of Formula (Ia)-(Id). In some cases, a compound of Formula
(Va)-(Vd) comprises the structure:
##STR00196##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00197##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00198##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00199##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00200##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00201##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00202##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00203##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00204##
In some cases, a compound of Formula (Va)-(Vd) comprises the
structure:
##STR00205##
[0352] In some embodiments, a compound is provided comprising
Formula (VI):
##STR00206##
wherein
[0353] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0354] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0355] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0356] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0357] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0358] R.sup.4 is substituted with an imaging moiety selected from
the group consisting of .sup.18F, .sup.76Br, .sup.124I, and
.sup.131I; or is associated with an imaging moiety selected from
the group consisting of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In through a chelator; or is an imaging moiety selected
from the group consisting of .sup.18F, .sup.76Br, .sup.124I and
.sup.131I;
[0359] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0360] For a compound of Formula (VI), any suitable combination of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L groups may be used as
described herein. For example, wherein R.sup.1 is as described in
connection with a compound of Formula (IV) or (Ia)-(Id), R.sup.3
and/or R.sup.4 is as described in connection with a compound of
Formula (IIa) or (IV), and/or L is as described in connection with
a compound of Formula (Ia)-(Id). In some cases, R.sup.2 is halogen.
In certain embodiments, the imaging moiety is .sup.18F. In certain
embodiments, the imaging moiety is .sup.76Br. In certain
embodiments, the imaging moiety is .sup.124I. In certain
embodiments, the imaging moiety is .sup.131I. In some cases, the
imaging moiety is not .sup.131I. In some cases, the imaging moiety
is .sup.18F, .sup.76Br, or .sup.124I. In some cases, the imaging
moiety is .sup.18F or .sup.76Br.
[0361] In some embodiments, a compound of Formula (VI) comprises
the structure:
##STR00207##
wherein R.sup.1, R.sup.4, and L are as described herein. For
example, wherein R.sup.1 is as described in connection with a
compound of Formula (IV) or (Ia)-(Id), R.sup.4 is as described in
connection with a compound of Formula (IIa) or (IV), and/or L is as
described in connection with a compound of Formula (Ia)-(Id). In
some embodiments, a compound of Formula (VI) has the structure:
##STR00208##
In some embodiments, a compound of Formula (VI) comprises the
structure:
##STR00209##
In some embodiments, a compound of Formula (VI) comprises the
structure:
##STR00210##
In some embodiments, a compound of Formula (VI) comprises the
structure:
##STR00211##
In some embodiments, a compound of Formula (VI) comprises the
structure:
##STR00212##
In some embodiments, a compound is provided comprising the
formula:
##STR00213##
wherein
[0362] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0363] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0364] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0365] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0366] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1,
--NR.sup.A2SO.sub.2R.sup.A1.degree.--SO.sub.2N(R.sup.A2).sub.2,
--CN, --SCN, or --NO.sub.2;
[0367] wherein R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I;
[0368] wherein p and q are independently 0, 1, 2, 3, or 4.
[0369] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0370] In some embodiments, a compound is provided comprising
Formula (VII):
##STR00214##
wherein
[0371] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0372] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0373] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0374] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0375] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0376] wherein R.sup.4 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator; or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I;
[0377] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0378] For a compound of Formula (VII), any suitable combination of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L groups may be used as
described herein. For example, wherein R.sup.1 is as described in
connection with a compound of Formula (IV) or (Ia)-(Id), R.sup.3
and/or R.sup.4 is as described in connection with a compound of
Formula (IIa) or (IV), and/or L is as described in connection with
a compound of Formula (Ia)-(Id). In certain embodiments, the
imaging moiety is .sup.18F. In certain embodiments, the imaging
moiety is .sup.76Br. In certain embodiments, the imaging moiety is
.sup.124I. In certain embodiments, the imaging moiety is .sup.131I.
In some cases, the imaging moiety is not .sup.131I. In some cases,
the imaging moiety is .sup.18F, .sup.76Br, or .sup.124I. In some
cases, the imaging moiety is .sup.18F or .sup.76Br.
[0379] In some embodiments, a compound of Formula (VII) comprises
the structure:
##STR00215##
wherein R.sup.1, R.sup.4, and L are as described herein. For
example, wherein R.sup.1 is as described in connection with a
compound of Formula (IV) or (Ia)-(Id), R.sup.4 is as described in
connection with a compound of Formula (IIa) or (IV), and/or L is as
described in connection with a compound of Formula (Ia)-(Id). The
above compounds may optionally be substituted with R.sup.2 and/or
R.sup.3 (e.g., as described for Formula (VII)).
[0380] In some embodiments, a compound of Formula (VII) comprises
the structure:
##STR00216##
wherein R.sup.1, R.sup.4, and L are as described herein. For
example, wherein R.sup.1 is as described in connection with a
compound of Formula (IV) or (Ia)-(Id), R.sup.4 is as described in
connection with a compound of Formula (IIa) or (IV), and/or L is as
described in connection with a compound of Formula (Ia)-(Id).
[0381] In some embodiments, one or more of L, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, and R.sup.6 of a compound of Formula (Ia)-(Id),
(IIa)-(IIb), (III), (IV), (Va)-(Vd), (VI), or (VII) are selected
from Table A. In certain embodiments, L or R.sup.1 of a compound of
Formula (Ia), (Ib), (Ic), or (Id) is selected from Table A. In
certain embodiments, L and R.sup.1 of a compound of Formula (Ia),
(Ib), (Ic), or (Id) are selected from Table A. In some embodiments,
one of L, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6
of a compound of Formula (IIa) or (IIb) is selected from Table A.
In certain embodiments, two, three, four, five, six, or all of L,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 of a
compound of Formula (IIa) or (IIb) are selected from Table A. In
some embodiments, one of L, R.sup.1, R.sup.3, and R.sup.4 of a
compound of Formula (III) is selected from Table A. In certain
embodiments, two, three, or all of L, R.sup.1, R.sup.3, and R.sup.4
of a compound of Formula (III) are selected from Table A. In some
embodiments, one of L, R.sup.1, R.sup.3, R.sup.4, and R.sup.5 of a
compound of Formula (IV) is selected from Table A. In certain
embodiments, two, three, four, or all of L, R.sup.1, R.sup.3,
R.sup.4, and R.sup.5 of a compound of Formula (IV) are selected
from Table A. In some embodiments, one of L, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 of a compound of Formula (Va), (Vb), (Vc),
(Vd), (VI), or (VII) is selected from Table A. In certain
embodiments, two, three, four, or all of L, R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 of a compound of Formula (Va), (Vb), (Vc),
(Vd), (VI), or (VII) are selected from Table A.
TABLE-US-00001 TABLE A L R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5
R.sup.6 bond --NH.sub.2 --H --H --H --H --H --CH.sub.2--
--NHCH.sub.3 --Br --OCH.sub.2CH.sub.2F --Br --F
--CH.sub.2CH.sub.2-- --NHCH.sub.2CH.sub.3 --CF.sub.3
--OCH.sub.2CH.sub.2.sup.18F --CF.sub.3 --CH.sub.2CH.sub.2CH.sub.2--
--NHCH.sub.2CH.sub.2CH.sub.3 --O(CH.sub.2).sub.2F
--OCH.sub.2CH.sub.2Im --O(CH.sub.2).sub.2F --(CH.sub.2).sub.4--
##STR00217## --O(CH.sub.2).sub.2.sup.18F --.sup.18F
--O(CH.sub.2).sub.2.sup.18F --CH(CH.sub.3)-- ##STR00218##
--O(CH.sub.2).sub.2Im --Im --O(CH.sub.2).sub.2Im --CH.sub.2O--
##STR00219## --OH --CH.sub.2.sup.18F --OH --CH.sub.2CH.sub.2O--
##STR00220## --Cl --CH.sub.2Im --Cl --(CH.sub.2).sub.3O--
##STR00221## --I --CH.sub.2O(CH.sub.2).sub.4.sup.18F --I
--OCH.sub.2-- ##STR00222## --CH.sub.3 --CH.sub.2O(CH.sub.2).sub.4Im
--CH.sub.3 --OCH.sub.2CH.sub.2-- ##STR00223## --CN
--CH.sub.2CH.sub.2.sup.18F --CN --O(CH.sub.2).sub.3-- ##STR00224##
--OCH.sub.3 --CH.sub.2CH.sub.2Im --OCH.sub.3 ##STR00225##
##STR00226## --CH.sub.2CH.sub.3 ##STR00227## ##STR00228##
--CH.sub.2CH.sub.2CH.sub.2.sup.18F ##STR00229## ##STR00230##
--CH.sub.2CH.sub.2CH.sub.2Im --CH(CH.sub.3)CH.sub.2-- ##STR00231##
--OH --CH.sub.2CH(CH.sub.3)-- ##STR00232## --Br --CH.dbd.CH--
##STR00233## --O(CH.sub.2).sub.3.sup.18F ##STR00234## ##STR00235##
--O(CH.sub.2).sub.3Im --CH.dbd.N-- ##STR00236##
--(CH.sub.2).sub.4.sup.18F --NHCH.sub.2CH.sub.2-- ##STR00237##
--(CH.sub.2).sub.4Im ##STR00238## --O(CH.sub.2).sub.4.sup.18F
##STR00239## --O(CH.sub.2).sub.4Im ##STR00240## ##STR00241##
##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246##
##STR00247## ##STR00248## --OCH.sub.2.sup.18F ##STR00249##
--OCH.sub.2Im ##STR00250## ##STR00251## ##STR00252## ##STR00253##
##STR00254## ##STR00255## ##STR00256## ##STR00257## ##STR00258##
##STR00259## ##STR00260## ##STR00261## ##STR00262## ##STR00263##
##STR00264##
[0382] In some cases, a compound is provided of comprising the
formula:
##STR00265##
wherein
[0383] R.sup.9 and R.sup.10 are independently selected from the
group consisting of H, --OR.sup.11, F, Cl, Br, I, --CF.sub.3,
alkyl(C.sub.1-C.sub.4), and imaging moiety (I.sub.m);
[0384] R.sup.11, R.sup.12 and R.sup.13 are selected from the group
consisting of H, alkyl, and aryl; and
[0385] W and X are independently selected from the group consisting
of H, --OR.sub.4, --N(R.sup.11).sub.2, F, Cl, Br, --CF.sub.3,
I.sub.m, aryl, and heteroaryl;
[0386] wherein A) Y and Z are independently selected from the group
consisting of --CH--, --CH.sub.2--, --O--, --N--, --NR.sup.11--,
and --CH.dbd.CH-- when a linking group Q between Y and Z is present
or absent, wherein Q is selected from the group consisting of
--CH--, --CH.sub.2--, --CR.sup.11--, --N--, --NH--, --NR.sup.11--,
--O--, and --S--; or [0387] B) Y and Z are independently selected
from the group consisting of H, --OR.sub.4, --N(R.sup.11).sub.2, F,
Cl, Br, --CF.sub.3, I.sub.m, aryl, and heteroaryl when linking
group Q is absent;
[0388] wherein I.sub.m is selected from the group consisting of
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I, and is present in
either W-Z or R.sup.9-R.sup.13; or a salt thereof, provided the
compound is not of the formula:
##STR00266## ##STR00267##
[0389] In some cases, a compound is provided comprising the
formula:
##STR00268##
[0390] wherein R.sup.9 is independently selected from the group
consisting of H, --CF.sub.3, and alkyl(C.sub.1-C.sub.4);
[0391] W, Y and Z are independently selected from the group
consisting of H, --OR.sup.11, N(R.sup.11).sub.2, F, Cl, Br,
--CF.sub.3, I.sub.m, aryl and heteroaryl; and
[0392] R.sup.11 is selected from the group consisting of H, alkyl,
and aryl;
[0393] wherein I.sub.m is selected from the group consisting of
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I, and is present in
either W, Y, Z, R.sup.9, or R.sup.11, or a salt thereof;
[0394] provided the compound is not of the formula:
##STR00269## ##STR00270##
[0395] In some cases, a compound is provided comprising the
formula:
##STR00271##
[0396] wherein W and Y are independently selected from the group
consisting of H, --OR.sup.11, F, Cl, Br, --CF.sub.3, and I.sub.m;
and
[0397] R.sup.11 is alkyl,
[0398] wherein I.sub.m is selected from the group consisting of
.sup.18F, .sup.76Br, .sup.124I, and .sup.131I, and is present in
either W, Y, or R.sup.11; or a salt thereof;
[0399] provided the compound is not of the formula:
##STR00272##
[0400] In some embodiments, a compound comprises the formula:
##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277##
##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282##
##STR00283## ##STR00284##
or a salt thereof, wherein each fluorine may optionally be enriched
with .sup.18F and/or each Br may be optionally enriched with
.sup.76Br. In some embodiments, only one I.sub.m is present in the
compound.
[0401] In some embodiments, a compound of the invention is not:
##STR00285## ##STR00286##
wherein each fluorine may optionally be enriched in .sup.18F,
and/or each Br may be optionally enriched with .sup.76Br.
[0402] As used herein, the term "imaging agent" refers to any
chemical compound that includes an imaging moiety. An "imaging
moiety" refers to an atom or group of atoms that is capable of
producing a detectable signal itself, or upon exposure to an
external source of energy (e.g., electromagnetic radiation,
ultrasound, and the like). Non-limiting examples of imaging
moieties include .sup.11C, .sup.13N, .sup.18F, .sup.76Br,
.sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.99mTc, .sup.95Tc,
.sup.111In, .sup.62Cu, .sup.64Cu, .sup.67Ga, and .sup.68Ga. In some
embodiments, the imaging moiety is selected from the group
consisting of .sup.18F, .sup.76Br, .sup.131I, .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In. In certain embodiments, the imaging
moiety is directly associated (i.e., through a covalent bond) with
a compound as described herein (e.g., in the case of .sup.18F,
.sup.76Br, .sup.124I, or .sup.131I). In other embodiments, the
imaging moiety is associated with the compound through a chelator
(e.g., in the case of .sup.64Cu, .sup.89Zr, .sup.99mTc, and
.sup.111In). Chelators are described in more detail herein. In
certain embodiments, the imaging moiety is associated with the
compound through non-covalent interactions (e.g., electrostatic
interactions). In certain embodiments, the imaging moiety is
.sup.18F. In certain embodiments, the imaging moiety is .sup.76Br.
In certain embodiments, the imaging moiety is .sup.124I. In certain
embodiments, the imaging moiety is .sup.131I. In some cases, the
imaging moiety is not .sup.131I. In some cases, the imaging moiety
is .sup.18F, .sup.76Br, or .sup.124I. In some cases, the imaging
moiety is .sup.18F or .sup.76Br. In some cases, an imaging agent
comprises a single imaging moiety. In some cases, an imaging agent
comprises more than one imaging moiety (e.g., two imaging
moieties).
[0403] Imaging agents allow for the detection, imaging, and/or
monitoring of the presence and/or progression of a condition,
pathological disorder, and/or disease. Typically, the imaging agent
may be administered to a subject in order to provide information
relating to at least a portion of the subject (e.g., human). In
some cases, an imaging agent may be used to highlight a specific
area of a subject, rendering organs, blood vessels, tissues, and/or
other portions more detectable and more clearly imaged. By
increasing the detectability and/or image quality of the area being
studied, the presence and extent of disease and/or injury can be
determined.
[0404] In some embodiments, an imaging agent or composition thereof
is enriched with an isotope such as a radioisotope. In such a case,
the imaging agent or composition thereof may be referred to as
being "isotopically enriched." An "isotopically enriched"
composition refers to a composition comprising a percentage of one
or more isotopes of an element that is more than the percentage of
that isotope that occurs naturally. For example, a composition that
is isotopically enriched with a fluoride species may be
"isotopically enriched" with fluorine-18 (.sup.18F). Thus, with
regard to a plurality of compounds, when a particular atomic
position is designated as .sup.18F, it is to be understood that the
abundance (or frequency) of .sup.18F at that position (in the
plurality) is greater than the natural abundance (or frequency) of
.sup.18F, which is essentially zero.
[0405] In some embodiments, an atom designated as being enriched
may have a minimum isotopic enrichment factor of about 0.001%
(i.e., about 1 out of 10.sup.5 atoms is an enriched atom), 0.002%,
0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%,
about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about
0.5%, about 0.75%, about 1%, about 2%, about 3%, about 4%, about
5%, about 10%, about 15%, about 20%, about 30%, about 40%, about
50%, about 60%, about 70%, about 80%, about 90%, about 95%, or
greater. The minimum isotopic enrichment factor, in some instances,
may range from about 0.001% to about 1%. For example, in
embodiments wherein the imaging moiety is fluorine, a fluorine
designated as .sup.18F may have a minimum isotopic enrichment
factor of about 0.001% (i.e., about 1 out of 10.sup.5 fluorine
species is .sup.18F), 0.002%, 0.003%, 0.004%, 0.005%, 0.006%,
0.007%, 0.008%, 0.009%, 0.01%, about 0.05%, about 0.1%, about 0.2%,
about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1%, about
2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,
about 90%, about 95%, or greater. The isotopic enrichment of the
compounds provided herein can be determined using conventional
analytical methods known to one of ordinary skill in the art,
including mass spectrometry and HPLC.
[0406] In some embodiments, compositions, methods, uses, and
systems described herein include or use compounds of Formula
(Ia)-(Id), (IIa)-(IIb), (III), (IV), (Va)-(Vd), (VI), or (VII). In
some embodiments, the present invention relates to methods of
imaging, including methods of imaging a subject that includes
administering a composition that includes an imaging agent to the
subject by injection, infusion, or any other known method, and
imaging a region of interest of the subject. Regions of interest
may include, but are not limited to, the heart, a portion of the
heart, cardiovascular system, cardiac vessels, pancreas, adrenal
glands, salivary glands, thymus, or other organs with high
sympathetic innervation or high imaging agent uptake. Regions of
interest may also include tumors. In certain embodiments, the
imaging agent is used as a radiotracer for mapping the cardiac
nerve terminal in vivo using positron emission tomography (PET) or
other imaging techniques. An event of interest can be imaged and
detected and/or other information may be determined using methods
and/or systems of the disclosure.
[0407] The imaging agents as described herein may act as
norepinephrine transporter ligands that target or bind NET. In some
embodiments, the methods comprise detecting NET, including
determining NET levels, in a subject, wherein determining may
comprise determining the level, density, function, and/or
localization of NET in a subject. In certain embodiments, without
wishing to be bound by a particular theory, the imaging agent binds
to norepinephrine transporters (NET) allowing for imaging of
cardiac sympathetic innervation or activity. Accordingly, in some
aspects, methods for assessing cardiac sympathetic innervation
and/or myocardial sympathetic function are provided.
B. Chelators
[0408] In some cases, an imaging moiety may be associated with a
compound as described herein via association with a chelator (e.g.,
in embodiments where the imaging moiety is .sup.64Cu, .sup.89Zr,
.sup.99mTc, or .sup.111In). The term chelator is given its ordinary
meaning in the art and generally refers to a chemical moiety
capable of complexing an imaging moiety (e.g., a metal ion and/or
radionuclide), wherein the complex is stable under physiological
conditions. For example, generally, the imaging moiety remains
complexed with the chelator in vivo. In some embodiments, the
chelator is the moiety or group on a compound that binds to an
imaging moiety through one or more donor atoms and/or groups. The
chelator may be any chelator known in the art for complexing a
medically useful metal ion or radionuclide. In some embodiments,
the chelator comprises one, two, three, four, five, six, seven,
eight, nine, or ten donor atoms and/or groups. In embodiments where
the chelator comprises more than one donor atom and/or group, the
donor atoms/groups may be the same or different. Non-limiting
examples of donor atoms/groups include --OH, --O.sup.-, --COOR',
--COO.sup.-, --N(R').sub.2, --SR', --OPO.sub.3.sup.-, or
--OPO.sub.3R', wherein each R' can be the same of different and is
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl,
alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy,
alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl,
heterocyclylalkyl, each optionally substituted. In some cases, the
chelator may be a macrocycle. Non-limiting examples of chelators
are described in International PCT Publication No. WO2011/005322
and U.S. Pat. No. 6,511,648, each of which is incorporated herein
by reference. In some embodiments, the chelator comprises
diaminodithiol, mercaptoacetyltriglycine, monoaminomonoamide,
picolylamine monoacetic acid,
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,
bis(thiosemicarbazone), propyleneamine oxime,
ethylenediaminetetraacetic acid, and diethylenetriaminepentaacetic
acid.
[0409] In some cases, an imaging moiety associated with a chelator
may be further associated with one or more ancillary or co-ligands.
"Ancillary" or "co-ligands" may be ligands which serve to complete
the coordination sphere of the imaging moiety together with the
chelator. In some embodiments, the imaging moiety coordination
sphere may comprise one or more bonding atoms and/or groups form
the chelators or bonding units and optionally, one or more
ancillary and/or co-ligands. Ancillary or co-ligands useful in the
preparation of radiopharmaceuticals and in diagnostic kits useful
for the preparation of said radiopharmaceuticals may be comprised
of one or more oxygen, nitrogen, carbon, sulfur, phosphorus,
arsenic, selenium, and tellurium donor atoms.
C. Imaging Agent Precursors
[0410] In another aspect of the invention, imaging agent precursors
useful in the preparation of imaging agents as described herein are
provided. In certain embodiments, an imaging agent precursor as
described herein comprises a leaving group (e.g., a sulfonate,
halide) that can be replaced with a nucleophile in a substitution
reaction. The imaging agent precursor may also include functional
groups that are optionally protected. Earlier precursors in the
synthesis of imaging agents as described herein are also
encompassed by the present invention. In some embodiments, an
imaging agent precursor has a structure as described above for a
compound of Formula (Ia)-(Id), (IIa)-(IIb), (III), (IV), (Va)-(Vd),
(VI), or (VII), except that the substituent which includes the
imaging moiety instead includes a leaving group or a chelator group
which is not yet associated with an imaging moiety.
[0411] In certain embodiments, a compound (e.g., an imaging agent
precursor) for preparing an imaging agent is provided comprising
Formula (VIII):
R.sup.0'--Ar-L-R.sup.1 (VIII)
wherein
[0412] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0413] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0414] R.sup.0' is halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2,
--N(R.sup.A2).sub.3.sup.+, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --OSO.sub.2R.sup.A1, --Si(R.sup.A1).sub.3,
--Sn(R.sup.A1).sub.3, --B(OR.sup.A1).sub.2,
--NR.sup.A2SO.sub.2R.sup.A1, --NO.sub.2,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or
R.sup.0' is substituted with a leaving group or is a leaving group;
and
[0415] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0416] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof. In some embodiments, a compound of Formula (VIII)
is not of the formula:
##STR00287## ##STR00288## ##STR00289## ##STR00290##
wherein L.sub.G is a leaving group.
[0417] In some embodiments, Ar, L, and/or R.sup.1 may be as
described herein, for example, as described for a compound of
Formula (Ia).
[0418] As used herein, the term "leaving group" is given its
ordinary meaning in the art of synthetic organic chemistry and
refers to an atom or a group capable of being displaced by a
nucleophile. Examples of suitable leaving groups include, but are
not limited to, halides (such as chloride, bromide, or iodide),
alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,
arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),
arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino,
pixyl, and haloformates. In some cases, the leaving group is a
sulfonic acid ester, such as toluenesulfonate (tosylate, Ts),
methanesulfonate (mesylate, Ms), p-bromobenzenesulfonyl (brosylate,
Bs), or trifluoromethanesulfonate (triflate, Tf). In some cases,
the leaving group is a brosylate, such as p-bromobenzenesulfonyl.
In some cases, the leaving group is a nosylate, such as
2-nitrobenzenesulfonyl. In some embodiments, the leaving group is a
sulfonate-containing group. In some embodiments, the leaving group
is a tosylate group. The leaving group may also be a phosphineoxide
(e.g., formed during a Mitsunobu reaction) or an internal leaving
group such as an epoxide or cyclic sulfate.
[0419] In some embodiments, the leaving group is a sulfonate
leaving group. In some embodiments, R.sup.0' is selected from the
group consisting of alkoxy substituted with a leaving group, alkyl
substituted with a leaving group, and R.sup.0' is alkoxyalkyl
(e.g., alkoxymethyl) substituted with a leaving group. In some
embodiments, R.sup.0' is --OCH.sub.2L.sub.G, --OCH.sub.2CH.sub.2
L.sub.G, --OCH.sub.2CH.sub.2CH.sub.2 L.sub.G, or
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2 L.sub.G. In certain embodiments,
R.sup.0' is --CH.sub.2L.sub.G, --CH.sub.2CH.sub.2L.sub.G,
--CH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G. In certain embodiments,
R.sup.0' is --CH.sub.2OCH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G. In certain
embodiments, R.sup.0' is:
##STR00291##
wherein n is an integer between 0 and 6, inclusive; m is an integer
between 0 and 6, inclusive; and R.sup.7 is substituted or
unsubstituted, cyclic or acyclic alkyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic heteroaliphatic; substituted or
unsubstituted aryl; substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl; or substituted or
unsubstituted heteroarylalkyl.
[0420] In some embodiments, R.sup.0' is alkoxy substituted with a
leaving group. In some embodiments, R.sup.0' is --OCH.sub.2L.sub.G,
--OCH.sub.2CH.sub.2 L.sub.G, --OCH.sub.2CH.sub.2CH.sub.2 L.sub.G,
or --OCH.sub.2CH.sub.2CH.sub.2CH.sub.2 L.sub.G.
[0421] In some embodiments, R.sup.0' is alkyl substituted with a
leaving group. In some embodiments, R.sup.0' is --CH.sub.2L.sub.G,
--CH.sub.2CH.sub.2L.sub.G, --CH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G.
[0422] In some embodiments, R.sup.0' is alkoxyalkyl substituted
with a leaving group. In some embodiments, R.sup.0' is of the
formula:
##STR00292##
wherein n is an integer between 0 and 6, inclusive; m is an integer
between 0 and 6, inclusive; and R.sup.7 is substituted or
unsubstituted, cyclic or acyclic alkyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic heteroaliphatic; substituted or
unsubstituted aryl; substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl; or substituted or
unsubstituted heteroarylalkyl. In some embodiments, R.sup.7 is
substituted or unsubstituted C.sub.1-C.sub.6 alkyl. In some
embodiments, R.sup.7 is methyl. In some embodiments, R.sup.7 is
--CF.sub.3. In some embodiments, R.sup.7 is substituted or
unsubstituted aryl. In some embodiments, R.sup.7 is substituted or
unsubstituted phenyl. In some embodiments, R.sup.7 is:
##STR00293##
In some embodiments, R.sup.0' is alkoxymethyl substituted with a
leaving group. In some embodiments, R.sup.0' is
--CH.sub.2OCH.sub.2L.sub.G, --CH.sub.2OCH.sub.2CH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G.
[0423] In certain embodiments, a compound (e.g., an imaging agent
precursor) for preparing an imaging agent is provided comprising
Formula (IX):
R.sup.0--Ar-L-R.sup.1' (IX)
wherein
[0424] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0425] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0426] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; and
[0427] R.sup.1' is a substituted or unsubstituted
nitrogen-containing moiety, and R.sup.1' substituted with a leaving
group;
[0428] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0429] In some embodiments, Ar, L, and/or R.sup.0 for a compound of
Formula (IX) is as described for a compound of Formula (Ia).
[0430] In some embodiments, for a compound of Formula (IX), R.sup.1
is --N(R.sup.A).sub.2, heteroaryl, heterocyclic,
--C(.dbd.NH)NH.sub.2, --NHC(.dbd.NH)NH.sub.2,
--NR.sup.AC(.dbd.NR.sup.A)N(R.sup.A).sub.2;
--NHC(.dbd.NH)NHR.sup.A, or --NHC(.dbd.NH)N(R.sup.A).sub.2, wherein
each occurrence of R.sup.A is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted unsubstituted heterocyclyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl, or two R.sup.A groups may be joined to form an optional
substituted heterocyclic ring, provided R.sup.1' comprises at least
one leaving group. In some embodiments, R.sup.1 is a non-aromatic,
cyclic, substituted or unsubstituted nitrogen-containing moiety
comprising at least one leaving group. In some embodiments, R.sup.1
is selected from the group consisting of --NHC(.dbd.NH)NH.sub.2,
--NH.sub.2, --NHR.sup.A (wherein R.sup.A is as defined herein),
--NHCH.sub.3, --NHCH.sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2CH.sub.3,
##STR00294##
each substituted with at least one leaving group, and optionally
other substituents.
[0431] In certain embodiments, a compound is provided comprising
Formula (X):
##STR00295##
wherein
[0432] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0433] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0434] each of R.sup.2-R.sup.6 is independently hydrogen, halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
SO.sub.2R.sup.A1, NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; or any two
adjacent R.sup.2-R.sup.6 are joined to form an optionally
substituted or unsubstituted carbocyclic, heterocyclic, aryl, or
heteroaryl ring; and
[0435] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R groups are
joined to form an optionally substituted heterocyclic ring; and
[0436] wherein at least one of R.sup.1-R.sup.6 is substituted with
a leaving group.
[0437] For example, in some embodiments for a compound of Formula
(X), R.sup.4 can be substituted with a leaving group, and is
represented as R.sup.4', wherein R.sup.4' is selected from the
group consisting of hydrogen, halogen, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2NR.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1, --SC(.dbd.NR)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2, each
substituted with a leaving group. In some cases, R.sup.4' is
selected from the group consisting of C.sub.1-6 alkyl, alkoxy, or
alkoxyalkyl, each substituted with a leaving group. In some cases,
R.sup.4' is alkoxymethyl substituted with a leaving group. In some
cases, R.sup.4' is selected from the group consisting of
--CH.sub.2L.sub.G, --CH.sub.2CH.sub.2L.sub.G,
--CH.sub.2CH.sub.2CH.sub.2L.sub.G,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G, --OCH.sub.2L.sub.G,
--OCH.sub.2CH.sub.2L.sub.G, --OCH.sub.2CH.sub.2CH.sub.2L.sub.G,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2L.sub.G, --CH.sub.2OCH.sub.2CH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G, wherein L.sub.G
is a leaving group.
[0438] In some embodiments, R.sup.4' is alkyl substituted with a
leaving group. In some embodiments, R.sup.4 is C.sub.1-6 alkyl
substituted with a leaving group. In some embodiments, R.sup.4 is
--CH.sub.2L.sub.G, --CH.sub.2CH.sub.2L.sub.G,
--CH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2CH.sub.2CH.sub.2CHL.sub.G. In some embodiments, R.sup.4
is alkoxy substituted with a leaving group. In some embodiments,
R.sup.4' is --OCH.sub.2L.sub.G, --OCH.sub.2CH.sub.2L.sub.G,
--OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G.
[0439] In some embodiments, R.sup.4' is alkoxyalkyl substituted
with a leaving group. In some embodiments, R.sup.4' is of the
formula:
##STR00296##
wherein n is an integer between 0 and 6, inclusive; and m is an
integer between 0 and 6, inclusive. In some embodiments, R.sup.4'
is alkoxymethyl substituted with a leaving group. In some
embodiments, R.sup.4' is --CH.sub.2OCH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G.
[0440] In some embodiments, the leaving group is a sulfonate
leaving group. In some embodiments, R.sup.4' is
##STR00297##
wherein n is an integer between 0 and 6, inclusive; m is an integer
between 0 and 6, inclusive; and R.sup.7 is substituted or
unsubstituted, cyclic or acyclic alkyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic heteroaliphatic; substituted or
unsubstituted aryl; substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl; or substituted or
unsubstituted heteroarylalkyl. In some embodiments, R.sup.7 is
substituted or unsubstituted C.sub.1-C.sub.6 alkyl. In some
embodiments, R.sup.7 is methyl. In some embodiments, R.sup.7 is
--CF.sub.3. In some embodiments, R.sup.7 is substituted or
unsubstituted aryl. In some embodiments, R.sup.7 is substituted or
unsubstituted phenyl. In some embodiments, R.sup.7 is:
##STR00298##
[0441] Furthermore, each of the R.sup.4' groups described herein in
connection with a compound of Formula (X) may be combined with any
suitable R.sup.1 and/or L group described above, for example, in
connection with a compound of Formula (Ia).
[0442] In some embodiments, R.sup.3 is substituted with a leaving
group, and can therein be represented as R.sup.3', wherein R.sup.3'
may be any R.sup.4' group as described herein in connection with a
compound of Formula (IX).
[0443] In some embodiments, a compound of Formula (X) comprises
Formula (XI):
##STR00299##
wherein
[0444] L is a bond; substituted or unsubstituted alkylene;
substituted or unsubstituted alkenylene; or substituted or
unsubstituted heteroalkylene;
[0445] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0446] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A1, or
--CN;
[0447] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A1, or
--CN;
[0448] each occurrence of R.sup.A1 is independently hydrogen, or
optionally substituted alkyl; and each occurrence of R.sup.A2 is
independently hydrogen or optionally substituted alkyl, or two
R.sup.A2 groups are joined to form an optionally substituted
heterocyclic ring; and
[0449] wherein at least one of R.sup.3 and R.sup.4 is substituted
with an leaving group; or a salt thereof.
[0450] The compound of Formula (XI) may comprise any suitable
R.sup.3 and/or R.sup.4 group(s) as described herein in connection
with a compound of Formula (X), provided at least one of R.sup.3
and R.sup.4 is substituted with a leaving group (i.e., thereby
being R.sup.3' or R.sup.4'), and/or any L and/or R.sup.1 group as
described herein, for example, in connection with a compound of
Formula (Ia).
[0451] In some embodiments, a compound of Formula (XI) comprises
the structure:
##STR00300##
or salt thereof, wherein R.sup.4' and R.sup.3' may be any suitable
R.sup.4' and R.sup.3' as described herein in connection with a
compound of Formula (X) (e.g., is substituted with a leaving
group). In some embodiments, a compound of Formula (XI) comprises
the structure:
##STR00301##
R.sup.1 may be any suitable R.sup.1 as described in connection with
a compound of Formula (Ia); R.sup.3' and R.sup.4' may be any
suitable R.sup.3' and R.sup.4' as described herein in connection
with a compound of Formula (X). In some embodiments, a compound of
Formula (X) comprises the structure:
##STR00302##
R.sup.1 may be any suitable R.sup.1 as described in connection with
a compound of Formula (Ia); R.sup.3' and R.sup.4' may be any
suitable R.sup.3' and R.sup.4' as described above in connection
with a compound of Formula (X).
[0452] In some embodiments, a compound of Formula (X) comprises
Formula (XII):
##STR00303##
wherein
[0453] L is a bond; substituted or unsubstituted alkylene;
substituted or unsubstituted alkenylene; or substituted or
unsubstituted heteroalkylene;
[0454] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0455] R.sup.3 is halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A1, or
--CN;
[0456] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A1, or
--CN;
[0457] R.sup.5 is halogen, optionally substituted alkyl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A1, or
--CN;
[0458] each occurrence of R.sup.A1 is independently hydrogen, or
optionally substituted alkyl; and each occurrence of R.sup.A2 is
independently hydrogen or optionally substituted alkyl, or two
R.sup.A2 groups are joined to form an optionally substituted
heterocyclic ring; and
[0459] one or more of R.sup.3 and R.sup.4 is substituted with a
leaving group; or a salt thereof.
[0460] The compound of Formula (XII) may comprise any suitable
R.sup.3 and/or R.sup.4 as described herein, for example, in
connection with a compound of Formula (X), provided at least one of
R.sup.3 or R.sup.4 is substituted with a leaving group (i.e.,
thereby being R.sup.3' or R.sup.4'). For a compound of Formula
(XII), any suitable combination of R.sup.1, R.sup.5, and L groups
may be used as described herein. For example, wherein R.sup.1 is as
described in connection with a compound of Formula (IV) or (Ia),
and/or L is as described in connection with a compound of Formula
(Ia).
[0461] In some embodiments, compound is provided comprising Formula
(XIIIa)-(XIIId):
##STR00304##
wherein
[0462] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0463] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0464] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0465] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0466] each occurrence of R.sup.4 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --OR.sup.A1,
--N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR.sup.A2)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0467] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
[0468] provided at least one R.sup.4 is substituted with a leaving
group; or a salt thereof.
[0469] For a compound of Formula (XIIIa)-(XIIId), any suitable
combination of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L groups may
be used as described herein, provided at least one R.sup.4 group is
substituted with a leaving group (e.g., and thus is R.sup.4').
[0470] In some cases, a compound of Formula (XIIIa)-(XIIId)
comprises the structure:
##STR00305##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L are as described
herein, provided at least one R.sup.4 is R.sup.4'. For example,
wherein R.sup.1 is as described in connection with a compound of
Formula (IV) or (Ia)-(Id), R.sup.3 and/or R.sup.4 is as described
in connection with a compound of Formula (IIa) or (IV), and/or L is
as described in connection with a compound of Formula (Ia),
provided at least one R.sup.4 is substituted with a leaving group
(and thus is R.sup.4'). In some cases, compound of Formula
(XIIIa)-(XIIId) comprises the structure:
##STR00306##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00307##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00308##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00309##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00310##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00311##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00312##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00313##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00314##
In some cases, a compound of Formula (XIIIa)-(XIIId) comprises the
structure:
##STR00315##
[0471] In some embodiments, a compound is provided comprising
Formula (XIV):
##STR00316##
wherein
[0472] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0473] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0474] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR)SR.sup.A1, --SC(.dbd.NR)N(R.sup.A2).sub.2,
--C(.dbd.S)R.sup.A1, --C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0475] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0476] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0477] provided at least one R.sup.4 is substituted with a leaving
group;
[0478] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0479] For a compound of Formula (XIV), any suitable combination of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L groups may be used as
described herein, provided at least one R.sup.4 is substituted with
a leaving group, so that it is R.sup.4'. For example, wherein
R.sup.1 is as described in connection with a compound of Formula
(IV) or (Ia), R.sup.3 and/or R.sup.4 is as described in connection
with a compound of Formula (IIa) or (IV), and/or L is as described
in connection with a compound of Formula (Ia), provided at least
one R.sup.4 is substituted with a leaving group.
[0480] In some embodiments, a compound of Formula (XIV) comprises
the structure:
##STR00317##
wherein R.sup.1, R.sup.4', and L are as described herein. For
example, wherein R.sup.1 is as described in connection with a
compound of Formula (IV) or (Ia), R.sup.4' is as described in
connection with a compound of Formula (VIII), and/or L is as
described in connection with a compound of Formula (Ia). In some
embodiments, a compound of Formula (XIV) comprises the
structure:
##STR00318##
[0481] In some embodiments, imaging agent precursor comprises
Formula (XV):
##STR00319##
wherein
[0482] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0483] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0484] R.sup.2 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0485] R.sup.3 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1, --NR.sup.A2C(.dbd.NR)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0486] R.sup.4 is hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0487] provided at least one R.sup.4 is substituted with a leaving
group;
[0488] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt thereof.
[0489] For a compound of Formula (XV), any suitable combination of
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and L groups may be used as
described herein provided at least one R.sup.4 is substituted with
a leaving group (and thus is R.sup.4'). For example, wherein
R.sup.1 is as described in connection with a compound of Formula
(IV) or (Ia), R.sup.3 and/or R.sup.4 is as described in connection
with a compound of Formula (IIa) or (IV), and/or L is as described
in connection with a compound of Formula (ha), provided at least
one R.sup.4 is substituted with a leaving group (and thus is
R.sup.4').
[0490] In some embodiments, a compound of Formula (XV) comprises
the structure:
##STR00320##
wherein R.sup.1, R.sup.4', and L are as described herein.
D. Salts
[0491] As described herein, the imaging agents and precursors
described herein may be salts. In some cases, the salt may be a
pharmaceutically acceptable salt. Those of ordinary skill in the
art will be aware of suitable counter anions for forming a salt of
the imaging agents and imaging agent precursors described herein.
In addition, those of ordinary skill in the art will be aware that
the counter anion X.sup..crclbar. may have a charge of greater than
(-1) (e.g., (-2), (-3)), and in such embodiments, each counter
anion X .crclbar. may be associated with more than one molecule of
a compound. In some embodiments, the counter ion is halide,
phosphate, hydrogen phosphate, dihydrogen phosphate, hydrogen
sulfate, sulfate, trifluoroacetate, toluenesulfonate, acetate,
formate, citrate, ascorbate, mesylate (methanesulfonate), triflate
(trifluoromethanesulfonate), tartrate, lactate, or benzoate.
Additional non-limiting examples of suitable counter anions include
the conjugate base of inorganic acids (e.g., chloride, bromide,
iodide, fluoride, nitrate, sulfate, phosphate) or from the
conjugate base of organic acids (e.g., carboxylate, acetate,
benzoate, tartrate, adipate, lactate, formate, maleate, glutamate,
ascorbate, citrate, gluconate, oxalate, succinate, pamoate,
salicylate, isethionate, succinamate, mono-diglycollate,
di-isobutyrate, glucoheptonate). Still yet other non-limiting
examples of salts include adipate, alginate, aminosalicylate,
anhydromethylenecitrate, arecoline, aspartate, bisulfate,
camphorate, digluconate, dihydrobromide, disuccinate,
glycerophosphate, hemisulfate, fluoride, iodide,
methylenebis(salicylate), napadisylate, oxalate, pectinate,
persulfate, phenylethylbarbiturate, picrate, propionate,
thiocyanate, tosylate, undecanoate, acetate, benzenesulfonate,
benzoate, bicarbonate, bitartrate, bromide, calcium edentate,
camyslate, carbonate, chloride, citrate, dihydrochloride, edentate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
bromide, chloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, mucate,
napsylate, nitrate, pamoate (embonate), pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
subacetate, succinate, sulfate, tannate, tartrate, teoclate, and
triethiodide (see Berge et al., Journal of Pharmaceutical Sciences,
66(1), 1977, 1-19).
E. Methods of Synthesizing an Imaging Agent
[0492] In other aspects, methods are provided for synthesizing
imaging agents. The methods described herein may be used for the
synthesis of a variety of imaging agents as described herein from
imaging agent precursors as described herein. Generally, an imaging
agent may be synthesized by reacting an imaging agent precursor
with a reactant comprising the imaging moiety. In some cases, the
reaction involves the formation of a covalent bond between the
imaging agent precursor and the imaging moiety of the reactant. In
other cases, however, the reaction involves non-covalent
association of an imaging moiety with an imaging agent precursor
(e.g., via chelation). The following sections provide a number of
non-limiting embodiments for forming an imaging agent from an
imaging agent precursor. Those of ordinary skill in the art will be
aware of other suitable methods and techniques for forming an
imaging agent from an imaging agent precursor. In addition, other
steps which may be conducted in connection with the synthesis of an
imaging agent (e.g., formulation, purification) are also
described.
E1. General Reaction Conditions
[0493] The synthetic methods described herein may be carried out in
any suitable solvent, including, but are not limited to,
non-halogenated hydrocarbon solvents (e.g., pentane, hexane,
heptane, cyclohexane), halogenated hydrocarbon solvents (e.g.,
dichloromethane, chloroform, fluorobenzene,
trifluoromethylbenzene), aromatic hydrocarbon solvents (e.g.,
toluene, benzene, xylene), ester solvents (e.g., ethyl acetate),
ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane), and alcohol solvents (e.g., ethanol, methanol,
propanol, isopropanol, tert-butanol). In certain embodiments, a
protic solvent is used. In other embodiments, an aprotic solvent is
used. Non-limiting examples of solvents useful include acetone,
acetic acid, formic acid, dimethyl sulfoxide, dimethyl formamide,
acetonitrile, p-cresol, glycol, petroleum ether, carbon
tetrachloride, hexamethyl-phosphoric triamide, triethylamine,
picoline, and pyridine.
[0494] The methods may be carried out at any suitable temperature.
In some cases, the method is carried out at about room temperature
(e.g., about 20.degree. C., between about 20.degree. C. and about
25.degree. C., about 25.degree. C., or the like). In some cases,
however, the method is carried out at a temperature below or above
room temperature, for example, at about -78.degree. C. at about
-70.degree. C., about -50.degree. C., about -30.degree. C., about
-10.degree. C., about -0.degree. C., about 10.degree. C., about
30.degree. C., about 40.degree. C., about 50.degree. C., about
60.degree. C., about 70.degree. C., about 80.degree. C., about
90.degree. C., about 100.degree. C., about 120.degree. C., about
140.degree. C., or the like. In some embodiments, the method is
carried out at temperatures above room temperature, for example,
between about 25.degree. C. and about 120.degree. C., or between
about 25.degree. C. and about 100.degree. C., or between about
40.degree. C. and about 120.degree. C., or between about 80.degree.
C. and about 120.degree. C. The temperature may be maintained by
reflux of the solution. In some cases, the method is carried out at
temperatures between about -78.degree. C. and about 25.degree. C.,
or between about 0.degree. C. and about 25.degree. C.
[0495] The methods described herein may be carried out at any
suitable pH, for example, equal to or less than about 13, equal to
or less than about 12, equal to or less than about 11, equal to or
less than about 10, equal to or less than about 9, equal to or less
than about 8, equal to or less than about 7, or equal to or less
than about 6. In some cases, the pH may be greater than or equal to
1, greater than or equal to 2, greater than or equal to 3, greater
than or equal to 4, greater than or equal to 5, greater than or
equal to 6, greater than or equal to 7, or greater than or equal to
8. In some cases, the pH may be between about 2 and about 12, or
between about 3 and about 11, or between about 4 and about 10, or
between about 5 and about 9, or between about 6 and about 8, or
about 7.
[0496] The percent yield of a product may be greater than about
60%, greater than about 70%, greater than about 75%, greater than
about 80%, greater than about 85%, greater than about 90%, greater
than about 92%, greater than about 95%, greater than about 96%,
greater than about 97%, greater than about 98%, greater than about
99%, or greater.
E2. Halogenation
[0497] In some embodiments, an imaging agent is formed by reacting
an imaging agent precursor with an imaging moiety. In certain
embodiments, an imaging agent precursor comprises at least one
leaving group that is susceptible to being displaced by an imaging
moiety, such as, for example, a halogen (e.g., .sup.18F, .sup.76Br,
.sup.124I, .sup.131I). Thus, in certain embodiments, the methods
described herein involve reacting an imaging agent precursor
comprising a leaving group with a source of an imaging moiety.
[0498] In some embodiments, an imaging moiety displaces a leaving
group on a provided imaging agent precursor via a substitution
reaction, such as an S.sub.N2 or S.sub.N1 reaction, thereby
producing an imaging agent. In certain embodiments, a substitution
reaction is a one-step procedure which does not require a
subsequent deprotection step. That is, the substitution step is
performed on a fully deprotected imaging agent precursor. In
certain embodiments, a substitution reaction provided by the
present invention produces a fluorinated imaging agent (e.g., an
imaging agent comprising .sup.18F).
[0499] In some embodiments, a provided imaging agent is synthesized
via an aryl halogenation reaction (e.g., aryl fluorination, aryl
bromination, aryl iodination). Many techniques for synthesizing
aryl halides are known in the art. For example, in certain
embodiments, an imaging agent comprising an .sup.124I, .sup.131I,
or .sup.76Br imaging moiety is synthesized via a Sandmeyer reaction
from a aryl diazonium imaging agent precursor, with or without the
use of copper(I) catalysis (see, for example, Beletskaya et al.,
Synthesis, 2007, 2534-2538; Hubbard et al., J. Org. Chem., 2008,
73, 316-319; Filimonov et al., Org. Lett., 2008, 10, 3961-3964;
Krasnokutskaya et al., Synthesis, 2007, 81-84). In other
embodiments, an imaging agent comprising a .sup.18F imaging moiety
is synthesized via a related Balz-Schiemann reaction from a
diazonium imaging agent precursor. In certain embodiments, an
imaging agent comprising an .sup.124I or .sup.131I imaging moiety
is synthesized via an "aromatic Finkelstein" reaction from an aryl
bromide imaging agent precursor (see, for example, A. Klapars, S.
L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844-14845). In other
embodiments, an imaging agent comprising an .sup.124I, .sup.131I,
or .sup.76Br imaging moiety is synthesized by allowing a boronic
acid or ester imaging agent precursor to react with the appropriate
N-halosuccinimide reagent (Thiebes et al., Synlett, 1998, 141-142)
or copper bromide reagent (see, for example, Murphy et al., J. Am.
Chem. Soc., 2007, 129, 15434-15435; Thompson et al., Synthesis,
2005, 547-550). In some embodiments, an imaging agent comprising a
.sup.76Br imaging moiety is synthesized via an
organotrifluoroborate imaging agent precursor (see, for example, G.
W. Kabalka, A. R. Mereddy, Organometallics, 2004, 23, 4519-4521).
One of ordinary skill in the art will appreciate that there are
many other conditions under which activated or deactivated arenes
may be halogenated (see, for example, Kraszkiewicz et al.,
Synthesis, 2006, 1195-1199; Ganguly et al., Synthesis, 2010,
1467-1472; Iskra et al., Synthesis, 2004, 1869-1873; Castanet et
al., Tetrahedron Lett., 2002, 43, 5047-5048; Prakash et al., J. Am.
Chem. Soc., 2004, 126, 15570-15776; Lulinski et al., Synthesis,
2004, 441-445; Ganguly et al., Synthesis, 2005, 1103-1108; Rajesh
et al., Org. Chem., 2007, 72, 5867-5869; Kumar et al., Synthesis,
2010, 1629-1632; Zhou et al., Synthesis, 2011, 207-209; Menzel et
al., J. Org. Chem., 2006, 71, 2188-2191), and such a reaction may
be employed in certain embodiments to synthesize imaging agents
described herein. One of ordinary skill in the art will also
appreciate that many of the aryl halogenation reactions described
herein will also be effective for generating a haloalkene- or
haloalkyne-containing imaging agent, as well as
haloheteroaryl-containing imaging agents.
[0500] In some embodiments, an imaging agent comprising a .sup.18F
imaging moiety is synthesized via an aryl fluorination. See, for
example, Furuya et al., Synthesis, 2010(11): 1804-1821 (2010), for
an informative review of aryl fluorination reactions. For example,
in certain embodiments, an imaging agent comprising a .sup.18F
imaging moiety is synthesized via an nucleophilic fluorination
reaction. Examples of nucleophilic fluorination reactions include,
but are not limited to, the Halex process (Adams et al., Chem Soc
Rev 1999; 28:225; Horwitz et al., J. Org. Chem 1961; 26:3392;
Barlin et al., J. Chem. Soc., Perkin Trans 1 1972:1269; Pike et
al., J. Chem. Soc., Chem Commun 1995:2215; Shah et al., J. Chem.
Soc., Perkin Trans 1 1998:2043; Ermert et al., J Labelled Compd
Radiopharm 2004; 47:429), fluorodenitration (Adams et al., Chem Soc
Rev 1999; 28:225; Adams et al., J. Fluorine Chem 1998; 92:127),
displacement of ammonium with fluoride (Angelini et al., J.
Fluorine Chem 1985; 27:177), and fluorination of diaryliodonium
salts (Zhdankin et al., Chem Rev 2008; 108:5299; Beringer et al.,
J. Am. Chem Soc 1953; 75:2708; Ross et al., J. Am. Chem Soc 2007;
129:8018). Trialkylammonium fluoride reagents may also be employed
in nucleophilic fluorination reactions (Sun et al., Angew. Chem.,
Int. Ed 2006; 45:2720; Grushin et al., Organometallics 2008;
27:4825). In certain embodiments, a nucleophilic fluorination
reaction is Palladium catalyzed (see, for example, Grushin et al.,
Organometallics 2008; 27:4825; Watson et al., Science 2009;
325:1661). In other embodiments, an imaging agent comprising a
.sup.18F imaging moiety is synthesized via an electrophilic
fluorination reaction. Examples of electrophilic fluorination
reactions include, but are not limited to, fluorination of aryl
Grignards reagents (Anbarasan P, Neumann H, Beller M. Angew Chem,
Int Ed. 2010; 49:2219), fluorination of arylmagnesium reagents
(Yamada S, Gavryushin A, Knochel P. Angew Chem, Int Ed. 2010;
49:2215), fluorination of organometallic reagents such as arylzinc
halides, arylsilanes, arylstannanes, arylgermaniums, or arylboronic
acids (Bryce et al., J. Chem. Soc, Chem Commun 1986:1623; Tius et
al., Synth Commun 1992; 22:1461; Cazorla et al., Tetrahedron Lett
2009; 50:3936), fluorination of arylsilanes (Lothian et al.,
Synlett 1993:753), and fluorodestannylation reactions (Lothian et
al., Synlett 1993:753; Namavari et al., Appl Radiat Isot 1992;
43:989). In some embodiments, an electrophilic fluorination
reaction employs stoichiometric or catalytic palladium (see, for
example, Furuya et al., Angew Chem, Int Ed 2008; 47:5993) or silver
(see, for example, Furuya et al., J. Am. Chem Soc 2009; 131:1662;
Furuya et al., Org Lett 2009; 11:2860).
[0501] In some embodiments, a method of synthesizing an imaging
agent described herein involves the use of one or more reagents
(e.g., salts, catalysts) that facilitate a chemical reaction (e.g.,
a substitution reaction). In certain embodiments, a choice of salt
form allows for fluorination of an unprotected imaging agent
precursor. Without wishing to be bound by a particular theory, the
counter anion may interact with the guanidine functional group or
other nitrogen-containing group preventing it from interfering with
the fluorination reaction and/or preventing side reactions. In
certain embodiments, the salt is a mesylate (i.e.,
methanesulfonate), phosphate, sulfate, acetate, formate, benzoate,
trifluoroacetate, or tosylate salt.
[0502] In some embodiments, multiple substitution reactions may
occur through multiple leaving groups during synthesis of an
imaging agent from an imaging agent precursor. The methods
described herein exhibit improved yields may allow for the
synthesis of imaging agents, including imaging agents comprising a
radioisotope (e.g., .sup.18F). The imaging agents may be useful as
sensors, diagnostic tools, and the like. Synthetic methods for
preparing an imaging agent have also been designed to use an
automated synthesis system to prepare and purify imaging agents
that are enriched with a radioisotope.
E3. Fluorination
[0503] It should be understood, that while the following section
focuses on fluorination reactions, this is by no means limiting,
and the teaching of this section may be applied to other
halogenation reactions.
[0504] In some embodiments, an imaging moiety displaces a leaving
group on a provided imaging agent precursor via a substitution
reaction, such as an S.sub.N2 or S.sub.N1 reaction, thereby
producing an imaging agent. In certain embodiments, a substitution
reaction is a one-step procedure which does not require a
subsequent deprotection step. That is, the substitution step is
performed on a fully deprotected imaging agent precursor. In
certain embodiments, a substitution reaction provided by the
present invention produces a fluorinated imaging agent (e.g., an
imaging agent comprising .sup.18F).
[0505] In some embodiments, a method for synthesizing an imaging
agent comprises contacting an imaging agent precursor of the
invention (e.g., a compound of Formula (VIII)) with a fluoride
species resulting in the fluoride species replacing the leaving
group of the precursor to produce an imaging agent (e.g., a
compound of Formula (Ia)) comprising the fluorine species).
[0506] In some embodiments, an inventive method employs a reaction
described herein, such as in the description of halogenation
reactions above. For example, in certain embodiments, a compound of
Formula (VIII) is transformed to a compound of Formula (Ia) using a
nucleophilic substitution reaction, an electrophilic substitution
reaction, or an organometallic reaction as described herein.
[0507] In certain embodiments, a method according to the invention
involves a nucleophilic fluorination reaction. It will be
understood that the discussion of nucleophilic fluorination is
exemplary of the methods described herein and is not limiting. In
certain embodiments, an imaging agent precursor comprising a
leaving group is reacted in the presence of a fluoride species,
whereby S.sub.N2 or S.sub.N1 displacement of the leaving group by
the fluoride species produces an imaging agent. In some
embodiments, a fluoride species is isotopically enriched with
.sup.18F.
[0508] Those of ordinary skill in the art will be aware of suitable
conditions for fluorinating a compound. For example, see
International Patent Application No. PCT/US2011/024109, filed Feb.
8, 2011, published as International Patent Publication No.
WO/2011/097649, by Cesati et al., incorporated herein by reference.
In some cases, a compound of Formula (VIII), or a salt, free base,
or combination thereof, is exposed to a source of fluorine,
optionally enriched with an isotope of fluorine (e.g., enriched
with .sup.18F). In some cases, the source of fluorine is a fluoride
salt (e.g., KF, NaF, tetralkylammonium fluoride).
[0509] The following provides a specific non-limiting example of a
method of the present invention, comprising reaction an imaging
agent precursor with a fluoride species to form an imaging agent.
In desired, at least a portion of the imaging agent may optionally
be deprotected (e.g., a guanidine functional group) and/or purified
prior to use. In certain embodiments, the present invention
provides a method comprising reacting a compound of Formula
(VIII):
R.sup.0'--Ar-L-R.sup.1 (VIII)
wherein
[0510] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0511] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0512] R.sup.0' is halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1,
--C(.dbd.O)R.sup.A1, --C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; and
R.sup.0 is substituted with a leaving group L.sub.G or is a leaving
group L.sub.G;
[0513] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety;
[0514] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring; or
a salt, free base, or combination thereof; with a fluorinating
reagent under suitable conditions to form a compound of Formula
(Ia):
R.sup.0--Ar-L-R.sup.1 (Ia)
[0515] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2; and
R.sup.0 is substituted with a fluorine.
[0516] As described herein, R.sup.0' of formula (VIII) comprises a
leaving group. In some embodiments, a leaving group according to
the present invention is a sulfonate leaving group. In some
embodiments, R.sup.0' is alkoxy substituted with a leaving group.
In certain embodiments, R.sup.0' is --OCH.sub.2L.sub.G,
--OCH.sub.2CH.sub.2L.sub.G, --OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G. In some embodiments,
R.sup.0' is alkyl substituted with a leaving group. In certain
embodiments, R.sup.0' is --CH.sub.2L.sub.G,
--CH.sub.2CH.sub.2L.sub.G, --CH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G. In some embodiments,
R.sup.0' is alkoxyalkyl substituted with a leaving group.
[0517] In some embodiments, a method according to the present
invention employs a compound of Formula (VIII) wherein R.sup.0' is
of the formula:
##STR00321##
wherein n is an integer between 0 and 6, inclusive; m is an integer
between 0 and 6, inclusive; and R.sup.7 is substituted or
unsubstituted, cyclic or acyclic alkyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic alkenyl; substituted or
unsubstituted, cyclic or acyclic heteroaliphatic; substituted or
unsubstituted aryl; substituted or unsubstituted heteroaryl,
substituted or unsubstituted arylalkyl; or substituted or
unsubstituted heteroarylalkyl.
[0518] In some embodiments, R.sup.7 is substituted or unsubstituted
C.sub.1-C.sub.6 alkyl. In certain embodiments, R.sup.7 is methyl.
In certain other embodiments, R.sup.7 is CF.sub.3. In some
embodiments, R.sub.7 is substituted or unsubstituted aryl. In
certain embodiments, R.sup.7 is substituted or unsubstituted
phenyl. In certain embodiments, R.sup.7 is p-tolyl. In some
embodiments, R.sup.0' is alkoxymethyl substituted with a leaving
group. In certain embodiments, R.sup.0' is
--CH.sub.2OCH.sub.2L.sub.G, --CH.sub.2OCH.sub.2CH.sub.2L.sub.G,
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2L.sub.G, or
--CH.sub.2OCH.sub.2CH.sub.2CH.sub.2CH.sub.2L.sub.G.
[0519] In some embodiments, a provided compound of Formula (VIII)
for use in synthetic methods of the present invention is as
described in embodiments herein. In some embodiments, a provided
compound of Formula (Ia) for use in synthetic methods of the
present invention is as described in embodiments herein, such as a
provided compound of Formula (Ib), (Ic), (Id), (IIa)-(IIb), (III),
(IV), (Va)-(Vd), (VI), or (VII) and embodiments thereof described
herein.
[0520] As described above, in certain embodiments, a compound of
Formula (VIII) is allowed to react with a fluorinating reagent
under suitable conditions to form a compound of Formula (Ia). In
some embodiments, a fluorinating agent for use in a provided method
is a source of fluoride. In certain embodiments, a fluorinating
agent for use in a provided method is NaF or KF. In certain
embodiments, a fluorinating agent for use in a provided method is
isotopically enriched with .sup.18F. In certain embodiments,
suitable conditions for a fluorination reaction according to the
present invention comprise the presence of an ammonium salt or a
bicarbonate salt.
[0521] The fluorine source may comprise or be associated with or
may be used in connection with another reagent. In some
embodiments, an additional reagent may be capable of enhancing the
reactivity of the fluorine species or otherwise facilitating
conversion of the precursor to the imaging agent. For example, in
certain embodiments, an additional reagent is used in combination
with a multidentate ligand, such as a crown ether or a cryptand
that is capable of chelating a metal ion. In certain embodiments, a
multidentate ligand is, for example,
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (i.e.,
Kryptofix.RTM. 222). In certain embodiments, when KF is a fluorine
source, cryptands having a high affinity for potassium are useful
as they chelate potassium and thereby increase the reactivity of
the fluoride ion. In some embodiments, cryptands having an affinity
for potassium near that of Kryptofix.RTM. 222 (e.g., 75%, 80%, 85%,
90%, 95%, or more of the Kryptofix.RTM. 222's affinity for
potassium) are used. The reaction conditions may comprise one or
more solvents.
[0522] In some embodiments, the fluorination occurs in the presence
of K.sub.2CO.sub.3 and Kryptofix.RTM. 222 (or any another cryptand
having affinity for the cation of interest, including for example
potassium, near that of Kryptofix.RTM. 222) in MeCN (acetonitrile)
alone or in combination with t-BuOH, as the solvent. In some
embodiments, the molar ratio of K.sub.2CO.sub.3 to imaging agent
precursor ranges from about 0.5:1 to about 5:1, for example 0.5:1
to 1:1. In some embodiments, the molar ratio is about 0.66:1.
[0523] In some embodiments, fluorination occurs in the presence of
tetraalkylammonium carbonate or tetraalkylammonium bicarbonate in
MeCN as the solvent. In some embodiments, the molar ratio of
tetraalkylammonium carbonate or bicarbonate to imaging agent
precursor is 5:1. In some embodiments, the molar ratio ranges from
about 7:1 to about 3:1, or from about 6:1 to about 4:1, or about
5.5:1 to about 4.5:1. In some embodiments, the tetraalkylammonium
cation may be tetraethylammonium or tetrabutylammonium but it is
not so limited.
[0524] In certain embodiments, the synthetic methods described
herein involve a single-step preparation of imaging agents of the
invention (e.g., compounds of Formula (Ia)-(Id), (IIa)-(IIb),
(III), (IV), (Va)-(Vd), (VI), or (VII), or a salt, free base, or
combination thereof). In certain embodiments, a single-step method
involves fluorination of a completely or partially deprotected
precursor in the presence of, for example,
K.sub.2CO.sub.3/Kryptofix.RTM. 222 (or other suitable alternatives
to Kryptofix.RTM. 222) or tetraalkylammonium carbonate or
bicarbonate, in MeCN alone or in an MeCN mixture (such as an MeCN
and t-BuOH mixture). In certain embodiments, single-step
preparation methods are particularly suitable when particular salt
forms of the imaging agent precursors of the invention are used,
such as halide, acetate, formate, citric, ascorbate,
trifluoroacetate, tolunesulfonate, benzoate, acetate, phosphate,
sulfate, tosylate, and mesylate.
[0525] In some embodiments, an imaging agent precursor comprises a
protected nitrogen functional group (e.g., a protected guanidine
functional group) which may or may not be deprotected prior to, or
in some instances after, fluorination. For example, a guanidine
functional group may or may not be deprotected prior to
fluorination. In some embodiments, an imaging agent precursor
comprising a protected guanidine functional group is fluorinated,
optionally followed by deprotection. In other embodiments, an
imaging agent precursor comprising a protected guanidine functional
group is deprotected (e.g., according to the methods described
herein), followed by fluorination. As described herein, in certain
embodiments, a fluorine source is isotopically enriched with
.sup.18F.
[0526] In some embodiments, one or more reagents is used in a
reaction mixture comprising an imaging agent precursor and a
fluoride species. A "reagent," also referred to as an "additive,"
is used herein to mean any chemical compound added to a reaction
mixture. A reagent may be consumed or not consumed during the
reaction. A reagent may be a stoichiometric or catalytic reagent.
Exemplary reagents include catalysts, salts, oxidants, reductants,
chelating agents, bases, acids, metals, phase transfer reagents,
and others as would be appreciated by one of skill in the art.
[0527] A reagent may, in some embodiments, facilitate reaction
between an imaging agent precursor and a fluoride species and/or
may aid in stabilizing a resultant imaging agent. For example, in
certain embodiments, a fluoride species may have relatively low
reactivity (e.g., nucleophilicity), and addition of certain
reagents may enhance the reactivity of the fluoride species. As an
illustrative embodiment, a fluorine species may be a negatively
charged fluoride ion (e.g., an isotopically enriched .sup.18F ion),
and a reagent may be used to bind to any positively charged counter
ions present within the reaction mixture, thereby enhancing the
reactivity of the fluoride ion. An example of such a reagent is a
cryptand such as, but not limited to, Kryptofix (e.g.,
Kryptofix.RTM.-222). In some embodiments, a reagent decreases the
rate of undesired side reactions, as described below.
[0528] In some embodiments, a reagent may be combined with a
fluoride species prior to its contact with an imaging agent
precursor. For example, in certain embodiments, a solution
comprising a fluoride species and a reagent is prepared, and the
solution is added to an imaging agent precursor. In other
embodiments, a solid comprising a fluoride species and a reagent is
prepared, and the solid is contacted with an imaging agent
precursor in solution. In certain embodiments, a fluoride species
is adsorbed onto a solid support (e.g., an anion exchange column),
and a solution comprising the reagent is used to elute the fluoride
species from the solid support. The eluted solution is then
contacted with the imaging agent precursor, or is concentrated to
produce a solid, which is then contacted with the imaging agent
precursor in solution.
[0529] In some embodiments, a provided reagent is a bicarbonate
salt. As used herein, the term "bicarbonate salt" refers to a salt
comprising a bicarbonate or hydrogen carbonate ion (HCO.sub.3.sup.-
ion). In some embodiments, a bicarbonate salt is a metal
bicarbonate, such as sodium bicarbonate, calcium bicarbonate,
potassium bicarbonate, and magnesium bicarbonate. In certain
embodiments, a bicarbonate salt is potassium bicarbonate
(KHCO.sub.3). In some embodiments, a bicarbonate salt comprises a
non-metal counter ion, such as ammonium bicarbonate. For example, a
bicarbonate salt may be a tetraalkylammonium bicarbonate salt
having the formula, R.sub.4NHCO.sub.3, wherein R is alkyl. In some
embodiments, R may be lower alkyl, such as methyl, ethyl, propyl,
butyl, pentyl, hexyl, or the like. In certain embodiments, the
ammonium salt is Et.sub.4NHCO.sub.3. In other embodiments, the salt
is Me.sub.4NHCO.sub.3, i-Pr.sub.4NHCO.sub.3, n-Pr.sub.4NHCO.sub.3,
n-Bu.sub.4NHCO.sub.3, i-Bu.sub.4NHCO.sub.3, or
t-Bu.sub.4NHCO.sub.3.
[0530] In some embodiments, a provided reagent is a carbonate salt.
As used herein, the term "carbonate salt" refers to a salt
comprising a carbonate ion (CO.sub.3.sup.-2 ion). In some
embodiments, a carbonate salt is a metal carbonate, such as sodium
carbonate, calcium carbonate, potassium carbonate, and magnesium
carbonate. In certain embodiments, a carbonate salt is potassium
carbonate (K.sub.2CO.sub.3). In some embodiments, a carbonate salt
comprises a non-metal counter ion, such as ammonium carbonate. For
example, a carbonate salt may be a tetraalkylammonium carbonate
salt having the formula, (R.sub.4N).sub.2CO.sub.3, wherein R is
alkyl. In some embodiments, R may be a lower alkyl, such as methyl,
ethyl, propyl, butyl, pentyl, hexyl, or the like. In certain
embodiments, the ammonium salt is (Et.sub.4N).sub.2CO.sub.3. In
other embodiments, the salt is (Me.sub.4N).sub.2CO.sub.3,
(i-Pr.sub.4N).sub.2CO.sub.3, (n-Pr.sub.4N).sub.2CO.sub.3,
(n-Bu.sub.4N).sub.2CO.sub.3, (i-Bu.sub.4N).sub.2CO.sub.3, or
(t-Bu.sub.4N).sub.2CO.sub.3.
[0531] Without wishing to be bound by any particular theory, use of
bicarbonate, carbonate, and/or ammonium salts may aid in decreasing
the rate of competing reactions such as hydrolysis during
nucleophilic fluorination of an imaging agent precursor.
[0532] In some embodiments, a reagent is a salt comprising a cation
that forms a weakly coordinating salt with a fluoride species. As
used herein, a "cation that forms a weakly coordinating salt with a
fluoride species" refers to a cation that renders a fluoride
species reactive in the context of a fluorination reaction. For
example, a cation may not strongly bind to the fluoride species,
allowing the fluoride species to act as a nucleophile during a
nucleophilic fluorination reaction. Those of ordinary skill the art
would be able to select an appropriate cation that would be
suitable as a weakly coordinating counter ion for a fluoride
species. For example, a cation may be have a relatively large
atomic radius and/or may be a weak Lewis base. In some cases, a
cation may be selected to be lipophilic. In some cases, a cation
may comprise one or more alkyl groups. Examples of weakly
coordinating cations include cesium ions, ammonium ions, weakly
coordinating salts of hexamethylpiperidindium, S(NMe.sub.2).sub.3,
P(NMe.sub.2).sub.4, tetraaalkylphosphonium salts,
tetraarylphosphonium salts, (e.g. tetraphenylphosphonium),
hexakis(dimethylamino)diphosphazenium, and
tris(dimethylamino)sulfonium.
[0533] In some embodiments, a provided reagent is an ammonium salt,
i.e., a salt comprising a substituted or unsubstituted ammonium
ion. In some embodiments, an ammonium ion is a weakly coordinating
cation. In some embodiments, an ammonium salt has the formula,
R.sub.4NX, where each R can be the same or different and is alkyl,
heteroalkyl, aryl, heteroaryl, or heterocyclic, each optionally
substituted, and X is a negatively charged counter ion. In some
cases, R is alkyl, heteroalkyl, aryl, heteroaryl, or heterocyclic,
each optionally substituted. In some embodiments, ammonium salt may
include a range of negatively charged counter ions, including
halides, carbonates, and bicarbonates. Examples of ammonium salts
include, but are not limited to, ammonium bicarbonate salts,
ammonium hydroxide salts, ammonium acetate salts, ammonium lactate
salts, ammonium trifluoroacetate salts, ammonium methanesulfonate
salts, ammonium p-toluenesulfonate salts, ammonium nitrate salts,
ammonium halide salts (e.g., ammonium iodide salts), and ammonium
bisulfate salts.
[0534] In one set of embodiments, an ammonium salt is a
tetraalkylammonium salt, such as a tetraalkylammonium bicarbonate
salt. For example, an ammonium salt may have the formula,
R.sub.4NHCO.sub.3, wherein each R is independently alkyl. In some
cases, R is optionally substituted. In some embodiments, the alkyl
group is a lower C.sub.1-C.sub.6 alkyl group. In some embodiments,
an tetraalkylammonium salt is a basic tetraalkylammonium salt.
[0535] In some embodiments, a salt (e.g., bicarbonate salt and/or
ammonium salt) may be utilized in the reaction such that the molar
ratio of the salt to the imaging agent precursor is less than or
equal to about 10:1, or less than or equal to about 9:1, or less
than or equal to about 8:1, or less than or equal to about 7:1 or
less than or equal to about 6:1, or less than or equal to about
5:1, or less than or equal to about 4:1, or less than or equal to
about 3:1, or less than or equal to about 2:1, or less than or
equal to about 1:1. In some cases, the molar ratio of the salt to
the imaging agent precursor is between about 3:1 and about 8:1, or
between about 4:1 and about 7:1, or between about 5:1 and about
7:1, or between about 5:1 and about 8:1.
[0536] In some embodiments, a reagent is used in combination with a
species capable of enhancing the reactivity of the fluoride species
or otherwise facilitating conversion of the imaging agent precursor
to the imaging agent. For example, a species may be a compound
capable of chelating one or more ions (e.g., metal ions) that may
be present within the reaction mixture. Without wishing to be bound
by theory, a species may be used to chelate a counter ion to a
fluoride species, such as a potassium ion, thereby increasing the
reactivity (e.g., nucleophilicity) of the fluoride species. In
certain embodiments, a reagent is used in combination with a
multidentate ligand, such as a crown ether or a cryptand that is
capable of chelating a metal ion. The multidentate ligand (e.g.,
cryptand) may be selected based on the metal ion to be chelated. A
multidentate ligand may be, for example,
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane (e.g.,
Kryptofix.RTM. 222). Other cryptands will be known to those of
ordinary skill in the art.
[0537] Some embodiments involve use of a carbonate salt in
combination with
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane. In a
specific embodiment, potassium carbonate is used in combination
with
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane.
[0538] In another set of embodiments, it may be advantageous to
utilize the methods described herein in the absence of a cryptand.
The term "cryptand" is given its ordinary meaning in the art and
refers to a bi- or a polycyclic multidentate ligand for a cation.
For example, inventive methods may be carried out using an ammonium
salt, in the absence of a cryptand (e.g.,
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane). In
some embodiments, cryptands may increase the pH of the reaction
solution, which in the presence of another reagent (e.g. carbonate
salt) may adversely affect the yield and/or purity of the
fluorination reaction. Accordingly, in certain embodiments,
carrying out the fluorination reaction, in the absence of a
cryptand, and optionally in the presence of another reagent (e.g.,
ammonium and/or bicarbonate salt) may increase the yield and/or
purity of the reaction, as described herein.
[0539] In another set of embodiments, a method according to the
present invention is performed in the absence of a carbonate
salt.
[0540] As will be understood by one of ordinary skill in the art,
during fluorination (or other halogenation reactions), any
associated anionic species (e.g., in instances where the starting
material is a salt) may be exchanged. That is, in certain
embodiments, the starting material may be provided as a first salt
(e.g., trifluoroacetate, chloride), and the isolated product (e.g.,
the fluorinated product) may be isolated as a second, different
salt (e.g., formate, ascorbate, citrate, or trifluoroacetate). In
some embodiments, following formation of a salt, a counter anion
may be exchanged in an additional step. For example, an HCl salt of
a compound may be exposed to a suitable reagent (e.g., AgOAc or
AgOBz) such that the compound forms the corresponding salt of the
reagent (e.g., acetate salt or benzoate salt, respectively). As
another example, a TFA salt of a compound may be exposed to a
suitable reagent (e.g., phosphoric acid or methanesulfonic acid)
such that the compound forms the corresponding salt of the reagent
(e.g., phosphate salt or methanesulfonate salt, respectively). The
intermediate salt (e.g., trifluoroacetate salt or chloride salt in
the above-examples) may or may not be isolated prior to exposure to
the reagent.
[0541] Those of ordinary skill in the art will be able to select
and/or determine an appropriate set of reaction conditions (e.g.,
concentration, temperature, pressure, reaction time, solvents)
suitable for use in a particular application. In some embodiments,
an imaging agent may be further processed using one or more
purification techniques, and may optionally be combined with
additional components, such as a stabilizing agent.
[0542] In some embodiments, an imaging agent is formed as a salt
(e.g., a pharmaceutically acceptable salt). Pharmaceutically
acceptable excipients and other aspects of pharmaceutically
acceptable compositions are described herein.
[0543] Those of ordinary skill in the art would be able to select a
source of a fluoride species suitable for use in the methods
described herein. The term "fluoride species" as used herein refers
to a fluoride atom or group of atoms comprising at least one
fluoride atom, wherein the fluoride atom is capable of reacting
with another compound (e.g., an imaging agent precursor). In some
embodiments, an isotopically-enriched .sup.18F species may be
produced by the nuclear reaction .sup.18O (p,n).sup.18F from proton
bombardment of [.sup.18O]H.sub.2O in a cyclotron. In certain
embodiments, a method may involve treating a solution of the
.sup.18F species to remove any impurities, such as unreacted
[.sup.18O]H.sub.2O. For example, a solution of the .sup.18F species
may be filtered through an anion exchange column, where the
.sup.18F species is retained on the cationic resin matrix while the
[.sup.18O]H.sub.2O is eluted. The .sup.18F species is then removed
by washing the anion exchange column with various mixtures of
solvents and optional reagents (e.g., salt), forming an
.sup.18F-containing solution. In some embodiments, an anion
exchange column is washed with an aqueous solution of a salt, such
as K.sub.2CO.sub.3 or Et.sub.4NHCO.sub.3. In other embodiments, a
column is washed (e.g., with aqueous K.sub.2CO.sub.3), and the
resulting solution diluted (e.g., with MeCN) and/or concentrated
(e.g., to dryness using elevated temperature and/or reduced
pressure). Anhydrous [.sup.18F]KF and/or [.sup.18F]Et.sub.4NF may
be obtained and reacted with a compound or a salt thereof.
[0544] In some embodiments, a .sup.18F-containing solution is
combined with additional components prior to reaction with an
imaging agent precursor. For example, one or more solvents may be
added to dilute a .sup.18F-containing solution to a desired
concentration. In certain embodiments, a .sup.18F-containing
solution is diluted with acetonitrile (MeCN). In certain
embodiments, a .sup.18F-containing solution is diluted with
acetonitrile (MeCN) and t-BuOH.
[0545] In some embodiments, a .sup.18F-containing solution may be
concentrated to dryness by exposure to elevated temperature and/or
reduced pressure to form an anhydrous .sup.18F-containing solid. In
some embodiments, a .sup.18F-containing solid may further comprise
one or more reagents (e.g., salts). The chemical composition of a
.sup.18F-containing solid may depend on the number and kind of
reagents used in preparation of the .sup.18F-containing solution.
For example, a solution of potassium carbonate may be used to elute
a .sup.18F species from the anion exchange column, thereby
resulting in an .sup.18F-containing solid comprising [.sup.18F]KF.
In another example, a solution of tetraethylammonium bicarbonate is
used to elute a .sup.18F species from the anion exchange column,
thereby resulting in an .sup.18F-containing solid comprising
[.sup.18F]Et.sub.4NF.
[0546] In some embodiments, a solution comprising a .sup.18F
species is heated to a temperature ranging from room temperature to
about 200.degree. C. For example, a solution comprising a
[.sup.18F]-fluoride may be heated to elevated temperatures to
encourage evaporation of the solvent (e.g., to about 110.degree.
C.). In some embodiments, a solution is heated to a temperature
ranging from about 90-120.degree. C. or from about 100-150.degree.
C. In some embodiments, a solution is heated to about 75.degree.
C., about 85.degree. C., about 95.degree. C., about 105.degree. C.,
about 115.degree. C., about 125.degree. C., or greater. In some
embodiments, a solution is placed under a reduced pressure of about
100 mm Hg, about 125 mm Hg, about 150 mm Hg, about 175 mm Hg, about
200 mm Hg, about 225 mm Hg, about 250 mm Hg, about 275 mm Hg, about
300 mm Hg, about 325 mm Hg, about 350 mm Hg, about 375 mm Hg, about
400 mm Hg, or greater. In some embodiments, a solution is placed
under a reduced pressure of about 100 mbar, about 125 mbar, about
150 mbar, about 175 mbar, about 200 mbar, about 225 mbar, about 250
mbar, about 275 mbar, about 280 mbar, about 300 mbar, about 325
mbar, about 350 mbar, about 375 mbar, about 400 mbar, about 450
mbar, about 500 mbar, or greater. Those of ordinary skill in the
art would be able to select and/or determine conditions suitable
for a particular process. In some embodiments, a solution is
concentrated to dryness at about 150 mm Hg and about 115.degree. C.
In some embodiments, a solution is concentrated to dryness at about
375 mm Hg and about 115.degree. C. In some embodiments, a solution
is concentrated to dryness at about 400 mbar and about
110-150.degree. C. In some embodiments, a solution is concentrated
to dryness at about 280 mbar and about 95-115.degree. C.
[0547] In certain embodiments, a fluoride species and/or a reagent,
if present, is then contacted with an imaging agent precursor under
conditions that result in conversion of the imaging agent precursor
to the imaging agent product via nucleophilic fluorination. Those
of ordinary skill in the art would be able to select conditions
suitable for use in a particular reaction. For example, in certain
embodiments, the ratio of fluoride species to imaging agent
precursor may be selected to be about 1:10,000 or more, about
1:5000 or more, about 1:3000 or more, about 1:2000 or more, about
1:1000 or more, about 1:500 or more, about 1:100 or more, about
1:50 or more, about 1:10 or more, about 1:5 or more, or, in some
cases, about 1:1 or more. In some embodiments, a fluoride species
may be present at about 10 mol %, or about 5 mol %, or about 3 mol
%, or about 2 mol %, or about 1 mol % or about 0.5 mol %, or about
0.1 mol %, or about 0.05 mol %, or about 0.01 mol % relative to the
amount of imaging agent precursor. In some embodiments, a fluoride
species is isotopically enriched with .sup.18F. For example, in
some embodiments, the ratio of .sup.18F species to imaging agent
precursor may be selected to be about 1:1,000,000 or more, or about
1:500,000 or more, or about 1:250,000 or more, or about 1:100,000
or more, or about 1:50,000 or more, or about 1:25,000 or more, or
about 1:10,000 or more, about 1:5000 or more, about 1:3000 or more,
about 1:2000 or more, about 1:1000 or more, about 1:500 or more,
about 1:100 or more, about 1:50 or more, about 1:10 or more, about
1:5 or more, or, in some cases, about 1:1 or more.
[0548] In some embodiments, a nucleophilic fluorination reaction is
carried out in the presence of one or more solvents, for example,
an organic solvent, a non-organic solvent (e.g., an aqueous
solvent), or a combination thereof. In some embodiments, the
solvent is a polar solvent or a non-polar solvent. In some
embodiments, the solvent is an aqueous solution, such as water. In
some embodiments, the solvent comprises at least about 0.001%
water, at least about 0.01% water, at least about 0.1% water, at
least about 1% water, at least about 5%, at least about 10%, at
least about 20% water, at least about 30% water, at least about 40%
water, at least about 50% water, or greater. In some embodiments,
the solvent may comprise between about 0.1% and about 100% water,
about 1% to about 90%, about 1% to about 70%, about 1% to about
50%, or about 10% to about 50%. In some embodiments, the solvent
comprises no more than about 10% water, about 5% water, about 4%
water, about 3% water, about 2% water, about 1% water, or about
0.5% water. In some embodiments, the solvent comprises between
about 0.01% water and about 5% water, or between about 0.01% water
and about 2% water, or between about 0.1% water and about 0.2%
water.
[0549] Other examples of solvents useful in the methods include,
but are not limited to, non-halogenated hydrocarbon solvents (e.g.,
pentane, hexane, heptane, cyclohexane), halogenated hydrocarbon
solvents (e.g., dichloromethane, chloroform, fluorobenzene,
trifluoromethylbenzene), aromatic hydrocarbon solvents (e.g.,
toluene, benzene, xylene), ester solvents (e.g., ethyl acetate),
ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,
dimethoxyethane), and alcohol solvents (e.g., ethanol, methanol,
propanol, isopropanol, tert-butanol). Other non-limiting examples
of solvents include acetone, acetic acid, formic acid, dimethyl
sulfoxide, dimethyl formamide, acetonitrile, p-cresol, glycol,
petroleum ether, carbon tetrachloride, hexamethyl-phosphoric
triamide, triethylamine, picoline, and pyridine. In some
embodiments, a provided reaction is carried out in a polar solvent,
such as acetonitrile. In some embodiments, a solvent may be
selected so as to reduce and/or minimize the formation of side
products. In certain embodiments, a fluorination reaction is
carried out in MeCN as solvent. In certain embodiments, a
fluorination reaction is carried out in t-BuOH as solvent. In
certain embodiments, a fluorination reaction is carried out in a
mixture of MeCN and t-BuOH as solvent. In certain embodiments, a
fluorination reaction is carried out in DMF as solvent. In certain
embodiments, a fluorination reaction is carried out in DMSO as
solvent. In certain embodiments, a fluorination reaction is carried
out in THF as solvent.
[0550] In certain embodiments, an anhydrous .sup.18F-containing
solid, optionally comprising a reagent, may be contacted with a
solution of an imaging agent precursor (e.g., a tosylate
precursor), and the resulting solution is heated to an elevated
temperature for a select period of time. A solution may be, for
example, an acetonitrile solution. In other embodiments, a solution
of an .sup.18F species and reagent, if present, is contacted with a
solid imaging agent precursor or a solution of an imaging agent
precursor.
[0551] Some embodiments involve contacting an imaging agent
precursor with a fluoride species in a solution having a pH below
about 13, below about 12, or below about 11. In some cases, a
solution has a pH between about 8 and about 9, or between about 8
and about 10, or between about 7 and about 8. In certain
embodiments, a pH range for the fluorination reaction is greater
than about 6, or greater than about 7, or between and including
7-13, between and including 6-12, between and including 7-12,
between and including 8-12, between and including 9-12, and between
and including 10-12.
[0552] In some cases, a solution comprising a .sup.18F species,
imaging agent precursor, and, optionally, reagent, is heated to an
elevated temperature for a period of time. For example, a solution
may be heated to about 50.degree. C., about 60.degree. C., about
70.degree. C., about 80.degree. C., about 90.degree. C., about
100.degree. C., about 110.degree. C., about 120.degree. C., about
150.degree. C., about 170.degree. C., about 200.degree. C., about
225.degree. C., about 250.degree. C., or greater, for a period of
about 5 minutes or less, about 10 minutes or less, about 20 minutes
or less, about 30 minutes or less. It should be understood that
other temperatures and reaction times may be used. In some
embodiments, upon completion of the reaction, the reaction mixture
is cooled (e.g., to room temperature) and optionally diluted with a
solvent, such as water, or mixtures of solvents, such as
water/acetonitrile. In some embodiments, a reaction mixture is
heated to elevated temperatures to encourage evaporation of the
solvent (e.g., to about 95.degree. C.). In some embodiments, a
solution is heated to a temperature ranging from about
55-125.degree. C. In some cases, a solution is heated to about
65.degree. C., about 75.degree. C., about 85.degree. C., about
95.degree. C., about 105.degree. C., about 115.degree. C., or
greater. In some cases, a solution is placed under a reduced
pressure of about 100 mm Hg, about 125 mm Hg, about 150 mm Hg,
about 175 mm Hg, about 200 mm Hg, about 225 mm Hg, about 250 mm Hg,
about 275 mm Hg, about 300 mm Hg, about 325 mm Hg, about 350 mm Hg,
about 375 mm Hg, about 400 mm Hg, or greater. In some cases, a
solution is placed under a reduced pressure of about 100 mbar,
about 125 mbar, about 150 mbar, about 175 mbar, about 200 mbar,
about 225 mbar, about 250 mbar, about 275 mbar, about 280 mbar,
about 300 mbar, about 325 mbar, about 350 mbar, about 375 mbar,
about 400 mbar, about 450 mbar, about 500 mbar, or greater. Those
of ordinary skill in the art would be able to select and/or
determine conditions suitable for a particular process. In some
embodiments, a solution is concentrated to dryness under a flow of
inert gas at about 95.degree. C.
[0553] In some embodiments, upon completion of a fluorination
reaction, the resulting imaging agent is optionally subjected to
one or more purification steps. In some embodiments, an imaging
agent may be reconstituted in a solvent prior to purification
(e.g., by chromatography such as HPLC). In some cases, an imaging
agent is dissolved in water, acetonitrile, or combinations thereof.
In some embodiments, following formation of a solution comprising
an imaging agent and a solvent and prior to purification (e.g., by
HPLC), the solution is heated. In a particular embodiment, an
imaging agent is reconstituted in a water/acetonitrile mixture and
heated (e.g., to a temperature of about 90-100.degree. C.) for
about 1 minute, about 3 minutes, about 5 minutes, about 10 minutes,
about 20 minutes, about 30 minutes, or more. Following heating of
the mixture, the solution may be optionally cooled prior to
purification.
E4. Metal Chelation
[0554] In some embodiments, an imaging agent according to the
present invention does not contain a covalent-bound imaging moiety.
In some embodiments, a provided imaging agent comprises a chelator
associated with an imaging moiety (e.g., .sup.64Cu, .sup.89Zr,
.sup.99mTc, or .sup.111In). In some embodiments, a provided imaging
agent is formed via association of a chelator with an imaging
moiety. For example, in some embodiments, formation of a compound
of Formula (Ia) comprises associating the R.sup.0 group comprising
a chelator with an imaging moiety. Conditions for effecting
association of an imaging moiety with a chelator will depend on the
type of chelator being used and are well known in the art.
E5. Deprotection
[0555] In some embodiments, an imaging agent precursor and/or an
imaging agent is deprotected. For example, in embodiments wherein
the imaging agent precursor and/or imaging agent comprises a
protected nitrogen functional group (e.g., a protected guanidine),
the protected nitrogen functional group may be deprotected.
[0556] Those of ordinary skill in the art will be aware of suitable
conditions for deprotecting a protected nitrogen functional group
(e.g., a protected guanidine). The protecting groups may be remove
prior to, simultaneously, and/or subsequent formation of an imaging
agent from an imaging agent precursor. In some cases, the
deprotection occurs following formation of the imaging agent.
[0557] In some embodiments, suitable conditions comprise exposing a
compound comprising a protected nitrogen functional group (e.g.,
guanidine) to an acid. An acid may be added neat or in a solution
(e.g., such that the acid is at a concentration of about 0.1 M,
about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.75 M,
or about 1.0 M). In certain embodiments, a nitrogen-protecting
group is t-butyloxycarbonyl, and an acid used for deprotection is
trifluoroacetic acid. In certain embodiments, following
deprotection, a provided compound is a salt (e.g., a
trifluoroacetate salt).
[0558] In some embodiments, suitable conditions for deprotection
comprise acidic conditions. In certain embodiments, an acid is
provided at a ratio of about 2:1, about 1:1, about 1:2, about 1:3,
or about 1:4 compound:acid. In certain embodiments, the pH range
for deprotection of imaging agent precursors such as compounds of
Formula (VIII) (or alternatively of protected fluorinated imaging
agents of the invention) may be equal to or less than about 4,
including equal to or less than about 3, equal to or less than
about 2, and equal to or less than about 1.
[0559] In certain embodiments, deprotection conditions may comprise
one or more solvents. Non-limiting examples of solvents are
provided herein. A deprotection reaction may be carried out at any
suitable temperature, and in certain embodiments, a deprotection
reaction is carried out at room temperature or above room
temperature. The product of a deprotection reaction may be
analyzed, isolated, and/or purified using techniques known to those
of ordinary skill in the art (e.g., column chromatography, HPLC,
NMR, MS, IR, UV/Vis). In some embodiments, the product of a
deprotection reaction is isolated as a salt (e.g., via filtration,
crystallization). In certain embodiments, the salt is an ascorbate
salt. In certain embodiments, the salt is a formate salt. In some
embodiments, the salt is a citrate salt. In some embodiments, the
salt is a trifluoroacetate salt.
E6. Purification and Formulation
[0560] In some cases, the synthesis, purification, and/or
formulation of an imaging agent is performed using an automated
reaction system optionally comprising a cassette, wherein the
cassette comprises a synthesis module, a purification module,
and/or a formulation module. Automated reaction systems and
cassettes are described herein.
[0561] Purification and isolation may be performed using methods
known to those skilled in the art, including separation techniques
like chromatography, or combinations of various separation
techniques known in the art, for example, extractions,
distillation, and crystallization. In one embodiment, high
performance liquid chromatography (HPLC) is used with a solvent, or
mixture of solvents, as the eluent, to recover the product. In some
cases, the eluent includes a mixture of water and acetonitrile,
such as a 20:80 water:acetonitrile mixture. The content of water in
the eluent may vary from, for example, about 1% to about 30%. In
some cases, HPLC purification may be performed using a C18 column.
The product may be analyzed (e.g., by HPLC) to determine yield
(e.g., radiochemical yield) and/or radiochemical purity. The
radiochemical purity may be greater than about 50%, about 60%,
about 70%, about 80%, about 90%, about 95%, about 97%, about 98%,
about 99%, or more. The percent yield of a product may be greater
than 10%, greater than 20%, greater than 30%, greater than 40%,
greater than 50%, greater than about 60%, greater than about 70%,
greater than about 75%, greater than about 80%, greater than about
85%, greater than about 90%, greater than about 92%, greater than
about 95%, greater than about 96%, greater than about 97%, greater
than about 98%, greater than about 99%, or greater. In some
embodiments, the radiochemical yield ranges from 15-50%.
[0562] The product may be further processed using additional
purification techniques, such as filtration. In some cases, the
imaging agent is purified using HPLC, to produce a solution of HPLC
mobile phase and the imaging agent. The HPLC mobile phase may be
subsequently exchanged for a solution of ascorbic acid or a salt
thereof, and ethanol solution, by filtration through a C-18 resin
(e.g., C18 Sep-Pak.RTM. cartridge). In some embodiments, the
solution of the HPLC mobile phase and the imaging agent is filtered
through a C-18 resin, where the imaging agent remains on the resin
and the other components, such as acetonitrile and/or other
solvents or components, are removed via elution. The C-18 resin may
be further washed with a solution of ascorbic acid or a salt
thereof, and the filtrate discarded. To recover the purified
imaging agent, the C-18 resin is washed with a solvent, such as
ethanol, and the resulting solution is optionally further diluted
with an ascorbic acid solution or a salt thereof, as described
herein.
[0563] Optionally, the recovered product is combined with one or
more stabilizing agents, such as ascorbic acid or a salt thereof.
For example, a solution comprising the purified imaging agent may
be further diluted with a solution of ascorbic acid or a salt
thereof. As described herein, a formulation may be prepared via an
automated reaction system comprising a cassette.
[0564] In some cases, a solution comprising the imaging agent
product may be sterile filtered (e.g., using a 13 mm diameter,
Millipore, Millex PVDF 0.22 .mu.m sterilizing filter) into a
sterile product vial. The sterile product vial may be a
commercially available, pre-sterilized unit that is not opened
during the production process, as any imaging agents (or other
components) may be aseptically inserted through the septum prior to
use. Those of ordinary skill in the art would be able to select
suitable vials and production components, including commercially
available, pre-sterilized units comprising a 0.22 .mu.m pore size
membrane venting filter and quality control sampling syringes.
[0565] Following aseptic filtration, individual doses may be filled
in syringes, labeled, and shipped to a clinical site. Dosing
administration techniques, kits, cassettes, methods and systems
(e.g., automated reaction systems) for synthesis of the imaging
agent, and testing procedures are described herein. In some
embodiments, the product is dispensed into a 3 or 5 mL syringe and
labeled for distribution. Labels may be prepared at a radiopharmacy
and applied to a syringe shield and shipping container. Additional
labels may be provided in the shipping container for inclusion in
clinical site records.
F. Uses of Imaging Agents
[0566] In another aspect, the present invention provides methods of
imaging, including methods of imaging a subject that includes
administering a composition or formulation that includes an imaging
agent as described herein to the subject by injection, infusion, or
any other method of administration, and imaging a region of
interest of the subject. Regions of interest may include, but are
not limited to, the heart, a portion of the heart, the
cardiovascular system, cardiac vessels, blood vessels (e.g.,
arteries and/or veins), brain, pancreas, adrenal glands, other
organs, and tumors.
[0567] In some embodiments, methods of this disclosure include (a)
administering to a subject a composition that includes an imaging
agent as described herein, and (b) acquiring at least one image of
at least a portion of the subject. In some cases, the step of
acquiring employs positron emission tomography (PET) for
visualizing the distribution of the imaging agent within at least a
portion of the subject. As will be understood by those of ordinary
skill in the art, imaging using methods of this disclosure may
include full body imaging of a subject, or imaging of a specific
body region, organ, or tissue of the subject that is of interest.
For example, if a subject is known to have, or is suspected of
having myocardial ischemia, methods of this disclosure may be used
to image the heart of the subject. In some embodiments, imaging may
be limited to the heart or may include the heart and its associated
vasculature.
[0568] In some embodiments, imaging agents as described herein are
used to monitor and/or assess certain aspects of the sympathetic
nervous system (SNS). The SNS plays a role in normal cardiac
regulation and/or the pathogenesis of heart failure development
and/or progression. Generally, following myocardial insult (e.g.,
myocardial infarction, valve regurgitation, hypertension),
compensatory activation of the SNS is induced to help maintain
sufficient cardiac output. Sustained elevation of the cardiac SNS
can cause elevated cardiac norepinephrine (NE) release, down
regulation of the beta1 adrenergic receptor, and/or down regulation
of the NE transporter (NET), which can result in spillover of NE.
Elevated levels of NE can be attributed to cardiac myocyte
hypertrophy, fibroblast activation, collagen deposition, and/or
myocyte apoptosis, which can result in ventricle remodeling and/or
susceptibility to arrhythmia.
[0569] In some embodiments, assessment of the changes and/or the
presence of a neurotransmitter in a subject, and certain parameters
relating to the neurotransmitter provides feedback relating to
cardiac events. For example, assessment of NET in a subject can be
used to provide feedback relating to cardiac events and/or cardiac
exposure to NE. In some cases, the neurotransmitter is a monoamine
other than NE.
[0570] In some embodiments, the neurotransmitter is NE. Utilizing
an imaging agent that targets NET permits imaging of the location,
concentration, density, and/or distribution of NETs and also can be
used to detect changes in NETs over time, for example, by acquiring
a first NET image in a subject or region of a subject; obtaining a
subsequent NET image of the subject or the region of the subject
and comparing the first and subsequent images. Differences between
the images can provide information on the change in NET status in
the subject or region of the subject. Changes in a NET parameter
(e.g., location, density, concentration, and/or distribution) over
time may be assessed and correlated with disease onset,
progression, and/or regression. In some embodiments, a method
comprises administering a dose of a pharmaceutically acceptable
composition to a subject, and acquiring at least one image of a
portion of the subject, wherein the image allows for the assessment
and/or detection of NET in the subject. In some cases, the
detection comprises detection of the level (e.g., concentration) of
NET, detection of the density of NET, detection of NET function,
and/or detection of the localization of NET.
[0571] In some embodiments, changes in NET (e.g., density,
localization, concentration, function) may be used to assess the
presence and/or absence of a condition, disease, and/or disorder.
For example, in some cases, changes in NET may be used to assess
cardiac sympathetic innervation and/or myocardial sympathetic
function in a subject. For example, an increase or decrease in NET
concentration in a portion of the subject (e.g., heart) may
indicate the cardiac sympathetic innervation in that portion of the
subject. In some cases, subjects with impaired NET functions are
correlated with heart failure and/or rapid myocardial
reorganization.
[0572] In some embodiments, an imaging agent that targets NET may
also be used to observe, estimate, and/or quantify localized blood
flow to tissue. More specifically, there may be instances in which
the level of imaging agent (or radioactivity) observed in the
myocardium, is decreased compared to normal or below threshold.
There may be various causes of this decreased signal, one of which
may be reduced blood flow to and through the myocardium. In order
to determine the cause, the subject may be imaged using a different
imaging agent and/or a different imaging modality suitable for
detecting blood flow. Comparison of images obtained using the
different methods can reveal whether the decrease or absence of
signal from the imaging agent that targets NET is attributable to
blood flow rather than to a difference in NET level, activity and
the like. In other embodiments of the invention, the myocardium may
be imaged serially, for example immediately after administration of
the imaging agent, in order to observe movement of the imaging
agent into the heart. Such serial images should yield information
about blood flow through the heart. Later images are also obtained
as these reveal a more steady state of blood flow into and out of
the heart as well as blood retention in the heart. In this way,
alterations in global, local, or regional blood flow may be
distinguished from local or regional changes in NET density,
localization, concentration, and function as described above.
[0573] In some embodiments, an imaging agent that targets NET is
used to assess the ability of a therapeutic agent and/or treatment
to modify NET. For example, images acquired from a subject
administered an imaging agent before therapeutic treatment can be
compared to images acquired from the same subject after therapeutic
treatment of the subject to determine if the treatment has affected
the location, concentration, and/or density of NET for the subject.
Similarly, images at different times and/or before and after
treatment can be used to detect changes in NET in a subject over
time and/or with treatment.
[0574] In some aspects, global images (e.g., global NET images) are
acquired, and in other aspects of the invention, regional images
(e.g., regional NET images) are acquired following administration
of an imaging agent that targets NET, wherein a global image is an
image of all or substantially all of an organ (e.g., heart, kidney,
pancreas), and a regional image is an image of only a portion of an
organ. Images can be acquired using an image collection system such
as a PET system, a SPECT system, or any other suitable imaging
system.
[0575] In some embodiments, images may be acquired over a single
time interval, and in other embodiments, they may be acquired as a
series of images of the same or different acquisition durations
beginning either at the time of administration or at a later
time.
[0576] In some embodiments, the imaging agents may be used to image
cardiac innervation. In some embodiments, agents for imaging
cardiac innervation may be utilized in the assessment of heart
failure. In certain embodiments, the methods comprise an assessment
of heart failure progression in a subject, wherein the assessment
may include determination of the effectiveness of a treatment
regimen. In some cases, the treatment regimen may include a beta
blocker. In other cases, the treatment may require implantation of
a pacemaker or implantable cardioverter-defibrillator (ICD). In
certain embodiments, agents for imaging cardiac innervation may be
useful in the prediction of a time course for heart failure disease
progression.
[0577] In some embodiments, methods of diagnosing or assisting in
diagnosing a disease or condition, assessing efficacy of a
treatment of a disease or condition, or imaging of a subject with a
known or suspected cardiovascular disease or condition changing
sympathetic innervations are provided. A cardiovascular disease can
be any disease of the heart or other organ or tissue supplied by
the vascular system. The vascular system includes coronary
arteries, and all peripheral arteries supplying the peripheral
vascular system and the brain, as well as veins, arterioles,
venules, and capillaries. In cases, cardiac innervation may be
examined, as abnormalities in cardiac innervation have been
implicated in the pathophysiology of many heart diseases, including
sudden cardiac death, congestive heart failure, diabetic autonomic
neuropathy, myocardial ischemia, and cardiac arrhythmias. Other
non-limiting examples of cardiovascular diseases of the heart
include diseases such as coronary artery disease, myocardial
infarction, myocardial ischemia, angina pectoris, congestive heart
failure, cardiomyopathy (congenital or acquired), arrhythmia, or
valvular heart disease. In some embodiments, the methods disclosed
herein are useful for monitoring and measuring cardiac innervation.
For example, a method described herein can determine the presence
or absence of cardiac innervation. Conditions of the heart may
include damage, not brought on by disease but resulting from injury
e.g., traumatic injury, surgical injury. Methods described herein
can be used in some embodiments to determine global or regional
changes in cardiac sympathetic innervation.
[0578] In some cases, a subject whom an imaging agent as described
herein may be administered may have signs or symptoms suggestive of
a disease or condition associated with abnormalities in cardiac
innervation. In some cases, use of the imaging agent can be used to
diagnose early or pre-disease conditions that indicate that a
subject is at increased risk of a disease. Imaging methods
described herein may be used to detect cardiac innervation in
subjects already diagnosed as having a disease or condition
associated with abnormalities in cardiac innervation, or in
subjects that have no history or diagnosis of such a disease or
condition. In other instances, the methods may be used to obtain
measurements that provide a diagnosis or aid in providing a
diagnosis of a disease or condition associated with abnormalities
in cardiac innervation. In some instances, a subject may be already
undergoing drug therapy for a disease or condition associated with
abnormalities in cardiac innervation, while in other instances a
subject may be without present therapy for a disease or condition
associated with abnormalities in cardiac innervation. In some
embodiments, the method may be used to assess efficacy of a
treatment for a disease or condition. For example, the heart can be
visualized using contrast/imaging agents described herein before,
during, and/or after treatment of a condition affecting the heart
of a subject. Such visualization may be used to assess a disease or
condition, and aid in selection of a treatment regimen, e.g.
therapy, surgery, medications, for the subject.
[0579] In some embodiments, an imaging agent as described herein is
employed for determining the presence or absence of a tumor in a
subject. In some embodiments, the tumor is a NET-expressing tumor.
In some embodiments, an imaging agent of the invention is employed
for determining the response to therapy of a tumor in a subject.
Methods for determining the presence of a tumor and/or for
determining the response to therapy of a tumor in a subject can
follow the same or similar methods as described for methods of
imaging a subject.
[0580] Regional denervated myocardium may exhibit comparable
effective refractory period (ERP) to normal innervated area but
increased sensitivity to NE induced ERP shortening, or increased
ERP but similar sensitivity to NE induced ERP shortening. In
addition, heterogeneity of sympathetic innervation may render the
heart abnormal electrophysiologically and may increase sensitivity
to drugs which interact with cardiac ion channel conductance, such
as antiarrhythmic drugs. In some cases, the presence of cardiac
denervation in a subject may increase the subject's sensitivity
and/or cardiac risk to antiarrhythmic agent treatments that induce
electrophysiological changes. In some embodiments, an imaging agent
as described herein may be used to determine whether a subject has
an enhanced cardiac risk to an antiarrhythmic agent treatment,
including, for example, antiarrhythmic agents that induce
electrophysiological changes. For example, in some embodiments, the
images obtained from a subject using an imaging agent as described
herein may be used to aid in the selection of an antiarrhythmic
agent and/or may be used to determine an appropriate dose and/or
adjustment of a dose (e.g., increase or decrease) of an
antiarrhythmic agent for administration to the subject by
determining the presence, absence, and/or extent of cardiac
denervation. If cardiac denervation is present, an antiarrhythmic
agent which does not induce electrophysiological changes may be
administered and/or the dose of an antiarrhythmic agent which is
known to induce electrophysiological changes may be reduced. In
some embodiments, the electrophysiological change comprise QT
prolongation. In some embodiments, a reduced dose of an
antiarrhythmic agent may be determined via a dose titration,
wherein the subject is monitored during and/or following
administration of the drug to determine or assess the presence of
electrophysiological changes depending on the dose of the
antiarrhythmic agent.
[0581] Antiarrhythmic agents that induce electrophysiological
changes in the heart include, for example, agents known to block
ion channels (e.g., calcium-, sodium-, or potassium-channels).
Non-limiting examples of such agents include, but are not limited
to, dofetilide, ibutilide, amiodarone, sotalol, and dronedarone.
The invention contemplates the use of reduced doses of these agents
in some instances including for example where cardiac denervation
exists.
[0582] Antiarrhythmic agents that do not induce
electrophysiological changes in the heart and/or that induce
minimal, electrophysiological changes in the heart include, for
example, some beta-blockers. Non-limiting of such agents include,
but are not limited to, opranolol, esmolol, timolol, metoprolol,
atenolol, and bisoprolol. The invention contemplates the use of
these agents in some instances including for example where cardiac
denervation exists.
[0583] Other non-limiting examples of antiarrhythmic agent include
quinidine, procainamide, disopyramide, lidocaine, phenytoin,
mexiletine, tocainide, flecainide, propafenone, moricizine,
verapamil, diltiazem, adenosine, digoxin, and magnesium sulfate.
The invention contemplates the use of reduced doses of these agents
in some instances including for example where cardiac denervation
exists.
[0584] In some embodiments, an imaging agent as described herein
may be used to determine a subject's cardiac risk associated with
innervation dysfunction.
[0585] In some embodiments, an imaging agent as described herein is
used as an imaging agent in combination with positron emission
tomography (PET) or with other imaging methods including, but not
limited to, single photon emission computed tomography (SPECT)
imaging. In some cases, PET imaging may be used in cardiac
sympathetic neuronal imaging in a subject following administration
of the imaging agent to the subject. For example, the imaging agent
may be administered to a subject and imaged in the subject using
PET. As will be known to those of ordinary skill in the art, PET is
a non-invasive technique that allows serial images and measurements
to be obtained in a single subject over a time period. PET imaging
used may be carried out using known systems, methods, and/or
devices. In some embodiments, PET imaging is conducted using a
cardiac imaging system. A cardiac imaging system may include PET
imaging functionality; and a control unit configured to drive the
imaging functionality to perform a PET imaging procedure on a
portion of the subject of interest before, during, and/or after
administration of the imaging agent to the subject. In some cases,
the control unit is configured to drive the imaging functionality
to perform a PET imaging procedure. The control unit may comprise a
computer system and/or software. In such a case, the computer
system may be programmed or configured to execute the required
methods for acquiring and/or analyzing the images. Further, the
system may include a data storage device that is readable by a
machine, embodying a set of instructions executable by the machine
to perform the required methods of acquiring and/or analyzing the
images.
[0586] Imaging systems (e.g., cardiac imaging systems) and
components thereof will be known to those of ordinary skill in the
art. Many imaging systems and components (e.g., cameras, software
for analyzing the images) are known and commercially available, for
example, a Siemens Biograph-64 scanner or other scanner suitable
for imaging. In some embodiments, image data is acquired in list
mode, and such list data may be used to create static, dynamic, or
gated images. An appropriate period of time for acquiring images
can be determined by one of ordinary skill in the art, and may vary
depending on the cardiac imaging system, the imaging agent (e.g.,
amount administered, composition of the imaging agent, subject
parameters, area of interest). As used herein, a "period of
acquiring images" or an"image acquisition period" may be a period
of time for obtaining a single continuous image, and/or may be a
period during which one or more individual discrete images are
obtained. Thus, a period of image acquisition can be a period
during which one or more images of one or more regions of a subject
are acquired.
[0587] The term "list mode," as used herein, is given its ordinary
meaning in the art. With respect to PET, list mode is a form in
which the data that is used to create a PET image can be initially
collected. In list mode, each of or a portion of coincidence events
(i.e., each of a portion of detected photon pairs) generates an
entry in a list of events. Each entry includes various information
including, but not limited to, which detectors were involved, the
energy of the photons detected, the time of detection, and/or
whether there was a cardiac gating mark. The information can be
converted into one or more images by the process of rebinning
and/or histogramming, in which all or a portion of the events for
each pair of detectors is summed, followed by the resulting set of
projections (e.g., in the form of a sinogram wherein for each
slice, each horizontal line in the sinogram represents the
projections for coincidences at a given angle). List mode may be
contrasted with "histogram mode" in which the summations are
completed during acquisition so that the only raw data is the
sinogram. In some embodiments, histogram mode may be employed.
[0588] In embodiments where more than one type of imaging agent is
adminstered to a subject, a second imaging agent may be
administered to the subject, followed by acquisition of at least
one second image. The second imaging agent may be administered to
the subject after any suitable period of time has elapsed following
administration of the first imaging agent and/or acquisition of the
at least one first image. In some cases, the time between
administration of the first imaging agent and the second imaging
agent is about between about 1 minute and about 48 hours, or
between about 1 hour and about 48 hours, or between about 1 minute
and about 24 hours, or between about 1 hour and 24 hours, or
between about 10 minutes and about 12 hours, or between about 30
minutes and about 8 hours, or between about 30 minutes and about 6
hours, or between 30 minutes and about 3 hours, or between about 30
minutes and about 2 hours, or between about 1 hour and about 6
hours. In some cases, the time between administration of the first
imaging agent and the second imaging agent is at least about or
about 1 minute, at least about or about 5 minutes, at least about
or about 10 minutes, at least about or about 15 minutes, at least
about or about 20 minutes, at least about or about 30 minutes, at
least about or about 45 minutes, at least about or about 60
minutes, at least about or about 90 minutes, at least about or
about 2 hours, at least about or about 3 hours, at least about or
about 4 hours, at least about or about 5 hours, at least about or
about 6 hours, at least about or about 8 hours, at least about or
about 10 hours, at least about or about 12 hours, at least about or
about 18 hours, at least about or about 24 hours, or greater.
[0589] Those of ordinary skill in the art will be aware of suitable
periods of time for acquiring an image. In some embodiments, a
period of image acquisition after administration of an imaging
agent to a subject may be between about 0 seconds and about 60
minutes, between about 1 minute and about 30 minutes, between about
5 minutes and about 20 minutes, or at least about 1 minute, at
least about 3 minutes, at least about 5 minutes, at least about 6
minutes, at least about 7 minutes, at least about 8 minutes, at
least about 9 minutes, at least about 10 minutes, at least about 15
minutes, at least about 20 minutes, at least about 30 minutes, at
least about 45 minutes, at least about 60 minutes, at least about
90 minutes, at least about 2 hours, at least about 3 hours, at
least about 4 hours, at least about 5 hours, or greater. In some
embodiments, a period of image acquisition may begin prior to
administration of the imaging agent to a subject. For example, a
period of image acquisition may begin more than about 10 minutes,
about 5 minutes, about 4, minutes, about 3 minutes, about 2
minutes, about 1 minute, or about 0 minutes prior to administration
of the imaging agent to the subject. In some embodiments, imaging
may be continuous over the imaging period of time, or images may be
acquired at intervals such as in periodic or gated imaging.
[0590] In some embodiments, an imaging agent as described herein is
provided in ethanol/ascorbic acid. In some embodiments, an imaging
agent as described herein is provided as a composition comprising
ethanol, ascorbic acid or a salt thereof (e.g., as sodium
ascorbate), and water. In some cases, the composition comprises
less than or about 20 weight % ethanol, less than or about 15
weight % ethanol, less than or about 10 weight % ethanol, less than
or about 8 weight % ethanol, less than or about 6 weight % ethanol,
less than or about 5 weight % ethanol, less than or about 4 weight
% ethanol, less than or about 3 weight % ethanol, or less ethanol.
In some cases, the composition comprises less than or about 100
mg/mL, less than or about 75 mg/mL, less than or about 60 mg/mL,
less than or about 50 mg/mL, less than or about 40 mg/mL, less than
or about 30 mg/mL, less than or about 20 mg/mL, less than or about
10 mg/mL, or less ascorbic acid or a salt thereof (e.g., sodium
ascorbate) in water. A non-limiting, exemplary formulation of an
imaging agent includes about 5 weight % ethanol and about 50 mg/ml
ascorbic acid. As will be understood by those of ordinary skill in
the art, in the presence of ascorbic acid, at least a portion of
the imaging may be present as the ascorbate salt of the imaging
agent.
[0591] Additional components of a composition comprising an imaging
agent as described herein may be selected depending on the mode of
administration to the subject. Various modes of administration will
be known to one of ordinary skill in the art which effectively
deliver the pharmacological agents as described herein to a desired
tissue, cell, organ, or bodily fluid. In some embodiments, an
imaging agent as described herein is administered intravenously
(e.g., intravenous bolus injection) using methods known to those of
ordinary skill in the art. As used herein, a dose that is
"administered to a subject" means an amount of the imaging agent
that enters the body of the subject.
[0592] In some embodiments, the volume of the administered imaging
agent may be between 0 and about 3 mL, between about 3 mL and about
5 mL, or between about 5 mL and about 10 mL.
[0593] In some embodiments, due to factors such as partial
retention of imaging agent in a syringe, tubing, needles, or other
equipment used to administer the imaging agent to a subject, the
amount of an imaging agent that is measured or determined to be in
the a syringe or other equipment prepared for administration may be
more than the amount in the dose that is administered to the
subject. In some embodiments, an injection of an imaging agent is
followed by a flushing injection of normal saline into the subject,
using the same tubing, needle, port, etc., used for administration
of the imaging agent.
[0594] Flushing may be performed immediately following
administration of the imaging agent, or up to about 1 min, about 2
min, about 3 min, about 5 min, or more after the administration. In
some embodiments, flushing may be performed between 0 and 10
seconds, between 10 seconds and 25 seconds, or between 25 seconds
and 60 seconds.
[0595] The volume of saline or other agent for flushing may be up
to about 5 ml, about 6 ml, about 7 ml, about 8 ml, about 9 ml,
about 10 ml, about 15 ml, about 20 ml, or more. As will be
understood by those of ordinary skill in the art, in embodiments
where the imaging agent is administered using a syringe or other
container, the true amount of imaging agent administered to the
subject may be corrected for any imaging agent that remains in the
container. For example, the amount of radioactivity remaining in
the container, and tubing and needle or delivery instrument that
carried the imaging agent from the container and into the subject
can be determined after the imaging agent has been administered to
the subject and the difference between the starting amount of
radioactivity and the amount remaining after administration
indicates the amount that was delivered into the subject. In some
cases, the container or injection device (e.g., catheter, syringe)
may be rinsed with a solution (e.g., saline solution) following
administration of the imaging agent.
[0596] A composition of an imaging agent as described herein for
injection may be prepared in an injection syringe. Imaging agents
may be prepared by a radiopharmacy (e.g., using the methods
described herein) and/or a PET manufacturing center and provided to
a health-care professional for administration. A dose of the
imaging agent may be diluted with saline (e.g., as described
herein), if needed to obtain a practical dose volume. For example,
if the activity concentration of the imaging agent is so high that
only about 0.1 mL is needed for an appropriate dose for a subject,
the solution can be diluted, e.g., with sterile saline, so the
syringe contains about 0.5 ml to about 6 ml or more ml of the
imaging agent solution for administration. In some embodiments, an
injection volume for the imaging agent is between about 0.5 and
about 5 ml, about 1 and about 4 ml, about 2 and about 3 ml, at
least about 0.5 ml, about 1 ml, about 2 ml, about 3 ml, about 4 ml,
about 5 ml, about 6 ml, about 7 ml, about 8 ml, about 9 ml, about
10 ml, or more. Those of skill in the art will recognize how to
dilute an imaging agent to produce a sufficient dose volume for
administration. In some aspects, an imaging agent is provided in a
container such as a vial, bottle, or syringe, and may be
transferred, as necessary, into a suitable container, such as a
syringe for administration.
[0597] Components of a composition comprising an imaging agent as
described herein may be selected depending on the mode of
administration to the subject. Various modes of administration that
effectively deliver imaging agents as described herein to a desired
tissue, cell, organ, or bodily fluid will be known to one of
ordinary skill in the art. In some embodiments, the imaging agent
is administered intravenously (e.g., intravenous bolus injection)
using methods known to those of ordinary skill in the art.
[0598] The useful dosage of the imaging agent to be administered
and the particular mode of administration will vary depending upon
such factors as age, weight, and particular region to be imaged, as
well as the particular imaging agent used, the diagnostic use
contemplated, and the form of the formulation, for example,
suspension, emulsion, microsphere, liposome, or the like, as
described herein, and as will be readily apparent to those skilled
in the art.
[0599] Based on dosing studies, the desirable maximum dose
administered to a subject may be based on determining the amount of
imaging agent(s) as described herein, which limits the radiation
dose to about 5 rem to the critical organ (e.g., urinary bladder)
and/or about 1 rem effective dose (ED) or lower, as will be
understood by those of ordinary skill in the art. In embodiments
where more than one imaging agent is administered to the subject,
the desirable maximum dose administered to a subject may be based
on determining the amounts of the first imaging agent and/or the
second imaging agent, which limits the total radiation dose to
about 5 rem to the critical organ (e.g., urinary bladder) and/or
about 1 rem effective dose (ED) or lower. In some embodiments, a
desirable dose of imaging agent(s) may be less than or equal to
about 50 mCi, less than or equal to about 40 mCi, less than or
equal to about 30 mCi, less than or equal to about 20 mCi, less
than or equal to about 15 mCi, less than or equal to about 14 mCi,
less than or equal to about 13 mCi, less than or equal to about 12
mCi, less than or equal to about 11 mCi, or less than or equal to
about 10 mCi over a period of time of up to about 10 minutes, about
30 minutes, about 1 hour, about 2 hours, about 6 hours, about 12
hours, about 24 hours, or about 48 hours. In some embodiments, the
dose of each imaging agent administered per session or day is about
1 mCi, about 2 mCi, about 3 mCi, about 4 mCi, about 5 mCi, about 6
mCi, about 7 mCi, about 8 mCi, about 9 mCi, about 10 mCi, about 11
mCi, about 12 mCi, about 13 mCi, about 14 mCi, or any range
therein.
[0600] In some embodiments, studies may also be performed using an
agent specialized for tissue blood flow using methods known to
those familiar with the art. The images from these studies may then
be used to distinguish abnormalities seen in images due to changes
in NET from those due to alterations of global, regional or local
blood flow.
G. Methods for Assessing Perfusion and Innervation Mismatch
[0601] In some embodiments, methods and compositions for assessing
perfusion and innervation mismatch in a portion of a subject, for
example, a human subject, are provided. In some embodiments, the
methods and compositions may be employed for assessing perfusion
and innervation mismatch in a subject following a tissue insult. In
some embodiments, the tissue insult is a cardiac insult, for
example, a myocardial infarction. In some embodiments, the portion
of the subject being assessed for perfusion/innervation mismatch is
the heart or a portion of the heart. Other regions of interest may
include, but are not limited to, the cardiovascular system, cardiac
vessels, blood vessels (e.g., arteries and/or veins), brain,
pancreas, adrenal glands, other organs, and tumors.
[0602] In some embodiments, a method comprises administering to a
subject a first imaging agent and acquiring at least one first
image of a portion of the subject. A second imaging agent is then
administered to the subject and at least one second image of the
same portion of the subject is acquired. In some embodiments, the
first imaging agent is employed to image perfusion (e.g., cardiac
perfusion), and the second imaging agent is employed to image
innervation (e.g., cardiac innervation). In other embodiments, the
first imaging agent is employed to image innervation and the second
imaging agent is employed to image perfusion. The region of
mismatch of perfusion and innervation is based at least in part on
the first image and the second image. Imaging agents which may be
used to image innervation or perfusion will be known to those of
ordinary skill in the art and are described herein (e.g., see
Sections G1 and G2).
[0603] In some embodiments, the regional mismatch of perfusion and
innervation in a portion of a subject may be determined by
determining the difference in uptake of the first imaging agent
versus uptake of the second imaging agent in a portion of the
subject (e.g., the heart). As a non-limiting example, the first
imaging agent may be an imaging agent which is employed for imaging
perfusion (e.g., cardiac perfusion). Accordingly, the areas in the
at least one first image which indicate uptake of the first imaging
agent are areas in which there is perfusion. The second imaging
agent may be an imaging agent which is employed for imaging
innervation (e.g., cardiac innervation). The areas in the at least
one second image which indicate uptake of the second imaging agent
are the areas in which there is innervation. The difference in the
areas of uptake between the first image and the second image are
areas in which there is perfusion (e.g., as indicated by uptake of
the first imaging agent) but in which there is decreased or no
innervation (e.g., as indicated by lack of or decreased uptake of
the second imaging agent).
[0604] Generally, the mismatch is the observed difference in the
level of innervation and the level of perfusion in a portion of the
subject. The mismatch between innervation and perfusion areas, as
determined in accordance with the invention, may be expressed or
quantified using any suitable technique. In some embodiments, the
difference between uptake of the first imaging agent and the uptake
of the second imaging agent may be expressed as a percent of defect
size in a portion of the subject. For example, in embodiments where
the portion of the subject is a the heart or a portion of the
heart, the difference between uptake of the first imaging agent and
the uptake of the second imaging agent may be expressed as the
percent defect size in the left ventricle (LV). In some cases, the
difference between the uptake of the first imaging agent and the
second imaging agent may be expressed as a ratio. In some
embodiments, the mismatch may be determined and/or quantified using
polar maps of the images. In some embodiments, the defect areas for
perfusion and/or innervation may be defined as those regions in
which perfusion and/or innervation is less than 50% of the maximum
value of perfusion and/or innervation in a portion of a subject. In
some embodiments, the mismatch may be determined by subtracting the
perfusion defect from the innervation defect or otherwise
quantifying the difference between the perfusion and innervation
areas. In some embodiments, the mismatch may be determined using
software (e.g., MunichHeart.TM.; see, for example, Nekolla et al.,
Eur J Nucl Med 1998; 25(9):1313-21; Haas et al., J Am Coll Cardiol
1997; 30(7):1693-700; Nekolla et al., J Nucl Med 1999; 40(5):5P;
Hattori, et al., Europ. J. Nucl. Med. 2001; 28:221-229; Klein et
al., Circulation 105: 162-167 (2002); Ibrahim et al., J. Am. Coll.
Cardiol. 2000; 6; 39(5):864-70).
[0605] Those of ordinary skill in the art may be aware of suitable
methods and techniques for imaging a subject, for example, a human
subject In some embodiments, methods of imaging comprise (a)
administering to a subject a composition that includes an imaging
agent, and (b) acquiring at least one image of at least a portion
of the subject. In some cases, the step of acquiring an image
employs positron emission tomography (PET) for visualizing the
distribution of the imaging agent within at least a portion of the
subject. As will be understood by those of ordinary skill in the
art, imaging methods may include full body imaging of a subject, or
imaging of a specific body region, organ, or tissue of the subject
that is of interest. For example, if a subject is known to have, or
is suspected of having a cardiac insult (e.g., myocardial
infarction), the methods of this disclosure may be used to image
the heart of the subject. In some embodiments, imaging may be
limited to the heart or may include the heart and its associated
vasculature. Regions of interest may include, but are not limited
to, the heart, a portion of the heart, the cardiovascular system,
cardiac vessels, blood vessels (e.g., arteries and/or veins),
brain, pancreas, adrenal glands, other organs, tumors, and other
vascularized soft tissues. A particular region of interest is the
heart or a portion of the heart.
[0606] In some embodiments, the mismatch is determined in a subject
following a tissue insult. In such embodiments, the portion of the
subject being imaged may be the portion of the subject that
sustained the tissue insult and/or that was affected by the tissue
insult. In some embodiments, the tissue insult is an insult which
results in denervation of the tissue. In some embodiments, the
tissue insult is an insult which results in a perfusion defect
and/or denervation of the tissue. In some embodiments, the tissue
insult is an insult which results in a perfusion defect and
denervation of the tissue. In some embodiments, the tissue insult
is a cardiac insult. In some embodiments, the cardiac insult is a
myocardial infarction, congestive heart failure, diabetic autonomic
neuropathy, myocardial ischemia, and cardiac arrhythmias. Those of
ordinary skill in the art will be aware of other tissues which may
have an innervation defect including, for example, sympathetically
innervated tissues. In some cases, the tissue is a tissue which
expresses NET. Non-limiting examples of tissues which express NET
include pancreas, adrenal glands, thyroid, and tumors (e.g.,
neuroendocrine tumors, pheochromocytoma tumors). Non-limiting
examples of tissue insults include diseases which affect the tissue
(e.g., autoimmune disease (e.g., Graves disease), diabetes,
hyperthyroidism, hypothyroidism, acute pancreatitis, etc.), a tumor
in the tissue, and/or trauma of the tissue (e.g., blunt force
trauma, iatrogenic injury). It should be understood, that while
much of the following discussion focuses on the heart or a portion
of the heart and/or a tissue insult comprising a cardiac insult
(e.g., myocardial infarction), this is by no means limiting, and
the invention contemplates imaging and assessing mismatch in other
tissues and regions of the body, and those of ordinary skill in the
art will be able to apply the teachings herein to other tissues
and/or tissue insults.
[0607] The mismatch between innervation and perfusion may be
determined at any suitable time. In some embodiments, the mismatch
is determined at a single time point following a tissue insult
(e.g., myocardial infarction). In some cases, the mismatch is
determined at a time point near to the time at which the tissue
insult occurred. Without wishing to be bound by theory, determining
the mismatch at a time point close to the time at which the tissue
insult occurred may provide a better indication of the treatment
and/or diagnosis for the subject as the tissue may reinnervate over
time. In some cases, the difference in the mismatch is determined
within about 6 months, about 5 months, about 4 months, about 3
months, about 2 months, about 1 month, about 4 weeks, about 3
weeks, about 2 weeks, about 1 week, about 7 days, about 6 days,
about 5 days, about 4 days, about 3 days, about 2 days, about 1
days, about 24 hours, about 20 hours, about 18 hours, about 16
hours, about 14 hours, about 12 hours, about 10 hours, about 8
hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours,
about 2 hours, about 1 hour, about 50 minutes, about 40 minutes,
about 30 minutes, about 20 minutes, about 10 minutes, about 5
minutes, about 4 minutes, about 3 minutes, about 2 minutes, or
about 1 minute of the tissue insult. In some cases, the mismatch is
determined within 4 weeks of the tissue insult. In some cases, the
mismatch is determined within between about 1 week and about 6
months, between about 1 week and about 5 months, between about 1
week and about 4 months, between about 1 week and about 3 months,
between about 1 week and about 2 months, between about 1 week and
about 1 month, between about 1 week and about 4 weeks, between
about 2 weeks and about 2 months, between about 2 weeks and about 6
weeks, or between about 2 weeks and about 4 weeks of the tissue
insult.
[0608] In other embodiments, the mismatch may be determined at
multiple time points following a tissue insult (e.g., myocardial
infarction). In some cases, the change in the mismatch over time
may be useful in determining a course of treatment and/or a
diagnosis following a tissue insult. In some cases, the change or
lack of change in mismatch over time may indicate the effectiveness
or lack of effectiveness, respectively, of a course of treatment
being administered to the subject. For example, a decrease in the
region of mismatch over time may indicate reinnervation of the
tissue, and thus, may indicate that the course of treatment may be
effective. As another example, a lack of change in the region of
mismatch over time may indicate lack of reinnervation of the tissue
and thus, the course of treatment that the subject is undergoing is
not effective and/or another course of treatment may be warranted
and/or the treatment should be continued. The region of mismatch
may be determined 2 times, 3 times, 4 times, 5 times, 6 times, 8
times, 10 times, or 12 times within about 4 weeks, about 2 months,
about 3 months, about 4 months, about 5 months, about 6 months,
about 7 months, about 8 months, about 9 months, about 10 months,
about 11 months, about 1 year, about 2 years, about 3 years, about
4 years, or about 5 years following the tissue insult (e.g.,
myocardial infarction). The mismatch may be monitored at regular
frequency or irregular frequency.
[0609] In some embodiments, methods of diagnosing or assisting in
diagnosing a disease or condition, assessing efficacy of a
treatment of a disease or condition, or imaging of a subject with a
known or suspected cardiovascular disease or condition changing
sympathetic innervations are provided. A cardiovascular disease can
be any disease of the heart or other organ or tissue supplied by
the vascular system. The vascular system includes coronary
arteries, and all peripheral arteries supplying the peripheral
vascular system, as well as veins, arterioles, venules, and
capillaries. In cases where cardiac innervation and cardiac
perfusion are examined, differences in cardiac innervation and
perfusion may be implicated in the pathophysiology of many heart
diseases, including sudden cardiac death, congestive heart failure,
diabetic autonomic neuropathy, myocardial ischemia, and cardiac
arrhythmias. In some embodiments, the methods disclosed herein are
useful for monitoring and measuring mismatch between cardiac
innervation and perfusion. Methods described herein can be used in
some embodiments to determine global or regional changes in
differences between cardiac innervation and perfusion.
[0610] In some cases, a subject whom an imaging agent as described
herein is administered has signs or symptoms suggestive of a
disease or condition associated with a mismatch in innervation and
perfusion. Imaging methods described herein may be used to detect
innervation and/or perfusion in subjects already diagnosed as
having a disease or condition associated with a mismatch in
innervation and perfusion, or in subjects that have no history or
diagnosis of such a disease or condition. In other instances, the
methods is used to obtain measurements that provide a diagnosis or
aid in providing a diagnosis of a disease or condition associated
with a mismatch in innervation and perfusion. In some instances, a
subject is already undergoing drug therapy for a disease or
condition associated with a mismatch in innervation and perfusion,
while in other instances a subject is without present therapy for a
disease or condition associated with a mismatch in innervation and
perfusion. In some embodiments, the method is used to assess
efficacy of a treatment for a disease or condition. For example,
the heart can be visualized using contrast/imaging agents described
herein before, during, and/or after treatment of a condition
affecting the heart of a subject. Such visualization may be used to
assess a disease or condition and aid in selection of a treatment
regimen, e.g. therapy, surgery, or medication, for the subject.
[0611] In some embodiments, an imaging agent as described herein is
used as an imaging agent in combination with positron emission
tomography (PET) or with other imaging methods including, but not
limited to, single photon emission computed tomography (SPECT)
imaging. In some cases, PET imaging is used in innervation and/or
perfusion imaging in a subject following administration of an
imaging agent to the subject. For example, the imaging agent may be
administered to a subject and imaged in the subject using PET. As
will be known to those of ordinary skill in the art, PET is a
non-invasive technique that allows serial images and measurements
to be obtained in a single subject over a time period. PET imaging
used may be carried out using known systems, methods, and/or
devices, as described herein. In some embodiments, PET imaging is
conducted using a cardiac imaging system. A cardiac imaging system
may include PET imaging functionality; and a control unit
configured to drive the imaging functionality to perform a PET
imaging procedure on a portion of the subject of interest before,
during, and/or after administration of the imaging agent to the
subject. In some cases, the control unit is configured to drive the
imaging functionality to perform a PET imaging procedure. The
control unit may comprise a computer system and/or software. In
such a case, the computer system may be programmed or configured to
execute the required methods for acquiring and/or analyzing the
images. Further, the system may include a data storage device that
is readable by a machine, embodying a set of instructions
executable by the machine to perform the required methods of
acquiring and/or analyzing the images.
G1. Perfusion Imaging Agents
[0612] Some embodiments of the present invention comprise an
imaging agent for imaging perfusion (e.g., cardiac perfusion).
Those of ordinary skill in the art will be aware of imaging agents
which are capable of imaging perfusion.
[0613] In some embodiments, an imaging agent for imaging perfusion
(e.g., cardiac perfusion) may be a Complex-1 inhibitor. Complex 1
("MC-1") is a membrane-bound protein complex of 46 dissimilar
subunits. This enzyme complex is one of three energy-transducing
complexes that constitute the respiratory chain in mammalian
mitochondria. This NADH-ubiquinone oxidoreductase is the point of
entry for the majority of electrons that traverse the respiratory
chain, eventually resulting in the reduction of oxygen to water (Q.
Rev. Biophys. 1992, 25, 253-324). Mitochondria are
membrane-enclosed organelles distributed through the cytosol of
most eukaryotic cells. Mitochondria are especially concentrated in
myocardial tissue. Examples of inhibitors of MC-1 include deguelin,
piericidin A, ubicidin-3, rolliniastatin-1, rolliniastatin-2
(bullatacin), capsaicin, pyridaben, fenpyroximate, amytal, MPP+,
quinolines, and quinolones (BBA 1998, 1364, 222-235). Studies have
shown that interrupting the normal function of mitochondria could
advantageously concentrate certain compounds in the mitochondria,
and hence in the mitochondria-rich myocardial tissue. Compounds
that include an imaging moiety (e.g., .sup.18F) can be useful in
determining such a build-up of compounds and may be useful for
imaging perfusion. Accordingly, in some embodiments, an imaging
agent for imaging perfusion (e.g., cardiac perfusion) binds to the
mitochondrial Complex I of the electron transport chain with high
affinity (e.g., the imaging agent may exhibit selective uptake to
the heart due to the high density of mitochondria in the
myocardium).
[0614] In some embodiments, an imaging agent for imaging perfusion
comprises the formula:
##STR00322##
wherein:
[0615] J is selected from the group consisting of N(R.sup.28), S,
O, C(.dbd.O), C(.dbd.O)O, NHCH.sub.2CH.sub.2O, a bond, and
C(.dbd.O)N(R.sup.27);
[0616] when present, K is selected from the group consisting of
hydrogen, alkoxyalkyl optionally substituted with an imaging
moiety, alkyloxy optionally substituted with an imaging moiety,
aryl optionally substituted with an imaging moiety, C.sub.1-C.sub.6
alkyl optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety;
[0617] when present, L is selected from the group consisting of
hydrogen, alkoxyalkyl optionally substituted with an imaging
moiety, alkyloxy optionally substituted with an imaging moiety,
aryl optionally substituted with an imaging moiety, C.sub.1-C.sub.6
alkyl optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety;
[0618] M is selected from the group consisting of hydrogen,
alkoxyalkyl optionally substituted with an imaging moiety, alkyloxy
optionally substituted with an imaging moiety, aryl optionally
substituted with an imaging moiety, C.sub.1-C.sub.6 alkyl
optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety; or
[0619] L and M, together with the atom to which they are attached,
may form a three-, four-, five-, or six-membered carbocyclic
ring;
[0620] Q is halo or haloalkyl;
[0621] n is 0, 1, 2, or 3;
[0622] R.sup.21, R.sup.22, R.sup.27, and R.sup.28 are independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl optionally
substituted with an imaging moiety, and an imaging moiety;
[0623] R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
selected from hydrogen, halogen, hydroxyl, alkyloxy,
C.sub.1-C.sub.6 alkyl optionally substituted with an imaging
moiety, and an imaging moiety;
[0624] R.sup.29 is C.sub.1-C.sub.6 alkyl optionally substituted
with an imaging moiety; and
[0625] Y is selected from the group consisting of a bond, carbon,
and oxygen;
[0626] provided that when Y is a bond, K and L are absent, and M is
selected from the group consisting of aryl optionally substituted
with an imaging moiety and heteroaryl optionally substituted with
an imaging moiety; and provided that when Y is oxygen, K and L are
absent, and M is selected from hydrogen, alkoxyalkyl optionally
substituted with an imaging moiety, aryl optionally substituted
with an imaging moiety, C.sub.1-C.sub.6 alkyl optionally
substituted with an imaging moiety, and heteroaryl optionally
substituted with an imaging moiety;
[0627] provided that at least one imaging moiety is present in the
compound. In some embodiments, the imaging moiety is .sup.18F.
[0628] In some cases, J is selected from N(R.sup.27), S, O,
C(.dbd.O), C(.dbd.O)O, NHCH.sub.2CH.sub.2O, a bond, or
C(.dbd.O)N(R.sup.27). In some cases when present, K is selected
from hydrogen, alkoxyalkyl optionally substituted with an imaging
moiety, alkyloxy optionally substituted with an imaging moiety,
aryl optionally substituted with an imaging moiety, C.sub.1-C.sub.6
alkyl optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety. In some cases, when present, L is selected from hydrogen,
alkoxyalkyl optionally substituted with an imaging moiety, alkyloxy
optionally substituted with an imaging moiety, aryl optionally
substituted with an imaging moiety, C.sub.1-C.sub.6 alkyl
optionally substituted with an imaging moiety, heteroaryl
optionally substituted with an imaging moiety, and an imaging
moiety. In some cases, M is selected from hydrogen, alkoxyalkyl
optionally substituted with an imaging moiety, alkyloxy optionally
substituted with an imaging moiety, aryl optionally substituted
with an imaging moiety, C.sub.1-C.sub.6 alkyl optionally
substituted with an imaging moiety, heteroaryl optionally
substituted with an imaging moiety, and an imaging moiety. In some
cases, L and M, together with the atom to which they are attached,
form a three- or four-membered carbocyclic ring. In some cases Q is
halo or haloalkyl. In some cases, n is 0, 1, 2, or 3. In some
cases, R.sub.21, R.sub.22, R.sup.23, R.sup.24, R.sup.25, R.sup.26,
and R.sup.27 are independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl optionally substituted with an imaging
moiety, and an imaging moiety. In some cases R.sup.29 is
C.sub.1-C.sub.6 alkyl optionally substituted with an imaging
moiety. In some cases, Y is selected from a bond, carbon, and
oxygen; provided that when Y is a bond, K and L are absent and M is
selected from aryl and heteroaryl; and provided that when Y is
oxygen, K and L are absent and M is selected from hydrogen,
alkoxyalkyl optionally substituted with an imaging moiety, aryl,
C.sub.1-C.sub.6 alkyl optionally substituted with an imaging
moiety, and heteroaryl.
[0629] In some cases, J is O. In some cases R.sup.29 is methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, each may
be optionally substituted with an imaging moiety. In certain
embodiment, R.sup.29 is t-butyl. In some cases, Q is chloro. In
some cases, all of R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, R.sup.26, and R.sup.27 are hydrogen. In some cases, Y is
carbon, K and L are hydrogen, and M is alkoxyalkyl optionally
substituted with an imaging moiety, alkyloxy optionally substituted
with an imaging moiety, aryl optionally substituted with an imaging
moiety, C.sub.1-C.sub.6 alkyl optionally substituted with an
imaging moiety, heteroaryl optionally substituted with an imaging
moiety, or an imaging moiety. In some cases, Y is carbon, K and L
are hydrogen, and M is alkyloxy optionally substituted with an
imaging moiety.
[0630] In some embodiments, an imaging agent for imaging perfusion
comprises the formula:
##STR00323##
wherein:
[0631] W is alkyl or heteroalkyl, optionally substituted;
[0632] R.sup.1 is alkyl, optionally substituted;
[0633] R.sup.2 is hydrogen or halide;
[0634] each R.sup.3 can be the same or different and is alkyl
optionally substituted with an imaging moiety or heteroalkyl
optionally substituted with an imaging moiety; and
[0635] n is 1, 2, 3, 4, or 5.
[0636] In some embodiments, the imaging agent for imaging perfusion
(e.g., cardiac perfusion) comprises the structure:
##STR00324##
or a pharmaceutically acceptable salt thereof, hereinafter referred
to as "Imaging Agent-2."
[0637] Those of ordinary skill in the art will be aware of other
suitable imaging agents for imaging perfusion (e.g., cardiac
perfusion). For example, suitable imaging agents for imaging
perfusion include, but are not limited to, thallium-201,
technetium-99m sestamibi, technetium-99m tetrofosmin, rubidium-82
chloride, oxygen-15 water, and nitrogen-13 ammonia. In some
embodiments, an imaging agent for imaging perfusion is as described
in International Patent Publication No. WO 2005/079391, published
Sep. 1, 2005, to Casebier et al.; International Patent Publication
No. WO 2005/105159, published Nov. 10, 2005, to Radeke et al.,
International Patent Publication No. WO 2011/097649, published Aug.
11, 2011, to Cesati et al.; each of which is incorporated herein by
reference.
G2. Innervation Imaging Agents
[0638] Some embodiments of the present invention comprise an
imaging agent for imaging innervation (e.g., innervation of the
heart). Those of ordinary skill in the art will be aware of imaging
agents which are capable of imaging innervation.
[0639] In some embodiments, an imaging agent for imaging
innervation may be an agent, which is used to monitor and/or assess
certain aspects of the sympathetic nervous system (SNS). The SNS
plays a role in normal cardiac regulation and/or the pathogenesis
of heart failure development and/or progression. Generally,
following myocardial insult (e.g., myocardial infarction, valve
regurgitation, hypertension), compensatory activation of the SNS is
induced to help maintain sufficient cardiac output. Sustained
elevation of the cardiac SNS can cause elevated cardiac
norepinephrine (NE) release, down-regulation of the beta1
adrenergic receptor, and/or down-regulation of the NE transporter
(NET), which can result in spillover of NE. Elevated levels of NE
can be attributed to cardiac myocyte hypertrophy, fibroblast
activation, collagen deposition, and/or myocyte apoptosis, which
can result in ventricle remodeling and/or susceptibility to
arrhythmia.
[0640] In some embodiments, the imaging agents for imaging
innervation as described herein may act as norepinephrine
transporter ligands that target or bind NET. In some embodiments,
the methods comprise detecting NET, including determining NET
levels, in a subject, wherein the determining may comprise
determining the level, density, function, and/or localization of
NET in a subject or portion thereof. In certain embodiments,
without wishing to be bound by a particular theory, the imaging
agent binds to norepinephrine transporters (NET) allowing for
imaging of innervation (e.g., cardiac sympathetic innervation) or
NET activity.
[0641] In some embodiments, agents for imaging cardiac innervation
may be utilized in the assessment of heart failure. In certain
embodiments, the methods comprise an assessment of heart failure
progression in a subject, wherein the assessment may include
determination of the effectiveness of a treatment regimen. In some
cases, the treatment regimen may include a beta blocker. In other
cases, the treatment may require implantation of a pacemaker or
implantable cardioverter-defibrillator (ICD). In certain
embodiments, agents for imaging cardiac innervation may be useful
in the prediction of a time course for heart failure disease
progression.
[0642] In some aspects, global images (e.g., global NET images) are
acquired, and in other aspects, regional images (e.g., regional NET
images) are acquired following administration of an imaging agent
that targets NET, wherein a global image is an image of all or
substantially all of an organ (e.g., heart, kidney, pancreas), and
a regional image is an image of only a portion of an organ. In some
cases, changes in NET may be used to assess cardiac sympathetic
innervation and/or myocardial sympathetic function in a
subject.
[0643] Utilizing an imaging agent that targets NET permits imaging
of the location, concentration, density, and/or distribution of
NETs and also can be used to detect changes in NET location,
concentration, density and/or distribution over time, for example,
by acquiring a first NET image in a subject or region of a subject;
obtaining a subsequent NET image of the subject or the region of
the subject, and comparing the first and subsequent images.
Differences between the images can provide information on the
change in NET status in the subject or region of the subject.
Changes in a NET parameter (e.g., location, density, concentration,
and/or distribution) over time may be assessed and correlated with
disease onset, progression, and/or regression. In some cases, the
detection comprises detection of the level (e.g., concentration) of
NET, detection of the density of NET, detection of NET function,
and/or detection of the localization of NET.
[0644] In some embodiments, the imaging agent employed for imaging
innervation comprises the structure:
##STR00325##
or a pharmaceutically acceptable salt thereof, hereinafter referred
to as "Imaging Agent-1." In some embodiments, Imaging Agent-1 is
provided as a formate or ascorbate salt.
[0645] In some embodiments, a compound for imaging innervation is
provided comprising Formula (Ia):
R.sup.0--Ar-L-R.sup.1 (Ia)
wherein
[0646] Ar is substituted or unsubstituted, monocyclic or bicyclic
aryl; or substituted or unsubstituted, monocyclic or bicyclic
heteroaryl;
[0647] L is a bond; substituted or unsubstituted, cyclic or acyclic
alkylene; substituted or unsubstituted, cyclic or acyclic
alkenylene; substituted or unsubstituted, cyclic or acyclic
alkynylene; or substituted or unsubstituted, cyclic or acyclic
heteroaliphatic;
[0648] R.sup.1 is a substituted or unsubstituted
nitrogen-containing moiety; and
[0649] R.sup.0 is halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.A1, --N(R.sup.A2).sub.2, --SR.sup.A1, --C(.dbd.O)R.sup.A1,
--C(.dbd.O)OR.sup.A1, --C(.dbd.O)SR.sup.A1,
--C(.dbd.O)N(R.sup.A2).sub.2, --OC(.dbd.O)R.sup.A1,
--OC(.dbd.O)OR.sup.A1, --OC(.dbd.O)SR.sup.A1,
--OC(.dbd.O)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.O)R.sup.A2,
--NR.sup.A2C(.dbd.O)OR.sup.A1, --NR.sup.A2C(.dbd.O)SR.sup.A1,
--NR.sup.A2C(.dbd.O)N(R.sup.A2).sub.2, --SC(.dbd.O)R.sup.A1,
--SC(.dbd.O)OR.sup.A1, --SC(.dbd.O)SR.sup.A1,
--SC(.dbd.O)N(R.sup.A2).sub.2, --C(.dbd.NR.sup.A2)R.sup.A1,
--C(.dbd.NR.sup.A2)OR.sup.A1, --C(.dbd.NR.sup.A2)SR.sup.A1,
--C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --OC(.dbd.NR.sup.A2)R.sup.A1,
--OC(.dbd.NR.sup.A2)OR.sup.A1, --OC(.dbd.NR.sup.A2)SR.sup.A1,
--OC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--NR.sup.A2C(.dbd.NR.sup.A2)R.sup.A2,
--NR.sup.A2C(.dbd.NR)OR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)SR.sup.A1,
--NR.sup.A2C(.dbd.NR.sup.A2)N(R.sup.A2).sub.2,
--SC(.dbd.NR.sup.A2)R.sup.A1, --SC(.dbd.NR.sup.A2)OR.sup.A1,
--SC(.dbd.NR.sup.A2)SR.sup.A1,
--SC(.dbd.NR.sup.A2)N(R.sup.A2).sub.2, --C(.dbd.S)R.sup.A1,
--C(.dbd.S)OR.sup.A1, --C(.dbd.S)SR.sup.A1,
--C(.dbd.S)N(R.sup.A2).sub.2, --OC(.dbd.S)R.sup.A1,
--OC(.dbd.S)OR.sup.A1, --OC(.dbd.S)SR.sup.A1,
--OC(.dbd.S)N(R.sup.A2).sub.2, --NR.sup.A2C(.dbd.S)R.sup.A2,
--NR.sup.A2C(.dbd.S)OR.sup.A1, --NR.sup.A2C(.dbd.S)SR.sup.A1,
--NR.sup.A2C(.dbd.S)N(R.sup.A2).sub.2, --SC(.dbd.S)R.sup.A1,
--SC(.dbd.S)OR.sup.A1, --SC(.dbd.S)SR.sup.A1,
--SC(.dbd.S)N(R.sup.A2).sub.2, --S(.dbd.O)R.sup.A1,
--SO.sub.2R.sup.A1, --NR.sup.A2SO.sub.2R.sup.A1,
--SO.sub.2N(R.sup.A2).sub.2, --CN, --SCN, or --NO.sub.2;
[0650] each occurrence of R.sup.A1 is independently hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and each occurrence of
R.sup.A2 is independently hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, or an amino protecting group, or two R.sup.A2 groups
are joined to form an optionally substituted heterocyclic ring;
and
[0651] R.sup.0 or R.sup.1 is substituted with an imaging moiety
selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124, and .sup.131I, or is associated with an imaging moiety
selected from the group consisting of .sup.64Cu, .sup.89Zr,
.sup.99mTc, and .sup.111In through a chelator, or is an imaging
moiety selected from the group consisting of .sup.18F, .sup.76Br,
.sup.124I, and .sup.131I; or a salt thereof.
[0652] In some embodiments, the agent for imaging innervation
comprises a compound as described above in Section A entitled
"Imaging Agents." In some embodiments, the agent for imaging
innervation is of the formula:
##STR00326## ##STR00327## ##STR00328## ##STR00329## ##STR00330##
##STR00331## ##STR00332##
or a pharmaceutically acceptable salt thereof.
[0653] Those of ordinary skill in the art will be aware of other
suitable imaging agents for imaging innervation (e.g., cardiac
innervation). For example, other suitable imaging agents for
imaging innervation include, but are not limited to,
.sup.1231-meta-iodobenzylguanidine (MIBG),
.sup.11C-meta-hydroxyephedrine (HED) and .sup.11C-epinephrine. See,
for example, Bengel F M, Schwaiger M. Assessment of cardiac
sympathetic neuronal function using PET imaging. J Nucl Cardiol.
2004; 11(5):603-16; Henneman M M, Bengel F M, van der Wall E E,
Knuuti J, Bax J J. Cardiac neuronal imaging: application in the
evaluation of cardiac disease. J. Nucl Cardiol. 2008; 15(3):442-55;
Travin M I. Cardiac neuronal imaging at the edge of clinical
application. Cardiol Clin. 2009; 27(2):311-27; and Carrio I.
Cardiac neurotransmission imaging. J Nucl Med. 2001; 42(7):1062-76,
incorporated by reference herein. In some embodiments, an imaging
agent for imaging perfusion is as described in International Patent
Publication No. WO 2008/083056, published Jul. 10, 2008, to Purohit
et al., incorporated herein by reference.
H. Exemplary Cassettes and Reaction Systems
[0654] In some embodiments, systems, methods, kits, and cassettes
are provided for the synthesis of an imaging agent as described
herein. In some embodiments, an imaging agent may be prepared using
an automated reaction system comprising a disposable or single use
cassette. The cassette may comprise all the non-radioactive
reagents, solvents, tubing, valves, reaction vessels, and other
apparatus and/or components necessary to carry out the preparation
of a given batch of imaging agent. The cassette allows the reaction
system to have the flexibility to make a variety of different
imaging agents with minimal risk of cross-contamination, by simply
changing the cassette. By the term "cassette" is meant a piece of
apparatus designed to fit removably and interchangeably onto
automated reaction systems, in such a way that mechanical movement
of moving parts of the automated reaction system controls the
operation of the cassette from outside the cassette, i.e.,
externally. In certain embodiments, a cassette comprises a linear
arrangement of valves, each linked to a port where various
reagents, cartridges, syringes, and/or vials can be attached, by
either needle puncture of a septum-sealed vial, or by gas-tight,
marrying joints. Each valve may have a male-female joint which
interfaces with a corresponding moving arm of the automated
synthesizer. External rotation of the arm can control the opening
or closing of the valve when the cassette is attached to the
automated reaction system. Additional moving parts of the automated
reaction system are designed to clip onto syringe plunger tips, and
thus raise or depress syringe barrels. An automated reaction system
may further include a controller and one or more controllable
valves in electrical communication with the controller. An
automated reaction system may also include additional vessels,
valves, sensors, heaters, pressurizing elements, etc., in
electrical communication with the controller. An automated reaction
system may be operated by a controller using suitable software for
control of valve openings and closings, heating, cooling, pressure
levels, fluid movement, flow rate, etc. The automated reaction
system may optionally include a computer operating system,
software, controls, etc., or other component. In addition, the
automated reaction system may comprise a mount for the
cassette.
[0655] Examples of automated reaction systems (e.g., a nucleophilic
reaction system), include, but are not limited to, the Explora GN
or RN synthesis system (Siemens Medical Solutions USA, Inc.),
GE-Tracerlab-MX synthesis system (GE Healthcare), Eckert &
Zeigler Modular-Lab Synthesis system, etc., which are commonly
available at PET manufacturing facilities.
I. Noise Filtering Optimization
[0656] The invention also relates, in part, to methods for
optimizing noise filtering parameters for PET myocardial imaging.
The invention provides a methodology for obtaining optimal noise
filtering parameters for any 2D or 3D camera (or scanner as the
terms are used interchangeably) used to obtain PET images. The
invention also provides optimal noise filtering parameters to be
applied to imaging data. These parameters may be used in an imaging
data algorithm which may be performed manually or electronically
(e.g., via software).
[0657] In accordance with the invention, it has been found that a
cardiac phantom simulation using known patient myocardial
standardized uptake values (SUVs) is an effective method to
determine the optimal noise filter parameter set that can produce
high-quality diagnostic images. This has been exemplified, as
described in the Examples, from the use of imaging data obtained
with PET myocardial perfusion Imaging Agent-2.
[0658] One method comprises obtaining 3D perfusion imaging data
from a cardiac phantom having a defect, applying a series of
smoothing filters to the data, and selecting the filter that
provides less than 5% defect contrast degradation. The smoothing
filter is typically a weighted Gaussian function defined by full
width half maximum (FWHM) values. It was found in accordance with
the invention that a Gaussian filter set at FWHM of 8 mm was
optimal for 3D myocardial perfusion images acquired at rest and
after either pharmacological stress or exercise induced stress. As
shown in Table B of Example 2, a filter set at FWHM of 8 mm
achieves the desired defect contrast degradation of less than 5%
and a near maximal signal to noise ratio (SNR). At FWHM less than 8
mm the SNR decreases for each of these data sets and at FWHM more
than 8 mm the defect contrast degradation is above the desired 5%.
The cardiac phantom may have a defect of 45+/-15.degree.,
45+/-10.degree., 45+/-5.degree., 45+/-1.degree., or simply
45.degree..
[0659] Another method comprises obtaining 2D gated imaging data
from a cardiac phantom having a defect, applying a series of
smoothing filters to the data, and selecting the filter that
provides more than 90% left ventricular volume (LVV) accuracy. The
smoothing filter is typically a weighted Gaussian function defined
by FWHM values. It was found in accordance with the invention that
a Gaussian filter of FWHM of 15 mm was optimal for 2D gated images
acquired at rest, and a Gaussian filter of FWHM of 12 mm was
optimal for 2D gated images acquired after pharmacological and
exercise-induced stress. As shown in Table B, a filter set at FWHM
less than or greater than 15 mm achieved LVV accuracy ranging from
50-78% as compared to the FWHM 15 mm filter which achieved 93% LVV
accuracy, for images obtained at rest. A filter set at FWHM of 12
mm or 15 mm achieved LVV accuracies of about 93% and 91% for images
obtained after pharmacological and exercise-induced stress, while
FWHM less than 12 mm or greater than 15 mm achieved suboptimal LVV
accuracies ranging from 65-84%.
[0660] Thus, the invention provides a method comprising obtaining
3D perfusion images from a patient and applying to such images a
FWHM of 8 mm. The invention also provides obtaining 2D gated images
from a patient at rest, after pharmacological stress and after
exercised-induced stress and applying to such images a FWHM of 15
mm, 12 or 15 mm, and 12 or 15 mm, respectively.
[0661] It is to be understood that the foregoing methods can be
used when acquiring myocardial perfusion images using a variety of
myocardial perfusion imaging agents as described herein. In
important embodiments, the myocardial perfusion imaging agent
includes .sup.18F as an imaging moiety, e.g., Imaging Agent-2.
J. Pharmaceutical Compositions
[0662] The imaging agents described herein may be combined with one
or more pharmaceutically acceptable excipients to form a
pharmaceutical composition that is suitable for administration to a
subject, including a human. As would be appreciated by one of skill
in this art, the excipients may be chosen, for example, based on
the route of administration as described below, the imaging agent
being delivered, time course of delivery of the agent, and/or the
health/condition of the subject. The pharmaceutical composition may
be a solid or liquid.
[0663] Pharmaceutical compositions of the present invention and for
use in accordance with the present invention may include a
pharmaceutically acceptable excipient or carrier. As used herein,
the term "pharmaceutically acceptable excipient" or
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
which can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose, and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose, and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols such as propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; detergents such as Tween 80; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol; and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0664] Pharmaceutically acceptable excipients include any and all
solvents, diluents or other liquid vehicles, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and
the like, as suited to the particular dosage form desired. General
considerations in formulation and/or manufacture of pharmaceutical
compositions agents can be found, for example, in Remington's
Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack
Publishing Co., Easton, Pa., 1980), and Remington: The Science and
Practice of Pharmacy, 21st Edition (Lippincott Williams &
Wilkins, 2005).
[0665] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the compound of
the present invention (the "active ingredient") into association
with a carrier and/or one or more other accessory ingredients, and
then, if necessary and/or desirable, shaping and/or packaging the
product into a desired single or multidose unit.
[0666] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0667] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[0668] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutical compositions include inert
diluents, dispersing and/or granulating agents, surface active
agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering agents, lubricating agents, and/or oils.
Excipients such as cocoa butter and suppository waxes, coloring
agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present in the composition.
[0669] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
and combinations thereof.
[0670] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives.
[0671] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium iodide, sodium metabisulfite, sodium nitrite, sodium
sulfite, and sodium thiosulfate.
[0672] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, dipotassium edetate, and the like),
citric acid and salts and hydrates thereof (e.g., citric acid
monohydrate), fumaric acid and salts and hydrates thereof, malic
acid and salts and hydrates thereof, phosphoric acid and salts and
hydrates thereof, and tartaric acid and salts and hydrates thereof.
Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[0673] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, and sorbic acid. Exemplary alcohol
preservatives include ethanol, polyethylene glycol, phenol,
phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and
phenylethyl alcohol.
[0674] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, and phytic acid.
[0675] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115,
Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments,
the preservative is an anti-oxidant. In other embodiments, the
preservative is a chelating agent.
[0676] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen free
water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and
combinations thereof.
[0677] Liquid dosage forms for oral and parenteral administration
include pharmaceutically acceptable emulsions, microemulsions,
solutions, suspensions, syrups and elixirs. In addition to the
active ingredients, the liquid dosage forms may comprise inert
diluents commonly used in the art such as, for example, water or
other solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ,
olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions
can include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents. In
certain embodiments for parenteral administration, the conjugates
of the invention are mixed with solubilizing agents such as
Cremophor, alcohols, oils, modified oils, glycols, polysorbates,
cyclodextrins, polymers, and combinations thereof.
[0678] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0679] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0680] Suitable devices for use in delivering intradermal
pharmaceutical compositions described herein include short needle
devices such as those described in U.S. Pat. Nos. 4,886,499;
5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496;
and 5,417,662. Intradermal compositions can be administered by
devices which limit the effective penetration length of a needle
into the skin, such as those described in PCT publication WO
99/34850 and functional equivalents thereof. Jet injection devices
which deliver liquid vaccines to the dermis via a liquid jet
injector and/or via a needle which pierces the stratum corneum and
produces a jet which reaches the dermis are suitable. Jet injection
devices are described, for example, in U.S. Pat. Nos. 5,480,381;
5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;
5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;
5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460;
and PCT publications WO 97/37705 and WO 97/13537. Ballistic
powder/particle delivery devices which use compressed gas to
accelerate vaccine in powder form through the outer layers of the
skin to the dermis are suitable. Alternatively or additionally,
conventional syringes can be used in the classical Mantoux method
of intradermal administration.
[0681] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0682] The pharmaceutical compositions of this invention can be
administered to humans and/or to other animals parenterally (e.g.,
by intravenous, intramuscular, subcutaneous, or intraperitoneal
injection). The mode of administration will vary depending on the
intended use, as is well known in the art.
K. Kits
[0683] Systems, methods, kits, and/or cassettes are provided
comprising an imaging agent or an imaging agent precursor (or a
first imaging agent and a second imaging agent) as described herein
or a composition thereof and/or for preparation of an imaging
agent. In some embodiments, a kits comprises an imaging agent for
imaging perfusion and an imaging agent for imaging innervation
(e.g., as described in Sections G1 and G2). In some embodiments,
kits for the administration of an imaging agent are provided. In
some cases, the composition provided with the kit may be used for
or in the preparation of an imaging agent for detecting, imaging,
and/or monitoring a disorder or condition. Kits of the invention
may include, for example, a container comprising an imaging agent
or an imaging agent precursor and instructions for use. Kits may
comprise a sterile, non-pyrogenic, formulation comprising a
predetermined amount of an imaging agent or an imaging agent
precursor, and optionally other components. A container that may be
used in conjunction with an imaging agent for example, to deliver
and/or administer the imaging agent to a subject, may be a syringe,
bottle, vial, or tube. Instructions in a kit of the invention may
relate to methods for synthesizing an imaging agent or an imaging
agent precursor, methods of diluting the imaging agent or the
imaging agent precursor, methods of administering the imaging agent
to a subject for diagnostic imaging, or other instructions for use.
An imaging agent or an imaging agent precursor may be provided in a
kit and additional preparations before use may optionally include
diluting the imaging agent or imaging agent precursor to a usable
concentration.
[0684] In some cases, a kit can also include one or more vials
containing a diluent for preparing an imaging agent composition for
administration to a subject (e.g., a human). A diluent vial may
contain a diluent such as physiological saline or water for
diluting the imaging agent. For example, the imaging agent may be
packaged in a kit in a ready-to-inject formulation, or may require
some reconstitution or dilution whereby a final
composition/formulation for injection or infusion is prepared.
[0685] Instructions in a kit of the invention may also include
instructions for administering the imaging agent to a subject and
may include information on dosing, timing, stress induction, etc.
For example, a kit may include an imaging agent or imaging agent
precursor as described herein along with instructions describing
the intended application and the proper administration of the agent
to a subject. As used herein, "instructions" can define a component
of instruction and/or promotion, and typically involve written
instructions on or associated with packaging of the invention.
Instructions also can include any oral or electronic instructions
provided in any manner such that a user will clearly recognize that
the instructions are to be associated with the kit, for example,
audiovisual (e.g., videotape, DVD), internet, and/or web-based
communications. The written instructions may be in a form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceuticals products, which instructions can also
reflect approval by the agency of manufacture, use; or sale for
human administration. In some cases, the instructions can include
instructions for mixing a particular amount of the diluent with a
particular amount of a concentrated solution of the imaging agent
or a solid preparation of the imaging agent, whereby a final
formulation for injection or infusion is prepared for example, such
that the resulting solution is at a suitable concentration for
administration to a subject (e.g., at a concentration as described
herein). A kit may include a whole treatment regimen of the
inventive compound.
[0686] The kit may contain any one or more of the components
described herein in one or more containers. As an example, in one
embodiment, the kit may include instructions for mixing one or more
components of the kit and/or isolating and mixing a sample and
applying to a subject. The kit may include a container housing an
agent described herein (e.g., an imaging agent precursor or an
imaging agent). The agent may be in the form of a liquid, gel, or
solid (e.g., powder). The agent may be prepared sterilely, packaged
in a syringe, and shipped refrigerated. Alternatively it may be
housed in a vial or other container for storage. A second container
may have other agents prepared sterilely. Alternatively, the kit
may include an agent premixed and shipped in a syringe, vial, tube,
or other container. The kit may have one or more or all of the
components required to administer the agents to a subject, such as
a syringe or i.v. needle tubing and bag.
[0687] It also will be understood that containers containing the
components of a kit of the invention, whether the container is a
bottle, a vial (e.g., with a septum), an ampoule, an infusion bag,
or the like, can include additional indicia such as conventional
markings that change color when the preparation has been autoclaved
or otherwise sterilized. A kit of the invention may further include
other components, such as syringes, labels, vials, tubing,
catheters, needles, ports, and the like. In some aspect of the
invention, a kit may include a single syringe containing the
imaging agent of the invention sufficient for administration and in
some aspects of the invention a kit may include more than one
syringe.
[0688] Buffers useful in the preparation of imaging agents and kits
include, for example, phosphate, citrate, sulfosalicylate, and
acetate buffers. A more complete list can be found in the United
States Pharmacopoeia. Lyophilization aids useful in the preparation
of imaging agents and kits include, for example, mannitol, lactose,
sorbitol, dextran, FICOLL.RTM. polymer, and polyvinylpyrrolidine
(PVP). Stabilization aids useful in the preparation of imaging
agents and kits include, for example, ascorbic acid, cysteine,
monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic
acid, and inositol. Solubilization aids useful in the preparation
of imaging agents and kits include, for example, ethanol, glycerin,
polyethylene glycol, propylene glycol, polyoxyethylene sorbitan
monooleate, sorbitan monoloeate, polysorbates,
poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block
copolymers (e.g., Pluronics.RTM.) and lecithin. In certain
embodiments, the solubilizing aids are polyethylene glycol,
cyclodextrins, and Pluronics. Bacteriostats useful in the
preparation of imaging agents and kits include, for example, benzyl
alcohol, benzalkonium chloride, chlorbutanol, and methyl, propyl,
or butyl paraben.
L. Definitions
[0689] For convenience, certain terms employed in the
specification, examples, and appended claims are listed here.
[0690] Definitions of specific functional groups and chemical terms
are described in more detail below. For purposes of this invention,
the chemical elements are identified in accordance with the
Periodic Table of the Elements, CAS version, Handbook of Chemistry
and Physics, 75.sup.th Ed., inside cover, and specific functional
groups are generally defined as described therein. Additionally,
general principles of organic chemistry, as well as specific
functional moieties and reactivity, are described in Organic
Chemistry, Thomas Sorrell, University Science Books, Sausalito:
1999, the entire contents of which are incorporated herein by
reference.
[0691] Certain compounds of the present invention may exist in
particular geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-isomers,
R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the
racemic mixtures thereof, and other mixtures thereof, as falling
within the scope of the invention. Additional asymmetric carbon
atoms may be present in a substituent such as an alkyl group. All
such isomers, as well as mixtures thereof, are intended to be
included in this invention.
[0692] Isomeric mixtures containing any of a variety of isomer
ratios may be utilized in accordance with the present invention.
For example, where only two isomers are combined, mixtures
containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3,
98:2, 99:1, or 100:0 isomer ratios are all contemplated by the
present invention. Those of ordinary skill in the art will readily
appreciate that analogous ratios are contemplated for more complex
isomer mixtures.
[0693] If, for instance, a particular enantiomer of a compound of
the present invention is desired, it may be prepared by asymmetric
synthesis, or by derivation with a chiral auxiliary, where the
resulting diastereomeric mixture is separated and the auxiliary
group cleaved to provide the pure desired enantiomers.
Alternatively, where the molecule contains a basic functional
group, such as amino, or an acidic functional group, such as
carboxyl, diastereomeric salts are formed with an appropriate
optically-active acid or base, followed by resolution of the
diastereomers thus formed by fractional crystallization or
chromatographic means well known in the art, and subsequent
recovery of the pure enantiomers.
[0694] The term "aliphatic," as used herein, includes both
saturated and unsaturated, nonaromatic, straight chain (i.e.,
unbranched), branched, acyclic, and cyclic (i.e., carbocyclic)
hydrocarbons, which are optionally substituted with one or more
functional groups. As will be appreciated by one of ordinary skill
in the art, "aliphatic" is intended herein to include, but is not
limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and
cycloalkynyl moieties. Thus, as used herein, the term "alkyl"
includes straight, branched and cyclic alkyl groups. An analogous
convention applies to other generic terms such as "alkenyl",
"alkynyl", and the like. Furthermore, as used herein, the terms
"alkyl", "alkenyl", "alkynyl", and the like encompass both
substituted and unsubstituted groups. In certain embodiments, as
used herein, "aliphatic" is used to indicate those aliphatic groups
(cyclic, acyclic, substituted, unsubstituted, branched or
unbranched) having 1-20 carbon atoms. Aliphatic group substituents
include, but are not limited to, any of the substituents described
herein, that result in the formation of a stable moiety (e.g.,
aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic,
aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano,
amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino,
heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy,
heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,
heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the
like, each of which may or may not be further substituted).
[0695] As used herein, the term "alkyl" is given its ordinary
meaning in the art and refers to the radical of saturated aliphatic
groups, including straight-chain alkyl groups, branched-chain alkyl
groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl
groups, and cycloalkyl substituted alkyl groups. In some cases, the
alkyl group may be a lower alkyl group, i.e., an alkyl group having
1 to 10 carbon atoms (e.g., methyl, ethyl, propyl, butyl, pentyl,
hexyl, heptyl, octyl, nonyl, or decyl). In some embodiments, a
straight chain or branched chain alkyl may have 30 or fewer carbon
atoms in its backbone, and, in some cases, 20 or fewer. In some
embodiments, a straight chain or branched chain alkyl may have 12
or fewer carbon atoms in its backbone (e.g., C.sub.1-C.sub.12 for
straight chain, C.sub.3-C.sub.12 for branched chain), 6 or fewer,
or 4 or fewer. Likewise, cycloalkyls may have from 3-10 carbon
atoms in their ring structure, or 5, 6 or 7 carbons in the ring
structure. Examples of alkyl groups include, but are not limited
to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl,
t-butyl, cyclobutyl, hexyl, and cyclochexyl.
[0696] The term "alkylene" as used herein refers to a bivalent
alkyl group. An "alkylene" group is a polymethylene group, i.e.,
--(CH.sub.2).sub.z--, wherein z is a positive integer, e.g., from 1
to 20, from 1 to 10, from 1 to 6, from 1 to 4, from 1 to 3, from 1
to 2, or from 2 to 3. A substituted alkylene chain is a
polymethylene group in which one or more methylene hydrogen atoms
are replaced with a substituent. Suitable substituents include
those described herein for a substituted aliphatic group.
[0697] Generally, the suffix "-ene" is used to describe a bivalent
group. Thus, any of the terms defined herein can be modified with
the suffix "-ene" to describe a bivalent version of that moiety.
For example, a bivalent carbocycle is "carbocyclylene", a bivalent
aryl ring is "arylene", a bivalent benzene ring is "phenylene", a
bivalent heterocycle is "heterocyclylene", a bivalent heteroaryl
ring is "heteroarylene", a bivalent alkyl chain is "alkylene", a
bivalent alkenyl chain is "alkenylene", a bivalent alkynyl chain is
"alkynylene", a bivalent heteroalkyl chain is "heteroalkylene", a
bivalent heteroalkenyl chain is "heteroalkenylene", a bivalent
heteroalkynyl chain is "heteroalkynylene", and so forth.
[0698] The terms "alkenyl" and "alkynyl" are given their ordinary
meaning in the art and refer to unsaturated aliphatic groups
analogous in length and possible substitution to the alkyls
described above, but that contain at least one double or triple
bond respectively.
[0699] In certain embodiments, the alkyl, alkenyl and alkynyl
groups employed in the invention contain 1-20 aliphatic carbon
atoms. In certain other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-8 aliphatic
carbon atoms. In still other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-6 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain 1-4 carbon atoms.
Illustrative aliphatic groups thus include, but are not limited to,
for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl,
sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl,
t-pentyl, n-hexyl, sec-hexyl, moieties and the like, which again,
may bear one or more substituents. Alkenyl groups include, but are
not limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups
include, but are not limited to, ethynyl, 2-propynyl (propargy 1),
1-propynyl and the like.
[0700] The term "cycloalkyl," as used herein, refers specifically
to groups having three to ten, preferably three to seven carbon
atoms. Suitable cycloalkyls include, but are not limited to
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
the like, which, as in the case of other aliphatic,
heteroaliphatic, or hetercyclic moieties, may optionally be
substituted with substituents including, but not limited to
aliphatic; heteroaliphatic; aryl; heteroaryl; arylalkyl;
heteroarylalkyl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;
alkylthio; arylthio; heteroalkylthio; heteroarylthio; --F; --Cl;
--Br; --I; --OH; --NO.sub.2; --CN; --CF.sub.3; --CH.sub.2CF.sub.3;
--CHCl.sub.2; --CH.sub.2OH; --CH.sub.2CH.sub.2OH;
--CH.sub.2NH.sub.2; --CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x;
--CO.sub.2(R.sub.x); --CON(R.sub.x).sub.2; --OC(O)R.sub.x;
--OCO.sub.2R.sub.x; --OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2;
--S(O).sub.2R.sub.x; --NR.sub.x(CO)R.sub.x, wherein each occurrence
of R.sub.x independently includes, but is not limited to,
aliphatic, heteroaliphatic, aryl, heteroaryl, arylalkyl, or
heteroarylalkyl, wherein any of the aliphatic, heteroaliphatic,
arylalkyl, or heteroarylalkyl substituents described above and
herein may be substituted or unsubstituted, branched or unbranched,
cyclic or acyclic, and wherein any of the aryl or heteroaryl
substituents described above and herein may be substituted or
unsubstituted. Additional examples of generally applicable
substitutents are illustrated by the specific embodiments shown in
the Examples that are described herein.
[0701] The term "heteroaliphatic," as used herein, refers to an
aliphatic moiety, as defined herein, which includes both saturated
and unsaturated, nonaromatic, straight chain (i.e., unbranched),
branched, acyclic, cyclic (i.e., heterocyclic), or polycyclic
hydrocarbons, which are optionally substituted with one or more
functional groups, and that contain one or more oxygen, sulfur,
nitrogen, phosphorus, or silicon atoms, e.g., in place of carbon
atoms. In certain embodiments, heteroaliphatic moieties are
substituted by independent replacement of one or more of the
hydrogen atoms thereon with one or more substituents. As will be
appreciated by one of ordinary skill in the art, "heteroaliphatic"
is intended herein to include, but is not limited to, heteroalkyl,
heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl,
and heterocycloalkynyl moieties. Thus, the term "heteroaliphatic"
includes the terms "heteroalkyl," "heteroalkenyl", "heteroalkynyl",
and the like. Furthermore, as used herein, the terms "heteroalkyl",
"heteroalkenyl", "heteroalkynyl", and the like encompass both
substituted and unsubstituted groups. In certain embodiments, as
used herein, "heteroaliphatic" is used to indicate those
heteroaliphatic groups (cyclic, acyclic, substituted,
unsubstituted, branched or unbranched) having 1-20 carbon atoms.
Heteroaliphatic group substituents include, but are not limited to,
any of the substituents described herein, that result in the
formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl,
alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,
sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino,
azido, nitro, hydroxyl, thiol, halo, aliphaticamino,
heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy,
heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,
heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the
like, each of which may or may not be further substituted).
[0702] The term "heteroalkyl" is given its ordinary meaning in the
art and refers to an alkyl group as described herein in which one
or more carbon atoms is replaced by a heteroatom. Suitable
heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the
like. Examples of heteroalkyl groups include, but are not limited
to, alkoxy, amino, thioester, poly(ethylene glycol), and
alkyl-substituted amino.
[0703] The terms "heteroalkenyl" and "heteroalkynyl" are given
their ordinary meaning in the art and refer to unsaturated
aliphatic groups analogous in length and possible substitution to
the heteroalkyls described above, but that contain at least one
double or triple bond respectively.
[0704] Some examples of substituents of the above-described
aliphatic (and other) moieties of compounds of the invention
include, but are not limited to aliphatic; heteroaliphatic; aryl;
heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --OH; --NO.sub.2; --CN; --CF.sub.3;
--CHF.sub.2; --CH.sub.2F; --CH.sub.2CF.sub.3; --CHCl.sub.2;
--CH.sub.2OH; --CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2;
--CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x; --OC.sub.2(R.sub.x);
--CON(R.sub.x).sub.2; --OC(O)R.sub.x; --OCO.sub.2R.sub.x;
--OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2; --S(O).sub.2R.sub.x;
--NR.sub.x(CO)R.sub.x wherein each occurrence of R.sub.x
independently includes, but is not limited to, aliphatic,
alycyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,
alkylaryl, or alkylheteroaryl, wherein any of the aliphatic,
heteroaliphatic, alkylaryl, or alkylheteroaryl substituents
described above and herein may be substituted or unsubstituted,
branched or unbranched, cyclic or acyclic, and wherein any of the
aryl or heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additional examples of generally
applicable substituents are illustrated by the specific embodiments
shown in the Examples that are described herein.
[0705] The term "aryl" is given its ordinary meaning in the art and
refers to aromatic carbocyclic groups, optionally substituted,
having a single ring (e.g., phenyl), multiple rings (e.g.,
biphenyl), or multiple fused rings in which at least one is
aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or
phenanthryl). That is, at least one ring may have a conjugated pi
electron system, while other, adjoining rings can be cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. The aryl
group may be optionally substituted, as described herein.
Substituents include, but are not limited to, any of the previously
mentioned substitutents, i.e., the substituents recited for
aliphatic moieties, or for other moieties as disclosed herein,
resulting in the formation of a stable compound. In some cases, an
aryl group is a stable mono- or polycyclic unsaturated moiety
having preferably 3-14 carbon atoms, each of which may be
substituted or unsubstituted. "Carbocyclic aryl groups" refer to
aryl groups wherein the ring atoms on the aromatic ring are carbon
atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl
groups and polycyclic or fused compounds (e.g., two or more
adjacent ring atoms are common to two adjoining rings) such as
naphthyl groups.
[0706] The terms "heteroaryl" is given its ordinary meaning in the
art and refers to aryl groups comprising at least one heteroatom as
a ring atom. A "heteroaryl" is a stable heterocyclic or
polyheterocyclic unsaturated moiety having preferably 3-14 carbon
atoms, each of which may be substituted or unsubstituted.
Substituents include, but are not limited to, any of the previously
mentioned substitutents, i.e., the substituents recited for
aliphatic moieties, or for other moieties as disclosed herein,
resulting in the formation of a stable compound. In some cases, a
heteroaryl is a cyclic aromatic radical having from five to ten
ring atoms of which one ring atom is selected from S, O, and N;
zero, one, or two ring atoms are additional heteroatoms
independently selected from S, O, and N; and the remaining ring
atoms are carbon, the radical being joined to the rest of the
molecule via any of the ring atoms, such as, for example, pyridyl,
pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,
furanyl, quinolinyl, isoquinolinyl, and the like.
[0707] It will also be appreciated that aryl and heteroaryl
moieties, as defined herein may be attached via an alkyl or
heteroalkyl moiety and thus also include (alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, and
(heteroalkyl)heteroaryl moieties. Thus, as used herein, the phrases
"aryl or heteroaryl moieties" and "aryl, heteroaryl, (alkyl)aryl,
-(heteroalkyl)aryl, -(heteroalkyl)heteroaryl, and
-(heteroalkyl)heteroaryl" are interchangeable. Substituents
include, but are not limited to, any of the previously mentioned
substituents, i.e., the substituents recited for aliphatic
moieties, or for other moieties as disclosed herein, resulting in
the formation of a stable compound.
[0708] It will be appreciated that aryl and heteroaryl groups
(including bicyclic aryl groups) can be unsubstituted or
substituted, wherein substitution includes replacement of one or
more of the hydrogen atoms thereon independently with any one or
more of the following moieties including, but not limited to:
aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;
heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;
alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy;
heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; C.sub.1; Br; I; --OH; --NO.sub.2; --CN;
--CF.sub.3; --CH.sub.2F; --CHF.sub.2; --CH.sub.2CF.sub.3;
--CHCl.sub.2; --CH.sub.2OH; --CH.sub.2CH.sub.2OH;
--CH.sub.2NH.sub.2; --CH.sub.2SO.sub.2CH.sub.3; --C(O)R.sub.x;
--CO.sub.2(R.sub.x); --CON(R.sub.x).sub.2; --OC(O)R.sub.x;
--OCO.sub.2R.sub.x; --OCON(R.sub.x).sub.2; --N(R.sub.x).sub.2;
--S(O)R.sub.x; --S(O).sub.2R.sub.x; --NR.sub.x(CO)R.sub.x wherein
each occurrence of R.sub.x independently includes, but is not
limited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,
aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl,
alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl, wherein
any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic,
alkylaryl, or alkylheteroaryl substituents described above and
herein may be substituted or unsubstituted, branched or unbranched,
saturated or unsaturated, and wherein any of the aromatic,
heteroaromatic, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl substituents described above and herein may be
substituted or unsubstituted. Additionally, it will be appreciated,
that any two adjacent groups taken together may represent a 4, 5,
6, or 7-membered substituted or unsubstituted alicyclic or
heterocyclic moiety. Additional examples of generally applicable
substituents are illustrated by the specific embodiments described
herein.
[0709] The term "heterocycle" is given its ordinary meaning in the
art and refers to refer to cyclic groups containing at least one
heteroatom as a ring atom, in some cases, 1 to 3 heteroatoms as
ring atoms, with the remainder of the ring atoms being carbon
atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen,
phosphorus, and the like. In some cases, the heterocycle may be 3-
to 10-membered ring structures or 3- to 7-membered rings, whose
ring structures include one to four heteroatoms.
[0710] The term "heterocycle" may include heteroaryl groups,
saturated heterocycles (e.g., cycloheteroalkyl) groups, or
combinations thereof. The heterocycle may be a saturated molecule,
or may comprise one or more double bonds. In some cases, the
heterocycle is a nitrogen heterocycle, wherein at least one ring
comprises at least one nitrogen ring atom. The heterocycles may be
fused to other rings to form a polycylic heterocycle. The
heterocycle may also be fused to a spirocyclic group. In some
cases, the heterocycle may be attached to a compound via a nitrogen
or a carbon atom in the ring.
[0711] Heterocycles include, for example, thiophene,
benzothiophene, thianthrene, furan, tetrahydrofuran, pyran,
isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole,
dihydropyrrole, pyrrolidine, imidazole, pyrazole, pyrazine,
isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine, isoindole, indole, indazole, purine, quinolizine,
isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, pteridine, carbazole, carboline, triazole,
tetrazole, oxazole, isoxazole, thiazole, isothiazole,
phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,
phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
oxolane, thiolane, oxazole, oxazine, piperidine, homopiperidine
(hexamnethyleneimine), piperazine (e.g., N-methyl piperazine),
morpholine, lactones, lactams such as azetidinones and
pyrrolidinones, sultams, sultones, other saturated and/or
unsaturated derivatives thereof, and the like. The heterocyclic
ring can be optionally substituted at one or more positions with
such substituents as described herein. In some cases, the
heterocycle may be bonded to a compound via a heteroatom ring atom
(e.g., nitrogen). In some cases, the heterocycle may be bonded to a
compound via a carbon ring atom. In some cases, the heterocycle is
pyridine, imidazole, pyrazine, pyrimidine, pyridazine, acridine,
acridin-9-amine, bipyridine, naphthyridine, quinoline,
benzoquinoline, benzoisoquinoline, phenanthridine-1,9-diamine, or
the like.
[0712] The terms "halo" and "halogen" as used herein refer to an
atom selected from the group consisting of fluorine, chlorine,
bromine, and iodine.
[0713] The term "haloalkyl" denotes an alkyl group, as defined
above, having one, two, or three halogen atoms attached thereto and
is exemplified by such groups as chloromethyl, bromoethyl,
trifluoromethyl, and the like.
[0714] The term "amino," as used herein, refers to a primary
(--NH.sub.2), secondary (--NHR.sub.x), tertiary
(--NR.sub.xR.sub.y), or quaternary (--N.sup.+R.sub.xR.sub.yR.sub.z)
amine, where R.sub.x, R.sub.y, and R.sub.z are independently an
aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, or
heteroaryl moiety, as defined herein. Examples of amino groups
include, but are not limited to, methylamino, dimethylamino,
ethylamino, diethylamino, methylethylamino, iso-propylamino,
piperidino, trimethylamino, and propylamino.
[0715] The term "alkyne" is given its ordinary meaning in the art
and refers to branched or unbranched unsaturated hydrocarbon groups
containing at least one triple bond. Non-limiting examples of
alkynes include acetylene, propyne, 1-butyne, 2-butyne, and the
like. The alkyne group may be substituted and/or have one or more
hydrogen atoms replaced with a functional group, such as a
hydroxyl, halogen, alkoxy, and/or aryl group.
[0716] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used
herein refers to an alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom or through a
sulfur atom. In certain embodiments, the alkyl group contains 1-20
aliphatic carbon atoms. In certain other embodiments, the alkyl
group contains 1-10 aliphatic carbon atoms. In yet other
embodiments, the alkyl, alkenyl, and alkynyl groups employed in the
invention contain 1-8 aliphatic carbon atoms. In still other
embodiments, the alkyl group contains 1-6 aliphatic carbon atoms.
In yet other embodiments, the alkyl group contains 1-4 aliphatic
carbon atoms. Examples of alkoxy, include but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, t-butoxy,
neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not
limited to, methylthio, ethylthio, propylthio, isopropylthio,
n-butylthio, and the like.
[0717] The term "aryloxy" refers to the group, --O-aryl.
[0718] The term "acyloxy" refers to the group, --O-acyl.
[0719] The term "alkoxyalkyl" refers to an alkyl group substituted
with at least one alkoxy group (e.g., one, two, three, or more,
alkoxy groups). For example, an alkoxyalkyl group may be
--(C.sub.1-6-alkyl)-O--(C.sub.1-6-alkyl), optionally substituted.
In some cases, the alkoxyalkyl group may be optionally substituted
with another alkyoxyalkyl group (e.g.,
--(C.sub.1-6-alkyl)-O--(C.sub.1-6-alkyl)-O--(C.sub.1-6-alkyl),
optionally substituted.
[0720] It will be appreciated that the above groups and/or
compounds, as described herein, may be optionally substituted with
any number of substituents or functional moieties. That is, any of
the above groups may be optionally substituted. As used herein, the
term "substituted" is contemplated to include all permissible
substituents of organic compounds, "permissible" being in the
context of the chemical rules of valence known to those of ordinary
skill in the art. In general, the term "substituted" whether
preceeded by the term "optionally" or not, and substituents
contained in formulas of this invention, refer to the replacement
of hydrogen radicals in a given structure with the radical of a
specified substituent. When more than one position in any given
structure may be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at every position. It will be understood that
"substituted" also includes that the substitution results in a
stable compound, e.g., which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
etc. In some cases, "substituted" may generally refer to
replacement of a hydrogen with a substituent as described herein.
However, "substituted," as used herein, does not encompass
replacement and/or alteration of a key functional group by which a
molecule is identified, e.g., such that the "substituted"
functional group becomes, through substitution, a different
functional group. For example, a "substituted phenyl group" must
still comprise the phenyl moiety and cannot be modified by
substitution, in this definition, to become, e.g., a pyridine ring.
In a broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
herein. The permissible substituents can be one or more and the
same or different for appropriate organic compounds. For purposes
of this invention, the heteroatoms such as nitrogen may have
hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valencies of
the heteroatoms. Furthermore, this invention is not intended to be
limited in any manner by the permissible substituents of organic
compounds. Combinations of substituents and variables envisioned by
this invention are preferably those that result in the formation of
stable compounds useful for the formation of an imaging agent or an
imaging agent precursor. The term "stable," as used herein,
preferably refers to compounds which possess stability sufficient
to allow manufacture and which maintain the integrity of the
compound for a sufficient period of time to be detected and
preferably for a sufficient period of time to be useful for the
purposes detailed herein.
[0721] Examples of substituents include, but are not limited to,
halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
heterocyclyl, aromatic or heteroaromatic moieties, --CF.sub.3,
--CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl,
heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino,
halide, alkylthio, oxo, acylalkyl, carboxy esters, -carboxamido,
acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl,
alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl,
-carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl,
alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano,
alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. In some
embodiments, a substituent may also be an imaging moiety (e.g.,
18F) or a group for associating an imaging moiety (e.g., a
chelator).
[0722] Nitrogen-protecting groups are well known in the art and
include those described in detail in Protecting Groups in Organic
Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd edition, John
Wiley & Sons, 1999, incorporated herein by reference. For
example, nitrogen protecting groups include, but are not limited
to, carbamates (including methyl, ethyl and substituted ethyl
carbamates (e.g. Troc), to name a few), amides, cyclic imide
derivatives, N-alkyl and N-aryl amines, imine derivatives, and
enamine derivatives, to name a few. In some embodiments, the
nitrogen-protecting group is carbobenzyloxy (Cbz), p-methoxybenzyl
carbonyl (MeOZ), t-butyloxycarbonyl (Boc),
9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz),
benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM),
p-methoxyphenyl (PMP), or p-toluenesulfonyloxy (Ts).
[0723] Nitrogen-protecting groups such as amide groups include, but
are not limited to, formamide, acetamide, chloroacetamide,
trichloroacetamide, trifluoroacetamide, phenylacetamide,
3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide,
N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide,
o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide,
(N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide, and
o-(benzoyloxymethyl)benzamide.
[0724] Nitrogen-protecting groups such as carbamate groups include,
but are not limited to, methyl carbamate, ethyl carbamante,
9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl
carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl
carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl
carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl
carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate,
benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2 dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0725] Nitrogen-protecting groups such as sulfonamide groups
include, but are not limited to, p-toluenesulfonamide (Ts),
benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide
(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), .beta.-trimethylsilylethanesulfonamide
(SES), 9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0726] Other nitrogen-protecting groups include, but are not
limited to, phenothiazinyl(10)acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-pmethoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxolcyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys).
[0727] As used herein, the term "determining" generally refers to
the analysis of a species or signal, for example, quantitatively or
qualitatively, and/or the detection of the presence or absence of
the species or signals.
[0728] The term "diagnostic imaging," as used herein, refers to a
procedure used to detect an imaging agent.
[0729] The term "diagnosis" as used herein encompasses
identification, confirmation, and/or characterization of a
condition, a disease, and/or a disorder.
[0730] A "diagnostic kit" or "kit" comprises a collection of
components, termed the formulation, in one or more vials which are
used by the practicing end user in a clinical or pharmacy setting
to synthesize diagnostic radiopharmaceuticals. For example, the kit
may be used by the practicing end user in a clinical or pharmacy
setting to synthesize and/or use diagnostic radiopharmaceuticals.
In some embodiments, the kit may provide all the requisite
components to synthesize and use the diagnostic pharmaceutical
except those that are commonly available to the practicing end
user, such as water or saline for injection and/or the radioisotope
(e.g., .sup.18F). equipment for processing the kit during the
synthesis and manipulation of the radiopharmaceutical, if required,
equipment necessary for administering the radiopharmaceutical to
the subject such as syringes, shielding, imaging equipment, and the
like. In some embodiments, imaging agents may be provided to the
end user in their final form in a formulation contained typically
in one vial or syringe, as either a lyophilized solid or an aqueous
solution.
[0731] As used herein, a "portion of a subject" refers to a
particular region of a subject, location of the subject. For
example, a portion of a subject may be the brain, heart,
vasculature, cardiac vessels, tumor, etc., of a subject.
[0732] As used herein a "session" of testing may be a single
testing protocol that a subject undergoes.
[0733] As used herein, the term "subject" refers to a human or
non-human mammal or animal. Non-human mammals include livestock
animals, companion animals, laboratory animals, and non-human
primates. Non-human subjects also specifically include, without
limitation, horses, cows, pigs, goats, dogs, cats, mice, rats,
guinea pigs, gerbils, hamsters, mink, and rabbits. In some
embodiments of the invention, a subject is referred to as a
"patient." In some embodiments, a patient or subject may be under
the care of a physician or other health care worker, including, but
not limited to, someone who has consulted with, received advice
from or received a prescription or other recommendation from a
physician or other health care worker.
[0734] The term "perfusion" is given its ordinary meaning in the
art and refers to the flow of blood to a muscle or a tissue. The
term "cardiac perfusion" refers to the flow of blood to the heart.
The term "innervation" is given its ordinary meaning in the art and
refers to the supply of nervous energy or of nerve stimulus sent to
a portion of a subject. The term "cardiac innervation" refers to
the supply of nervous energy or of nerve stimulus sent to the heart
of a subject.
[0735] Any of the compounds described herein may be in a variety of
forms, such as, but not limited to, salts, solvates, hydrates,
tautomers, and isomers.
[0736] In certain embodiments, the imaging agent is a
pharmaceutically acceptable salt of the imaging agent. The term
"pharmaceutically acceptable salt" as used herein refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al., describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,
incorporated herein by reference. Pharmaceutically acceptable salts
of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4 salts.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counter ions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[0737] In certain embodiments, the compound is in the form of a
hydrate or solvate. The term "hydrate" as used herein refers to a
compound non-covalently associated with one or more molecules of
water. Likewise, the term "solvate" refers to a compound
non-covalently associated with one or more molecules of an organic
solvent.
[0738] In certain embodiments, the compound described herein may
exist in various tautomeric forms. The term "tautomer" as used
herein includes two or more interconvertable compounds resulting
from at least one formal migration of a hydrogen atom and at least
one change in valency (e.g., a single bond to a double bond, a
triple bond to a single bond, or vice versa). The exact ratio of
the tautomers depends on several factors, including temperature,
solvent, and pH. Tautomerizations (i.e., the reaction providing a
tautomeric pair) may be catalyzed by acid or base. Exemplary
tautomerizations include keto-to-enol; amide-to-imide;
lactam-to-lactim; enamine-to-imine; and enamine-to-(a different)
enamine tautomerizations.
[0739] In certain embodiments, the compounds described herein may
exist in various isomeric forms. The term "isomer" as used herein
includes any and all geometric isomers and stereoisomers (e.g.,
enantiomers, diasteromers, etc.). For example, "isomer" includes
cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers,
diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof,
and other mixtures thereof, as falling within the scope of the
invention. For instance, an isomer/enantiomer may, in some
embodiments, be provided substantially free of the corresponding
enantiomer, and may also be referred to as "optically enriched."
"Optically-enriched," as used herein, means that the compound is
made up of a significantly greater proportion of one enantiomer. In
certain embodiments the compound of the present invention is made
up of at least about 90% by weight of a preferred enantiomer. In
other embodiments the compound is made up of at least about 95%,
98%, or 99% by weight of a preferred enantiomer. Preferred
enantiomers may be isolated from racemic mixtures by any method
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts or prepared by asymmetric syntheses. See, for
example, Jacques, et al., Enantiomers, Racemates and Resolutions
(Wiley Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon
Compounds (McGrawHill, N.Y., 1962); Wilen, S. H. Tables of
Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,
Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
[0740] These and other aspects of the present invention will be
further appreciated upon consideration of the following Examples,
which are intended to illustrate certain particular embodiments of
the invention but are not intended to limit its scope, as defined
by the claims.
EXAMPLES
[0741] The following examples related to the compounds shown in
FIG. 1 or salts thereof. For example, Example 1 provides the
synthesis of the compound of Example 1 shown in FIG. 1.
Example 1
4-(4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine
##STR00333##
[0742] Part 1A--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]ami-
no}methylidene]carbamate
##STR00334##
[0744] 4-(2-Amino-1-hydroxyethyl)phenol hydrochloride (0.493 g, 2.6
mmol), was dissolved in dry DMF (10.0 mL) then successively treated
with N,N-diisopropylethylamine (645 .mu.L, 3.6 mmol) and
N,N'-di-Boc-1H-pyrazole-1-carboxamidine (1.15 g, 3.7 mmol), and the
resulting solution stirred 1 h at ambient temperature. All
volatiles were then removed in vacuo and the residue dissolved in
EtOAc with transfer to a separatory funnel. The EtOAc solution was
exhaustively washed with dilute aqueous solutions of KHSO.sub.4 and
Na.sub.2CO.sub.3 then dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. Purification by chromatography on silica
using a step gradient from 7:3 hexanes/EtOAc to 1:1 hexanes/EtOAc
afforded the title compound as a white solid (0.837 g, 2.12 mmol;
81.4%).
Part 1B--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]([2-[4-(2-fluoroethoxy)phenyl]-2-hydroxy-
ethyl]amino)methylidene]carbamate
##STR00335##
[0746] The product of Part 1A (0.312 g, 0.790 mmol) was dissolved
in dry DMSO (2.00 mL) then successively treated with
K.sub.2CO.sub.3 (0.164 g, 1.19 mmol), KI (1.16 mg, 0.007 mmol) and
1-bromo-2-fluoroethane (89.0 .mu.L, 1.19 mmol) at ambient
temperature. The resulting suspension was warmed to 50.degree. C.
and maintained 3 h. After cooling to ambient temperature, the
solution was partitioned between EtOAc and H.sub.2O (15 mL each)
with transfer to a separatory funnel. The layers separated and the
EtOAc layer washed with saturated aqueous NaCl, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Purification
by chromatography on silica using 9:1 hexanes/EtOAc afforded the
title compound as a white solid (0.178 g, 0.403 mmol; 51.0%).
Part 1C--Preparation of
4-(4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine, hydrochloric acid
salt
##STR00336##
[0748] The product of Part 1B (88.3 mg, 0.20 mmol) was dissolved in
a solution of Et.sub.3SiH/H.sub.2O/CF.sub.3CO.sub.2H (0.5:0.5/19
v/v/v; 2.0 mL) at ambient temperature then warmed to 55.degree. C.
and maintained 10 min. The resulting solution was cooled,
concentrated in vacuo then directly purified by HPLC on a
Phenomenex Luna C18 column (21.2.times.250 mm) using a 0.8%/min
gradient from 0-20% MeCN containing 0.1% HCO.sub.2H and 10%
H.sub.2O at 20 mL/min. The main product peak eluting at 17 min was
collected, pooled then lyophilized to a hygroscopic white powder.
The solids were re-dissolved in 0.5 N HCl and lyophilized to afford
the title compound as a white powder (14.2 mg, 0.055 mmol;
27.3%).
Part 1D--Preparation of Preparation of [.sup.18F]fluoride
[0749] [.sup.18F]Fluoride was produced by proton bombardment of
[.sup.18O]H.sub.2O in a cyclotron; the nuclear chemical
transformation is shown below and may be summarized as .sup.18O
(p,n).sup.18F. For purposes of the bombardment, the chemical form
of the .sup.18O is H.sub.2.sup.18O. The chemical form of the
resulting .sup.18F is fluoride ion.
.sup.18O+proton.fwdarw..sup.18F+neutron
[0750] According to established industry procedures,
[.sup.18O]H.sub.2O (2-3 mL) housed within a tantalum target body
using Havar.RTM. foil, was bombarded with 11 MeV protons (nominal
energy); where the proton threshold energy for the reaction is 2.57
MeV and the energy of maximum cross section is 5 MeV. Target
volume, bombardment time and proton energy each may be adjusted to
manage the quantity of [.sup.18F]fluoride produced.
Part 1E--Preparation of 2-[.sup.18F]fluoroethyl
4-methylbenzenesulfonate
[0751] An MP1 anion exchange cartridge containing 1,000 mCi of
[.sup.18F]NaF (produced according to the general procedure
described in Part 1D) was eluted with 0.20% aqueous K.sub.2CO.sub.3
(1.0 mL), using an automated liquid handling system, into a 25 mL
conical-bottomed silanized flask. All volatiles were removed by
applying a gentle stream of warm Ar and applied vacuum. The
contents of the flask were reconstituted with 0.5 mL of MeCN, and
concentrated again using warm Ar and applied vacuum (azeotropic
evaporation). A separate 5 mL conical-bottomed Wheaton.TM. vial was
used to prepared a solution of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (22.5
mg) and ethylene di-(p-toluenesulfonate) (3.8 mg) in MeCN (1.0 mL).
The constituents of the vial were transferred to the 25 mL flask
containing [.sup.18F]KF then positioned inside a microwave cavity
(model 520 Resonance Instruments, Skokie, Ill.) and irradiated for
3 min at 75 watts. After cooling, the contents of the microwave
reaction vial were filtered through an anion exchange resin to
remove residual fluoride ion, collected in a 5 mL conical-bottomed
Wheaton.TM. reaction vial and used without further purification in
the subsequent reaction.
Part 1F--Preparation of
4-{4-[2-(.sup.18F)fluoroethoxy]phenyl}imidazolidin-2-imine, formic
acid salt
##STR00337##
[0753] The product of Part 1E was transferred to a 5 mL
conical-bottomed Wheaton.TM. reaction vial containing the product
of Part 1A (4.0 mg), K.sub.2CO.sub.3 (10.9 mg) and anhydrous DMSO
(400 .mu.L). The resulting mixture was heated at 80.degree. C. for
30 min then cooled to ambient temperature then transferred to a
clean 25 mL pear-shaped flask and diluted with H.sub.2O (18.5 mL).
The contents of the pear shaped flask were passed through a Sep
Pak.TM. C18 cartridge and the cartridge was rinsed with H.sub.2O
(5.0 mL). The desired product was eluted from the cartridge with
MeCN (3.0 mL) into a 5 mL conical-bottomed Wheaton.TM. vial. All
volatiles were removed, and the residue treated with a solution of
trifluoroacetic acid in CH.sub.2Cl.sub.2 (1:1 v/v, 2.0 mL). The
resulting solution was warmed to 50.degree. C., maintained 15 min
then cooled to ambient temperature and concentrated to dryness.
Purification by HPLC on a Phenomenex Luna C18(2) column
(10.times.250 mm, 5 micron particle size, 100 Angstrom pore size)
using a 5.0%/min gradient of 0-100% MeCN containing 0.1% HCO.sub.2H
acid at a flow rate of 2.0 mL/min. The title compound was
collected, all volatiles removed, and the residue reconstituted
with 10% aqueous ethanol solution for biological experiments.
Example 2
4-(3-bromo-4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine,
hydrochloric acid salt
##STR00338##
[0754] Part 2A--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]{[2-hydroxy-2-(3-bromo-4-hydroxyphenyl)e-
thyl]amino}methylidene]carbamate
##STR00339##
[0756] The product of Part 1A (1.75 g, 4.43 mmol), was dissolved
H.sub.2O/MeCN (3:2 v/v, 75.0 mL) then successively treated with
NaBrO.sub.3 (0.735 g, 4.87 mmol) and NaHSO.sub.3 (0.507 g, 4.87
mmol) and the resulting solution stirred 40 min at ambient
temperature. Additional NaBrO.sub.3 (1.13 g, 7.5 mmol) and
NaHSO.sub.3 (0.780 g, 7.5 mmol) and the resulting solution stirred
3 h. Excess NaBrO.sub.3 was then consumed by the addition of
Na.sub.2S.sub.2O.sub.3 (2.1 g, 13.3 mmol). After 30 min, the MeCN
was removed in vacuo and the aqueous solution washed with
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 was further washed with
saturated aqueous NaCl, then dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue was purified by
chromatography on silica using a hexanes/EtOAc gradient to afford
the title compound as a white solid (0.635 g, 1.34 mmol;
30.2%).
Part 2B--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]({2-[3-bromo-4-(2-fluoroethoxy)phenyl]-2-
-hydroxyethyl}amino)methylidene]carbamate
##STR00340##
[0758] The product of Part 2A (0.306 g, 0.645 mmol) was dissolved
in dry DMSO (3.00 mL) then successively treated with
K.sub.2CO.sub.3 (0.134 g, 0.968 mmol), KI (single crystal) and
1-bromo-2-fluoroethane (48 .mu.L, 0.645 mmol) at ambient
temperature. The resulting suspension was warmed to 50.degree. C.
and maintained 1.5 h. After cooling to ambient temperature, the
solution was partitioned between EtOAc and H.sub.2O with transfer
to a separatory funnel. The layers separated and the EtOAc layer
washed with H.sub.2O followed by saturated aqueous NaCl then dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification by chromatography on silica using a hexanes/EtOAc
gradient afforded the title compound as a white solid (0.218 g,
0.419 mmol; 64.9%).
Part 2C--Preparation of
4-(3-bromo-4-(2-fluoroethoxy)phenyl)imidazolidin-2-imine,
hydrochloric acid salt
##STR00341##
[0760] The product of Part 2B (90.0 mg, 0.173 mmol) was dissolved
in aqueous CF.sub.3CO.sub.2H (1:40 v/v; 2.0 mL) at ambient
temperature then warmed to 55.degree. C. and maintained 15 min. The
resulting solution was cooled, concentrated in vacuo then directly
purified by HPLC on a Phenomenex Luna C18 column (21.2.times.250
mm) using a 0.6%/min gradient from 5-23% MeCN containing 0.1%
HCO.sub.2H and 10% H.sub.2O at 20 mL/min. The main product peak
eluting at 2 min was collected, pooled then lyophilized to a
hygroscopic white powder. The solids were re-dissolved in 0.5 N HCl
and lyophilized to afford the title compound as a white powder
(18.6 mg, 0.055 mmol; 31.7%).
Part 2D--Preparation of
4-{4-[2-(.sup.18F)fluoroethoxy]phenyl}imidazolidin-2-imine, formic
acid salt
##STR00342##
[0762] The product of Part 1E was transferred to a 5 mL
conical-bottomed Wheaton.TM. reaction vial containing the product
of Part 2A (4.0 mg), K.sub.2CO.sub.3 (10.9 mg) and anhydrous DMSO
(400 .mu.L). The resulting mixture was heated at 80.degree. C. for
30 min then cooled to ambient temperature then transferred to a
clean 25 mL pear-shaped flask and diluted with H.sub.2O (18.5 mL).
The contents of the pear shaped flask were passed through a Sep
Pak.TM. C18 cartridge and the cartridge was rinsed with H.sub.2O
(5.0 mL). The desired product was eluted from the cartridge with
MeCN (3.0 mL) into a 5 mL conical-bottomed Wheaton.TM. vial. All
volatiles were removed, and the residue treated with a solution of
trifluoroacetic acid in CH.sub.2Cl.sub.2 (1:1 v/v, 2.0 mL). The
resulting solution was warmed to 50.degree. C., maintained 15 min
then cooled to ambient temperature and concentrated to dryness.
Purification by HPLC on a Phenomenex Luna C18(2) column
(10.times.250 mm, 5 micron particle size, 100 Angstrom pore size)
using a 5.0%/min gradient of 0-100% EtOH containing 0.1% HCO.sub.2H
acid at a flow rate of 2.0 mL/min. The title compound was
collected, all volatiles removed, and the residue reconstituted
with 10% aqueous ethanol solution for biological experiments.
Example 3
1-(3-bromo-4-(fluoromethyl)benzyl)guanidine
##STR00343##
[0763] Part 3A--Preparation of
3-bromo-4-(dibromomethyl)benzonitrile
##STR00344##
[0765] A solution of 3-bromo-4-methyl-benzonitrile (5.00 g, 25.5
mmol) was dissolved in CCl.sub.4 (170 mL) and successively treated
with NBS (18.2 g, 102 mmol) and benzoyl peroxide (0618 g, 2.55
mmol) at ambient temperature. The resulting solution was warmed to
reflux, maintained 48 h then cooled to ambient temperature and
filtered through a scintered glass funnel of medium porosity. The
filtrate was concentrated, and the crude orange solid thus obtained
purified by chromatography on silica using 49:1 hexanes/EtOAc to
afford the title compound as a white solid (8.80 g, 24.9 mmol;
97.5%).
Part 3B--Preparation of 3-bromo-4-formylbenzonitrile
##STR00345##
[0767] A solution of the product of Part 3A (8.80 g, 24.9 mmol) was
dissolved in wet DMSO (83 mL) at ambient temperature then warmed to
120.degree. C. and maintained 6 h. After cooling to ambient
temperature, the resulting solution was diluted with H.sub.2O with
transfer to a separatory funnel then washed EtOAc. The EtOAc
solution was separated, washed with H.sub.2O and saturated aqueous
NaCl then dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to a yellow solid. Subsequent purification by chromatography
on silica using 20:1 hexanes/EtOAc afforded the title compound as a
white solid (3.10 g, 14.8 mmol; 59.3%).
Part 3C--Preparation of 3-bromo-4-(hydroxymethyl)benzonitrile
##STR00346##
[0769] A solution of the product of Part 3B (3.10 g, 14.7 mmol) was
dissolved MeOH (74 mL) at ambient temperature then cooled to
0.degree. C. using an ice bath. NaBH.sub.4 (0.279 g, 7.38 mmol) was
then added in one portion and the resulting solution maintained 40
min at 0.degree. C. Dilute aqueous HCl was added to consume excess
NaBH.sub.4 then all volatiles removed in vacuo. The residue was
redissolved in EtOAc with transfer to a separatory funnel,
successively washed with 5% aqueous citric acid and H.sub.2O, then
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification by chromatography on silica using a step gradient from
9:1 hexanes/EtOAc to 1:1 hexanes/EtOAc afforded the title compound
as a white solid (1.90 g, 8.96 mmol; 60.7%).
Part 3D--Preparation of [4-(aminomethyl)-2-bromophenyl]methanol
##STR00347##
[0771] LiAlH.sub.4 (34.0 mmol; 34.0 mL of a 1.0 M solution in THF)
was cooled to 0.degree. C. using an ice bath then treated with MeOH
(102 mmol; 26.4 mL of a 3.86 M solution in THF) dropwise over 5
min. The product of Part 3C (0.900 g, 4.24 mmol) was then added and
the resulting solution warmed slowly to ambient temperature as the
ice bath melted. After 16 h total reaction time, the solution was
diluted with H.sub.2O (9.0 mL) and the resulting suspension
filtered through a scintered glass funnel of medium porosity. The
solids were exhaustively washed with H.sub.2O and Et.sub.2O then
transferred to a separatory funnel and split. The aqueous layer was
further washed with Et.sub.2O and EtOAc and the combined organic
layers dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to a yellow solid (0.591 g), which was used without further
purification in the subsequent reaction.
Part 3E--Preparation of tert-but-2-yl
[(Z)-{[3-bromo-4-(hydroxymethyl)benzyl]amino}{[(tert-but-2-yl
oxy)carbonyl]amino}methylidene]carbamate
##STR00348##
[0773] A solution of the product of Part 3D (0.585 g, 2.71 mmol)
was dissolved MeCN (9.00 mL) at ambient temperature then treated
with N,N'-di-Boc-1H-pyrazole-1-carboxamidine (1.00 g, 3.25 mmol) in
one portion at ambient temperature. After 30 min, all volatiles
were removed in vacuo and the residue purified by chromatography on
silica using 5:1 hexanes/EtOAc to afford the title compound as a
white foam (0.860 g, 1.88 mmol; 69.2%).
Part 3F--Preparation of
1-[3-bromo-4-(fluoromethyl)benzyl]guanidine, trifluoroacetic acid
salt
##STR00349##
[0775] Deoxo-Fluor.RTM. (0.240 mmol; 103 .mu.L of a 50% solution in
THF) was diluted with CH.sub.2Cl.sub.2 (137 .mu.L) then cooled to
-78.degree. C. and treated with a solution of the product of Part
3E (0.218 mmol; 218 .mu.L of a 1.0 M solution in CH.sub.2Cl.sub.2)
dropwise over 5 min. After 2 h, additional Deoxo-Fluor.RTM. (0.044
mmol; 19 .mu.L) was added, the resulting solution stirred 1 h at
-78.degree. C. then treated with saturated aqueous NaHCO.sub.3(273
.mu.L) before warming to ambient temperature. The layers were then
separated and the aqueous layer washed with CH.sub.2Cl.sub.2
(2.times.164 .mu.L). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, concentrated in vacuo then redissolved
in dioxane (200 .mu.L) and treated with concentrated HCl (600
.mu.L) at ambient temperature. After 1 h, all volatiles were
removed and the residue purified by HPLC on a Phenomenex Luna C18
column (21.2.times.250 mm) using a 2%/min gradient from 0-60% MeCN
containing 0.1% CF.sub.3CO.sub.2H and 10% H.sub.2O at 20 mL/min.
The main product peak was collected, pooled and lyophilized to a
white solid (14 mg, 37 mmol; 17%).
Part 3G--Preparation of tert-but-2-yl
[(Z)-{[3-bromo-4-(bromomethyl)benzyl]-amino}{[(tert-but-2-yl
oxy)carbonyl]amino}methylidene]carbamate
##STR00350##
[0777] A solution of the product of Part 3E (75.0 mg, 0.164 mmol)
was dissolved dry CH.sub.2Cl.sub.2 (2.00 mL) then successively
treated with CBr.sub.4 (109 mg, 0.327 mmol) and PPh3 (85.8 mg,
0.327 mmol) at ambient temperature; within 2 h, complete conversion
to the expected product was observed. All volatiles were then
removed in vacuo and the residue purified by chromatography on
silica using hexanes/EtOAc to afford the title compound as a white
solid that was used without further purification in the subsequent
fluorination reaction.
Part 3H--Preparation of
1-{3-bromo-4-[[.sup.18F]fluoromethyl]benzyl}guanidine, formic acid
salt
##STR00351##
[0779] An MP1 anion exchange cartridge containing 1,000 mCi of
[.sup.18F]NaF (produced according to the general procedure
described in Part 1D) was eluted with 0.20% aqueous K.sub.2CO.sub.3
(1.0 mL), using an automated liquid handling system, into a 25 mL
conical-bottomed silanized flask. All volatiles were removed by
applying a gentle stream of warm Ar and applied vacuum. The
contents of the flask were reconstituted with 0.5 mL of MeCN, and
concentrated again using warm Ar and applied vacuum (azeotropic
evaporation). The residue was treated with a solution of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (19.7
mg) in MeCN (0.90 mL) then transferred to a solution of the product
of Part 3G (3.8 mg) in dry MeCN (0.40 mL). The resulting solution
was heated to 49.degree. C., maintained 45 min then cooled to
ambient temperature and concentrated. The residue thus obtained was
redissolved in CH.sub.2Cl.sub.2 (0.40 mL) then treated with
CF.sub.3CO.sub.2H (1.00 mL) at ambient temperature. After 30 min,
all volatiles were removed and the residue purified by HPLC on a
Phenomenex Luna C18(2) column (250.times.10 mm, 5 micron particle
size, 100 Angstrom pore size) using a 5.0%/min gradient of 0-100%
MeCN containing 0.1% HCO.sub.2H acid at a flow rate of 2.0 mL/min.
The title compound was collected, all volatiles removed, and the
residue reconstituted with 10% aqueous ethanol solution for
biological experiments.
Example 4
1-(3-bromo-4-((2-fluoroethoxy)methyl)benzyl)guanidine
##STR00352##
[0780] Part 4A--Preparation of
1-{3-bromo-4-[(2-fluoroethoxy)methyl]benzyl}guanidine,
trifluoroacetic acid salt
##STR00353##
[0782] The product of Part 3E (0.100 g, 0.218 mmol) was dissolved
in wet DMSO (2.20 mL) then treated with powdered NaOH (17.0 mg,
0.436 mmol) at ambient temperature. After 30 min, 2-fluoroethyl
4-methylbenzenesulfonate (48.0 mg, 0.218 mmol) was added in one
portion and the resulting solution warmed to 75.degree. C. and
maintained 80 min. After cooling to ambient temperature, the
solution was diluted with H.sub.2O, with transfer to a separatory
funnel then exhaustively washed with EtOAc. The combined EtOAc
washes were further washed with 5% aqueous citric acid then dired
over Na2SO4, filtered and concentrated in vacuo. The crude residue
was redissolved in dioxane (200 .mu.L) then treated with
concentrated HCl (600 .mu.L) at ambient temperature. After 1 h, all
volatiles were removed and the residue purified by HPLC on a
Phenomenex Luna C18 column (21.2.times.250 mm) using a 2%/min
gradient from 0-30% MeCN containing 0.1% CF.sub.3CO.sub.2H and 10%
H.sub.2O at 20 mL/min. The main product peak was collected, pooled
and lyophilized to a white solid (10.7 mg, 25.6 .mu.mol;
11.7%).
Part 4B--Preparation of
1-{3-bromo-4-[(2-[.sup.18F]fluoroethoxy)methyl]benzyl}guanidine,
trifluoroacetic acid salt
##STR00354##
[0784] The product of Part 1E was transferred to a 5 mL
conical-bottomed Wheaton.TM. reaction vial containing the product
of Part 3E (4.0 mg), KOH (1.6 mg) and anhydrous DMSO (400 .mu.L).
The resulting mixture was heated at 80.degree. C. for 45 min,
cooled to ambient temperature, concentrated in vacuo then treated
with CF.sub.3CO.sub.2H (1.00 mL) and warmed to 50.degree. C. After
15 min, the resulting mixture was cooled to ambient temperature,
concentrated to dryness then purified by HPLC on a Phenomenex Luna
C18(2) column (10.times.250 mm, 5 micron particle size, 100
Angstrom pore size) using a 5.0%/min gradient of 0-100% MeCN
containing 0.1% HCO.sub.2H acid at a flow rate of 2.0 mL/min. The
title compound was collected, all volatiles removed, and the
residue reconstituted with 10% aqueous ethanol solution for
biological experiments.
Example 5
1-[4-(2-fluoroethyl)benzyl]guanidine
##STR00355##
[0785] Part 5A--Preparation of 4-(2-fluoroethyl)benzonitrile
##STR00356##
[0787] Deoxo-Fluor.RTM. (0.843 g, 3.81 mmol) was dissolved in
CH.sub.2Cl.sub.2 (0.50 mL) then cooled to -78.degree. C. and
treated with a solution of 4-(2-hydroxyethyl)benzonitrile (3.47
mmol; 1.50 mL of a 2.31 M solution in CH.sub.2Cl.sub.2) dropwise
over 5 min. The resulting mixture warmed slowly to ambient
temperature as the cooling bath evaporated overnight. Saturated
aqueous NaHCO.sub.3(50 mL) was then added with transfer to a
separatory funnel and the layers separated. The aqueous layer
washed with CH.sub.2Cl.sub.2 (3.times.25 mL) and the combined
organic layers dried over MgSO.sub.4, filtered and concentrated in
vacuo. Subsequent purification by chromatography on silica using
4:1 hexanes/EtOAc afforded the title compound as a pale yellow oil
(0.305 g, 2.04 mmol; 59.0%).
Part 5B--Preparation of 1-[4-(2-fluoroethyl)phenyl]methanamine
##STR00357##
[0789] The product of Part 5A (0.210 g, 1.41 mmol) was dissolved in
MeOH (13.0 mL) then successively treated with concentrated HCl
(1.00 mL) and Pd/C (0.141 mmol; 10 mol %) at ambient temperature.
The headspace of the reaction vessel was sparged with 1 atm H.sub.2
then maintained 2 h. Upon complete reduction, the headspace was
sparged with dry N2 and the catalyst removed by filtration through
Celite. The filter cake was exhaustively washed with MeOH and the
combined filtrates concentrated in vacuo to a white powder. The
crude material was used without further purification in the
subsequent reaction.
Part 5C--Preparation of 4-(2-fluoroethyl)benzylguanidine,
trifluoroacetic acid salt
##STR00358##
[0791] The product of Part 5B (0.150 g, 0.791 mmol) was dissolved
in MeCN (4.00 mL) and successively treated with
N,N-diisopropylethylamine (152 mL, 0.867 mmol) and
1H-pyrazole-1-carboximidamide (0.128 g, 0.870 mmol) at ambient
temperature. After 1 h, all volatiles were removed in vacuo and the
residue purified by HPLC on a Phenomenex Luna C18 column
(21.2.times.250 mm) using 1%/min gradient from 2-32% MeCN
containing 0.1% CF.sub.3CO.sub.2H and 10% H.sub.2O at 20 mL/min.
The main product peak was collected, pooled and lyophilized to a
white solid (0.189 g, 0.484 mmol; 61.2%).
Part 5D--Preparation of 2-[4-(aminomethyl)phenyl]ethanol
##STR00359##
[0793] 4-(2-Hydroxyethyl)benzonitrile (0.402 g, 2.73 mmol) was
dissolved in MeOH (10.0 mL) then successively treated with
concentrated HCl (0.50 mL) and Pd/C (0.145 mmol; 5 mol %) at
ambient temperature. The headspace of the reaction vessel was
sparged with 1 atm H.sub.2 then maintained 16 h. Upon complete
reduction, the headspace was sparged with dry N2 and the catalyst
removed by filtration through Celite. The filter cake was
exhaustively washed with MeOH and the combined filtrates
concentrated in vacuo to a white powder. The crude material was
used without further purification in the subsequent reaction.
Part 5E--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]{[4-(2-hydroxyethyl)benzyl]amino}methyli-
dene]carbamate
##STR00360##
[0795] The product of Part 5D (0.553 g, 2.95 mmol) was dissolved in
MeCN (5.00 mL) and successively treated with
N,N-diisopropylethylamine (513 .mu.L, 2.95 mmol) and
N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.915 g, 2.95 mmol) at
ambient temperature. After 2 h, all volatiles were removed in vacuo
and the residue redissolved in CH.sub.2Cl.sub.2 (15 mL) with
transfer to a separatory funnel. The CH.sub.2Cl.sub.2 solution was
successively washed with 10% aqueous citric acid, H.sub.2O and
saturated aqueous NaCl (1.times.15 mL each) then dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Subsequent
purification by chromatography on silica, using a hexanes/EtOAc
gradient from 0-100% EtOAc over 17 min, afforded the title compound
as a white solid (0.777 g, 1.97 mmol; 67.0%).
Part 5F--Preparation of
2-{4-[(N',N'-bis(tert-butoxycarbonyl)carbamimidamido)methyl]-phenyl}ethyl
4-methylbenzenesulfonate
##STR00361##
[0797] The product of Part 5E (0.363 g, 0.918 mmol) was dissolved
in CH.sub.2Cl.sub.2 (4.00 mL) and successively treated with
p-toluenesulfonyl chloride (0.264 g, 1.38 mmol) and pyridine (164
.mu.L, 2.03 mmol) at 0.degree. C. After 16 h, the resulting
solution was diluted with CH.sub.2Cl.sub.2 (10 mL) with transfer to
a separatory funnel. The CH.sub.2Cl.sub.2 solution was successively
washed with 5% aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous
NaCl (1.times.15 mL each) then dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Subsequent purification by
chromatography on silica, using a hexanes/EtOAc gradient from
0-100% EtOAc over 17 min, afforded the title compound as a white
solid (0.393 g, 0.717 mmol; 77.8%).
Part 5G--Preparation of
1-[4-[2-[.sup.18F]fluoroethyl]benzyl]guanidine, formic acid
salt
##STR00362##
[0799] An MP1 anion exchange cartridge containing 1,000 mCi of
[.sup.18F]NaF (produced according to the general procedure
described in Part 1D) was eluted with 0.20% aqueous K.sub.2CO.sub.3
(1.0 mL), using an automated liquid handling system, into a 25 mL
conical-bottomed silanized flask. All volatiles were removed by
applying a gentle stream of warm Ar and applied vacuum. The
contents of the flask were reconstituted with 0.5 mL of MeCN, and
concentrated again using warm Ar and applied vacuum (azeotropic
evaporation). The residue was treated with a solution of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (20.5
mg) in MeCN (0.90 mL) then transferred to a solution of the product
of Part 5F (3.97 mg) in dry MeCN (0.40 mL). The resulting solution
was heated to 60.degree. C., maintained 45 min then cooled to
ambient temperature and concentrated. The residue thus obtained was
redissolved in CF.sub.3CO.sub.2H (1.00 mL), stirred 15 min at 4o
.degree. C. then cooled and concentrated. Subsequent purification
by HPLC on a Phenomenex Luna C18(2) column (250.times.10 mm, 5
micron particle size, 100 Angstrom pore size) using a 5.0%/min
gradient of 0-100% MeCN containing 0.1% HCO.sub.2H acid at a flow
rate of 2.0 mL/min. The title compound was collected, all volatiles
removed, and the residue reconstituted with 10% aqueous ethanol
solution for biological experiments.
Example 8
1-(3-bromo-4-(2-fluoroethyl)benzyl)guanidine
##STR00363##
[0800] Part 8A--Preparation of
3-bromo-4-(2-hydroxyethyl)benzonitrile
##STR00364##
[0802] 4-(2-Hydroxyethyl)benzonitrile (1.22 g, 8.29 mmol) was
dissolved in H.sub.2O/H.sub.2SO.sub.4 (1:1 v/v, 8.00 mL) then
treated with NBS (1.48 g, 8.32 mmol) in one portion at ambient
temperature. The reaction vessel was then covered with aluminum
foil and maintained 48 h. The resulting solution was transferred to
a separatory funnel, neutralized with 10% aqueous NaOH then washed
with EtOAc (3.times.20 mL). The combined EtOAc washes were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Subsequent purification by chromatography on silica using 3:1
hexanes/EtOAc afforded the title compound as a pale yellow oil
(0.285 g, 1.26 mmol; 15.2%).
Part 8B--Preparation of 3-bromo-4-(2-fluoroethyl)benzonitrile
##STR00365##
[0804] Deoxo-Fluor.RTM. (0.291 g, 1.32 mmol) was dissolved in
CH.sub.2Cl.sub.2 (2.00 mL) then cooled to -78.degree. C. and
treated with a solution of the product of Part 8A (0.270 g, 1.19
mmol) dropwise over 5 min. The resulting mixture warmed slowly to
ambient temperature as the cooling bath evaporated overnight.
Saturated aqueous NaHCO.sub.3(50 mL) was then added with transfer
to a separatory funnel and the layers separated. The aqueous layer
washed with CH.sub.2Cl.sub.2 (3.times.25 mL) and the combined
organic layers dried over MgSO.sub.4, filtered and concentrated in
vacuo. Subsequent purification by chromatography on silica using
3:1 hexanes/EtOAc afforded the title compound as a pale yellow oil
(0.115 g, 0.504 mmol; 42.2%).
Part 8C--Preparation of
1-[3-bromo-4-(2-fluoroethyl)phenyl]methanamine
##STR00366##
[0806] LiAlH.sub.4 (3.79 mmol; 3.79 mL of a 1.0 M solution in THF)
was cooled to 0.degree. C. using an ice bath then treated with MeOH
(461 .mu.L, 11.4 mmol) dropwise over 5 min. The product of Part 8B
(0.482 mmol; 3.00 mL of a 0.16 M solution in THF) was then added
and the resulting solution warmed slowly to ambient temperature as
the ice bath melted. After 6 h, excess LiAlH.sub.4 was consumed by
the careful addition of H.sub.2O (0.50 mL). The resulting white
suspension was successively treated with 15% aqueous NaOH (0.50 mL)
and H.sub.2O (1.50 mL) and stirred for 15 min to a fine white
slurry. The resulting mixture was filtered through a pad of Celite
and concentrated in vacuo. The crude material thus obtained was
purified by chromatography on silica using 4:1
CH.sub.2Cl.sub.2/MeOH to afford the title compound as a pale yellow
oil (11.0 mg, 0.047 mmol; 9.8%).
Part 8D--Preparation of
1-[3-bromo-4-(2-fluoroethyl)benzyl]guanidine, trifluoroacetic acid
salt
##STR00367##
[0808] The product of Part 8C (11.0 mg, 0.047 mmol) was dissolved
in MeCN (2.00 mL) and successively treated with
N,N-diisopropylethylamine (18.2 .mu.L, 0.104 mmol) and
1H-pyrazole-1-carboximidamide (15.3 mg, 0.104 mmol) at ambient
temperature. After 2 h, all volatiles were removed in vacuo and the
residue purified by HPLC on a Phenomenex Luna C18 column
(21.2.times.250 mm) using 1%/min gradient from 10-40% MeCN
containing 0.1% CF.sub.3CO.sub.2H and 10% H.sub.2O at 20 mL/min.
The main product peak was collected, pooled and lyophilized to a
white solid.
Part 8E--Preparation of
2-[4-(aminomethyl)-2-bromophenyl]ethanol
##STR00368##
[0810] LiAlH.sub.4 (8.85 mmol; 8.85 mL of a 1.0 M solution in THF)
was cooled to 0.degree. C. using an ice bath then treated with MeOH
(1.08 mL, 26.4 mmol) dropwise over 5 min. The product of Part 8A
(1.11 mmol; 1.00 mL of a 1.11 M solution in THF) was then added and
the resulting solution warmed slowly to ambient temperature as the
ice bath melted. After 4.5 h, excess LiAlH.sub.4 was consumed by
the careful addition of H.sub.2O (0.335 mL). The resulting white
suspension was successively treated with 15% aqueous NaOH (0.335
mL) and H.sub.2O (1.01 mL) and stirred for 15 min to a fine white
slurry. The resulting mixture was filtered through a pad of Celite
and the filter cake exhaustively washed with THF and MeOH
(3.times.0.5 mL each). The combined filtrate was concentrated in
vacuo to a pale yellow oil that was used without further
purification in the subsequent reaction.
Part 8F--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]{[3-bromo-4-(2-hydroxyethyl)benzyl]amino-
}methylidene]carbamate
##STR00369##
[0812] The product of Part 8E (0.162 g, 0.704 mmol) was dissolved
in MeCN (1.00 mL) and successively treated with
N,N-diisopropylethylamine (123 .mu.L, 0.705 mmol) and
N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.219 g, 0.705 mmol) at
ambient temperature. After 0.5 h, all volatiles were removed in
vacuo and the residue redissolved in CH.sub.2Cl.sub.2 (15 mL) with
transfer to a separatory funnel. The CH.sub.2Cl.sub.2 solution was
successively washed with 10% aqueous citric acid, H.sub.2O and
saturated aqueous NaCl (1.times.15 mL each) then dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Subsequent
purification by chromatography on silica, using a hexanes/EtOAc
gradient from 0-100% EtOAc over 17 min, afforded the title compound
as a colorless oil (0.235 g, 0.497 mmol; 70.7%).
Part 8G--Preparation of
2-{3-bromo-4-[(N',N''-bis(tert-butoxycarbonyl)carbamimid-amido)methyl]phe-
nyl}ethyl 4-methylbenzenesulfonate
##STR00370##
[0814] The product of Part 8F (0.220 g, 0.465 mmol) was dissolved
in CH.sub.2Cl.sub.2 (2.00 mL) and successively treated with
p-toluenesulfonyl chloride (0.133 g, 0.698 mmol) and pyridine (83
.mu.L, 1.03 mmol) at 0.degree. C. After 5 h, the resulting solution
was diluted with CH.sub.2Cl.sub.2 (10 mL) with transfer to a
separatory funnel. The CH.sub.2Cl.sub.2 solution was successively
washed with 5% aqueous NaHCO.sub.3, H.sub.2O and saturated aqueous
NaCl (1.times.15 mL each) then dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Subsequent purification by
chromatography on silica, using a hexanes/EtOAc gradient from
0-100% EtOAc over 17 min, afforded the title compound as a white
solid (0.183 g, 0.292 mmol; 62.7%).
Part 8H--Preparation of
1-{4-[3-bromo-2-[.sup.18F]fluoroethyl]benzyl}guanidine, formic acid
salt
##STR00371##
[0816] An MP1 anion exchange cartridge containing 1,000 mCi of
[.sup.18F]NaF (produced according to the general procedure
described in Part 1D) was eluted with 0.20% aqueous K.sub.2CO.sub.3
(1.0 mL), using an automated liquid handling system, into a 25 mL
conical-bottomed silanized flask. All volatiles were removed by
applying a gentle stream of warm Ar and applied vacuum. The
contents of the flask were reconstituted with 0.5 mL of MeCN, and
concentrated again using warm Ar and applied vacuum (azeotropic
evaporation). The residue was treated with a solution of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (21.7
mg) in MeCN (0.90 mL) then transferred to a solution of the product
of Part 8G (5.00 mg) in dry DMSO (0.50 mL). The resulting solution
was heated to 80.degree. C., maintained 30 min then cooled to
ambient temperature and concentrated. The residue thus obtained was
redissolved in CF.sub.3CO.sub.2H (1.00 mL), stirred 15 min at
40.degree. C. then cooled and concentrated. Subsequent purification
by HPLC on a Phenomenex Luna C18(2) column (250.times.10 mm, 5
micron particle size, 100 Angstrom pore size) using a 5.0%/min
gradient of 0-100% MeCN containing 0.1% HCO.sub.2H acid at a flow
rate of 2.0 mL/min. The title compound was collected at 14 min, all
volatiles removed, and the residue reconstituted with 10% aqueous
ethanol solution for biological experiments.
Example 11
1-((6-(2-fluoroethoxy)naphthalen-2-yl)methyl)guanidine
##STR00372##
[0817] Part 11A--Preparation of
6-(2-fluoroethoxy)naphthalene-2-carbonitrile
##STR00373##
[0819] 6-Hydroxynaphthalene-2-carbonitrile (2.00 g, 11.8 mmol) was
dissolved in DMSO (36.0 mL) and successively treated with
1-bromo-2-fluoroethane (1.32 mL, 17.7 mmol) and K.sub.2CO.sub.3
(4.90 g, 35.5 mmol) at ambient temperature. The resulting
suspension was stirred 16 h then filtered through a scintered glass
funnel of medium porosity and treated with EtOAc (150 mL). The
EtOAc solution was transferred to a separatory funnel where it was
successively washed with H.sub.2O (200 mL), 5 N NaOH (50 mL) and
saturated aqueous NaCl then dried over MgSO.sub.4, filtered and
concentrated in vacuo to a pale yellow solid that was used without
further purification in the subsequent reaction.
Part 11B--Preparation of
1-[6-(2-fluoroethoxy)naphthalen-2-yl]methanamine
##STR00374##
[0821] The product of Part 11A (0.750 g, 3.49 mmol) was dissolved
in Et.sub.2O/THF (1:1 v/v, 24.0 mL), cooled to 0.degree. C. and
treated with LiAlH.sub.4 (0.463 g, 12.2 mmol) portionwise over 5
min. After 3 h, excess LiAlH.sub.4 was consumed by the careful
addition of H.sub.2O (0.463 mL). The resulting white suspension was
successively treated with 15% aqueous NaOH (0.463 mL) and H.sub.2O
(1.39 mL) and stirred for 15 min to a fine white slurry. The
resulting mixture was filtered through a pad of Celite and the
filtrate concentrated in vacuo to a pale yellow solid that was used
without further purification in the subsequent reaction.
Part 11C--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino][[6-(2-fluoroethoxy)naphthalen-2-yl]amin-
o]methylidene]arbamate
##STR00375##
[0823] The product of Part 11B (0.500 g, 2.28 mmol) was dissolved
in MeOH (25.0 mL) and successively treated with
N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.849 g, 2.74 mmol) at
ambient temperature. After 2 h, all volatiles were removed in vacuo
and the residue purified by chromatography on silica to afford the
title compound as a white solid.
Part 11D--Preparation of
1-{[6-(2-fluoroethoxy)naphthalen-2-yl]methyl}guanidine,
hydrochloric acid salt
##STR00376##
[0825] The product of Part 11C (75.0 mg, 0.163 mmol) was dissolved
in dioxane (1.00 mL) then treated with concentrated HCl (1.50 mL)
at ambient temperature. After 3 h, all volatiles were removed in
vacuo, the residue redissolved in H.sub.2O/MeCN (1:1 v/v) then
lyophilized to a pale yellow solid (48.0 mg, 0.161 mmol;
>98%).
Part 11E--Preparation of methyl
6-((tert-butyldimethylsilyl)oxy)naphthalene-2-carboxylate
##STR00377##
[0827] Methyl 6-hydroxynaphthalene-2-carboxylate (1.00 g, 4.95
mmol) was dissolved in DMF (20.0 mL) and successively treated with
tert-butyldimethylsilyl chloride (1.11 mL, 7.42 mmol) and imidazole
(0.673 g, 9.89 mmol) at ambient temperature. After 16 h, the
solution was partitioned between EtOAc and H.sub.2O with transfer
to a separatory funnel. The layers separated and the EtOAc layer
washed with H.sub.2O (210 mL) and saturated aqueous NaCl (300 mL)
then dried over MgSO.sub.4, filtered and concentrated in vacuo to a
white solid that was used without further purification in the
subsequent reaction.
Part 11F--Preparation of
(6-((tert-butyldimethylsilyl)oxy)naphthalen-2-yl)methanol
##STR00378##
[0829] The product of Part 11E (0.500 g, 1.58 mmol) was dissolved
in Et.sub.2O (5.00 mL), cooled to 0.degree. C. and treated with
LiAlH.sub.4 (0.180 g, 4.74 mmol) portionwise over 5 min. After 10
min, excess LiAlH.sub.4 was consumed by the careful addition of
H.sub.2O. The resulting white suspension was successively treated
with 15% aqueous NaOH and H.sub.2O and stirred for 15 min to a fine
white slurry. The resulting mixture was filtered through a pad of
Celite and the filtrate concentrated in vacuo to a white solid that
was used without further purification in the subsequent
reaction.
Part 11G--Preparation of tert-butoxy
[(E)-amino((tert-butoxycarbonyl){[(6-tert-butyldimethylsilyl)oxy)naphthal-
en-2-yl)methyl]amino}methylidene]carbamate
##STR00379##
[0831] The product of Part 11F (0.250 g, 0.870 mmol) was dissolved
in THF (5.00 mL), successively treated with
1,3-bis(tert-butoxycarbonyl)guanidine (0.451 g, 1.74 mmol) and
PPh.sub.3 (0.456 g, 1.74 mmol) then cooled to 0.degree. C. DIAD
(336 .mu.L, 1.74 mmol) was then added dropwise over 5 min at the
ice bath removed. After 4 h, all volatiles were removed and the
residue directly purified by chromatography on silica using 4:1
hexanes/Et.sub.2O to afford the title compound as a white solid
(0.451 mg, 0.851 mmol; 97.9%).
Part 11H--Preparation of tert-butoxy
[(E)-amino{(tert-butoxycarbonyl)[(6-hydroxynaphthalen-2-yl)methyl]amino}m-
ethylidene]carbamate
##STR00380##
[0833] The product of Part 11G (0.100 g, 0.189 mmol) was dissolved
in THF (0.50 mL) then treated with tetrabutylammonium fluoride
(0.567 mmol; 0.567 mL of a 1.0 M solution in THF) at ambient
temperature. After 2 h, all volatiles were removed and the residue
purified by chromatography on silica using 4:1 hexanes/EtOAc to
afford the title compound as a white solid (45.0 mg, 0.108 mmol;
57.3%).
Part 11I--Preparation of
1-{[6-(2-[.sup.18F]fluoroethoxy)naphthalen-2-yl]methyl}guanidine,
formic acid salt
##STR00381##
[0835] The product of Part 1E was transferred to a 5 mL
conical-bottomed Wheaton.TM. reaction vial containing the product
of Part 11H (4.2 mg), K.sub.2CO.sub.3 (3.6 mg) and anhydrous DMSO
(400 .mu.L). The resulting mixture was heated at 80.degree. C. for
45 min then cooled to ambient temperature, treated with
CF.sub.3CO.sub.2H (1.00 mL) and warmed to 50.degree. C. After 15
min, the resulting mixture was cooled to ambient temperature,
concentrated to dryness then purified by HPLC on a Phenomenex Luna
C18(2) column (10.times.250 mm, 5 micron particle size, 100
Angstrom pore size) using a 5.0%/min gradient of 0-100% MeCN
containing 0.1% HCO.sub.2H acid at a flow rate of 2.0 mL/min. The
title compound was collected, all volatiles removed, and the
residue reconstituted with 10% aqueous ethanol solution for
biological experiments.
Example 12
1-((6-(3-fluoropropoxy)naphthalen-2-yl)methyl)guanidine
##STR00382##
[0836] Part 12A--Preparation of tert-butoxy
[(E)-amino((tert-butoxycarbonyl){[(6-(3-fluoropropoxy)naphthalen-2-yl)met-
hyl]amino}methylidene]carbamate
##STR00383##
[0838] The product of Part 11H (75.0 mg, 0.181 mmol) was dissolved
in dry DMF (3.00 mL), successively treated with 3-fluoropropyl
4-methylbenzenesulfonate (62.8 mg, 0.271 mmol) and K.sub.2CO.sub.3
(99.7 mg, 0.772 mmol) then warmed to 50.degree. C. and maintained
48 h. All volatiles were removed, and the residue purified by
preparative TLC using 4:1 pentane/EtOAc for development, to afford
the title compound as a white powder (36.0 mg, 0.076 mmol;
41.9%).
Part 12B--Preparation of
1-{[6-(2-fluoropropoxy)naphthalen-2-yl]methyl}guanidine,
trifluoroacetic acid salt
##STR00384##
[0840] The product of Part 12A (36.0 mg, 0.076 mmol) was dissolved
in dioxane (1.00 mL) then treated with concentrated HCl (1.00 mL)
at ambient temperature. After 45 min all volatiles were removed in
vacuo, the residue redissolved in H.sub.2O/MeCN (1:1 v/v, 2.0 mL)
then directly purified by HPLC on a Phenomenex Luna C18 column
(21.2.times.250 mm) using a 3%/min gradient from 0-90% MeCN
containing 0.1% CF.sub.3CO.sub.2H and 10% H.sub.2O at 20 mL/min to
afford the title compound as a white powder (18.0 mg, 0.046 mmol;
61.0%).
Part 12C--Preparation of 2-[.sup.18]fluoropropyl
4-methylbenzenesulfonate
[0841] An MP1 anion exchange cartridge containing 1,000 mCi of
[.sup.18F]NaF (produced according to the general procedure
described in Part 1D) was eluted with 0.20% aqueous K.sub.2CO.sub.3
(1.0 mL), using an automated liquid handling system, into a 25 mL
conical-bottomed silanized flask. All volatiles were removed by
applying a gentle stream of warm Ar and applied vacuum. The
contents of the flask were reconstituted with 0.5 mL of MeCN, and
concentrated again using warm Ar and applied vacuum (azeotropic
evaporation). A separate 5 mL conical-bottomed Wheaton.TM. vial was
used to prepared a solution of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (19.3
mg) and propylene di-(p-toluenesulfonate) (4.0 mg) in MeCN (1.0
mL). The constituents of the vial were transferred to the 25 mL
flask containing [.sup.18F]KF then positioned inside a microwave
cavity (model 520 Resonance Instruments, Skokie, Ill.) and
irradiated for 3 min at 75 watts. After cooling, the contents of
the microwave reaction vial were filtered through an anion exchange
resin to remove residual fluoride ion, collected in a 5 mL
conical-bottomed Wheaton.TM. reaction vial and used without further
purification in the subsequent reaction.
Part 12D--Preparation of
1-{[6-(2-[.sup.18F]fluoropropoxy)naphthalen-2-yl]methyl}guanidine,
formic acid salt
##STR00385##
[0843] The product of Part 12C was transferred to a 5 mL
conical-bottomed Wheaton.TM. reaction vial containing the product
of Part 11H (4.0 mg), K.sub.2CO.sub.3 (2.8 mg) and anhydrous DMSO
(400 .mu.L). The resulting mixture was heated at 80.degree. C. for
30 min then cooled to ambient temperature, treated with
CF.sub.3CO.sub.2H (1.00 mL) and warmed to 50.degree. C. After 15
min, the resulting mixture was cooled to ambient temperature,
concentrated to dryness then purified by HPLC on a Phenomenex Luna
C18(2) column (10.times.250 mm, 5 micron particle size, 100
Angstrom pore size) using a 5.0%/min gradient of 0-100% MeCN
containing 0.1% HCO.sub.2H acid at a flow rate of 2.0 mL/min. The
title compound was collected, all volatiles removed, and the
residue reconstituted with 10% aqueous ethanol solution for
biological experiments.
Example 21
1-(2-(5-(2-fluoroethoxy)-1H-indol-3-yl)ethyl)guanidine
##STR00386##
[0844] Part 21A--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]{[2-(5-hydroxy-1H-indol-3-yl)ethyl]amino-
}methylidene]carbamate
##STR00387##
[0846] Serotonin hydrochloride (2.00 g, 11.3 mmol) was dissolved in
MeCN (38.0 mL) and successively treated with
N,N-diisopropylethylamine (1.98 mL, 11.3 mmol) and
N,N'-di-Boc-1H-pyrazole-1-carboxamidine (4.20 g, 13.6 mmol) at
ambient temperature. After 30 min, the resulting suspension was
filtered though a scintered glass funnel of medium porosity, the
filtrate diluted with H.sub.2O then transferred to a separatory
funnel and washed with EtOAc. The combined washes were further
treated with H.sub.2O and saturated aqueous NaCl then dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Subsequent
purification by chromatography on silica using a step gradient from
3:1 hexanes/EtOAc to 1:1 hexanes/EtOAc afforded the title compound
as a white solid (2.90 g, 6.93 mmol; 61.0%).
Part 21B--Preparation of tert-butyl
[(Z)-[(tert-butoxycarbonyl)amino]{[2-(5-(3-fluoroethoxy)-1H-indol-3-yl)et-
hyl]amino}methylidene]carbamate
##STR00388##
[0848] The product of Part 21A (0.400 g, 0.956 mmol) was dissolved
in DMF (38.0 mL) and successively treated with Cs.sub.2CO.sub.3
(1.60 g, 4.78 mmol) and 1-bromo-2-fluoroethane (178 .mu.L, 2.39
mmol) at ambient temperature. The resulting suspension was warmed
to 70.degree. C., maintained 1 h then cooled to ambient temperature
and partitioned between EtOAc and H.sub.2O. The layers separated
and the EtOAc layer further washed with saturated aqueous NaCl,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Subsequent purification by chromatography on silica, using a
hexanes/EtOAc gradient from 0-100% EtOAc over 15 min, afforded the
title compound as a white solid (0.176 g, 0.379 mmol; 39.6%).
Part 21C--Preparation of
1-(2-(5-(2-fluoroethoxy)-1H-indol-3-yl)ethyl)guanidine,
trifluoroacetic acid salt
##STR00389##
[0850] The product of Part 21B (0.100 g, 0.215 mmol) was dissolved
in dioxane (1.00 mL) and treated with concentrated HCl (3.00 mL) at
ambient temperature. After 30 min, all volatiles were removed in
vacuo and the residue directly purified by HPLC on a Phenomenex
Luna C18 column (21.2.times.250 mm) using an 8.3%/min gradient from
0-100% MeCN containing 0.1% CF.sub.3CO.sub.2H and 10% H.sub.2O at
20 mL/min. The main product peak was collected, pooled and
lyophilized to a white solid. NOTE: an accurate yield could not be
obtained due to the extreme hydroscopicity of the selected salt
form.
Part D--Preparation of
1-(2-(5-(2-[.sup.18F]fluoroethoxy)-1H-indol-3-yl)ethyl)guanidine,
formic acid salt
##STR00390##
[0852] The product of Part 1E was transferred to a 5 mL
conical-bottomed Wheaton.TM. reaction vial containing the product
of Part 21A (3.3 mg), Cs.sub.2CO.sub.3 (13.1 mg) and anhydrous DMF
(400 .mu.L). The resulting mixture was heated at 80.degree. C. for
45 min then cooled to ambient temperature and concentrated in
vacuo. The residue was treated with CF.sub.3CO.sub.2H (1.00 mL)
then warmed to 40.degree. C. and maintained 20 min. The resulting
mixture was cooled to ambient temperature, concentrated to dryness
then purified by HPLC on a Phenomenex Luna C18(2) column
(10.times.250 mm, 5 micron particle size, 100 Angstrom pore size)
using a 5.0%/min gradient of 0-100% MeCN containing 0.1% HCO.sub.2H
acid at a flow rate of 2.0 mL/min. The title compound was
collected, all volatiles removed, and the residue reconstituted
with 10% aqueous ethanol solution for biological experiments.
Example 33
1-(4-(3-fluoropropyl)phenethyl)guanidine
##STR00391##
[0853] Part 33A--Preparation of
[4-(3-hydroxyprop-1-yn-1-yl)phenyl]acetonitrile
##STR00392##
[0855] (4-Iodophenyl)acetonitrile (1.00 g, 4.12 mmol), PPh.sub.3
(11.0 mg, 0.041 mmol) and propargyl alcohol (243 .mu.L, 4.12 mmol)
were dissolved in N,N-diethylamine (14.0 mL) then treated with 8.0
mg CuI (0.041 mmol; 1.0 mol %) and 11.0 mg PdCl.sub.2 (0.041 mmol;
1.0 mol %) at ambient temperature. After 48 h, all volatiles were
removed in vacuo and the residue purified by chromatography on
silica using a hexanes/EtOAc gradient from 0-100% EtOAc over 18 min
to afford the title compound as an orange solid (0.453 g, 2.65
mmol; 64.3%).
Part 33B--Preparation of 3-[4-(2-aminoethyl)phenyl]propan-1-01,
hydrochloric acid salt
##STR00393##
[0857] The product of Part 33A (0.386 g, 2.26 mmol) was dissolved
in EtOH (22.0 mL) then successively treated with concentrated HCl
(3.00 mL) and Pd/C (0.363 mmol; 16 mol %) at ambient temperature.
The headspace of the reaction vessel was sparged with 50 psi
H.sub.2 then maintained 16 h. Upon complete reduction, the
headspace was sparged with dry N2 and the catalyst removed by
filtration through Celite. The filter cake was exhaustively washed
with EtOH and the combined filtrates concentrated in vacuo to an
orange solid (0.420 g). The crude material was used without further
purification in the subsequent reaction.
Part 33C--Preparation of tert-butoxy
{(Z)-({2-[4-(3-hydroxypropyl)phenyl]ethyl}amino)[(tert-butoxycarbonyl)ami-
no]methylidene}carbamate
##STR00394##
[0859] The product of Part 33B (2.26 mmol theoretical) was
dissolved in MeCN (1.00 mL) and successively treated with
N,N-diisopropylethylamine (816 .mu.L, 4.69 mmol) and
N,N'-di-Boc-1H-pyrazole-1-carboxamidine (0.831 g, 2.68 mmol) at
ambient temperature. After 45 min, the solution was diluted with
H.sub.2O with transfer to a separatory funnel then washed with
EtOAc. The combined EtOAc washes were further washed with H.sub.2O
and saturated aqueous NaCl then dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Subsequent purification by
chromatography on silica, using a hexanes/EtOAc gradient from
0-100% EtOAc over 18 min, afforded the title compound as a pale
yellow solid (0.288 g, 0.683 mmol; 30.3%).
Part 33D--Preparation of tert-butoxy
{(Z)-({2-[4-(3-fluoropropyl)phenyl]ethyl}amino)[(tert-butoxycarbonyl)amin-
o]methylidene}carbamate
##STR00395##
[0861] Deoxo-Fluor.RTM. (115 .mu.L, 0.521 mmol) was diluted with
CH.sub.2Cl.sub.2 (57 .mu.L) then cooled to 0.degree. C. and treated
with a solution of the product of Part 33C (0.474 mmol; 100 .mu.L
of 4.74 M solution in CH.sub.2Cl.sub.2) dropwise over 2 min. The
resulting mixture warmed slowly to ambient temperature as the
cooling bath evaporated overnight. All volatiles were removed in
vacuo and the residue directly purified by chromatography on silica
using a hexanes/EtOAc gradient from 0-100% EtOAc over 18 min to
afford the title compound as a white solid (24.5 mg, 0.0578 mmol;
12.2%).
Part 33E--Preparation of 1-(4-(3-fluoropropyl)phenethyl)guanidine,
trifluoroacetic acid salt
##STR00396##
[0863] The product of Part 33D (20.0 mg, 0.047 mmol) was dissolved
in dioxane (1.00 mL) then treated with concentrated HCl (3.00 mL)
at ambient temperature. After 30 min all volatiles were removed in
vacuo, the residue redissolved in H.sub.2O/MeCN (1:1 v/v, 2.0 mL)
then directly purified by HPLC on a Phenomenex Luna C18 column
(21.2.times.250 mm) using a 7.1%/min gradient from 0-100% MeCN
containing 0.1% CF.sub.3CO.sub.2H and 10% H.sub.2O at 20 mL/min to
afford the title compound as a white powder (16.0 mg, 0.047 mmol;
>98%).
Part 33F--Preparation of
3-{4-[2-(N',N''-bis(tert-butoxycarbonyl)carbamimidamido)ethyl]phenyl}prop-
yl 4-methylbenzenesulfonate
##STR00397##
[0865] The product of Part 33C (20.0 mg, 0.047 mmol) was dissolved
in CH.sub.2Cl.sub.2 (336 .mu.L) and successively treated with
p-toluenesulfonyl chloride (13.0 mg, 0.071 mmol) and pyridine (38
.mu.L, 0.470 mmol) at 0.degree. C. After 16 h, the resulting
solution was diluted with CH.sub.2Cl.sub.2, with transfer to a
separatory funnel then successively washed with 5% aqueous
CuSO.sub.4, H.sub.2O and saturated aqueous NaCl. After drying over
Na.sub.2SO.sub.4, the solution was filtered and concentrated in
vacuo then purified by chromatography on silica, using a
hexanes/EtOAc gradient from 0-100% EtOAc over 18 min, to afford the
title compound as a colorless oil (5.0 mg, 8.7 .mu.mol; 18.3%).
Part 33G--Preparation of
1-(4-(3-[.sup.18F]fluoropropyl)phenethyl)guanidine, formic acid
salt
##STR00398##
[0867] An MP1 anion exchange cartridge containing 1,000 mCi of
[.sup.18F]NaF (produced according to the general procedure
described in Part 1D) was eluted with 0.20% aqueous K.sub.2CO.sub.3
(1.0 mL), using an automated liquid handling system, into a 25 mL
conical-bottomed silanized flask. All volatiles were removed by
applying a gentle stream of warm Ar and applied vacuum. The
contents of the flask were reconstituted with 0.5 mL of MeCN, and
concentrated again using warm Ar and applied vacuum (azeotropic
evaporation). The residue was treated with a solution of
4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (20.0
mg) in MeCN (0.90 mL) then transferred to a solution of the product
of Part 33F (4.4 mg) in dry MeCN (0.40 mL). The constituents of the
vial were then positioned inside a microwave cavity (model 520
Resonance Instruments, Skokie, Ill.) and irradiated for 3 min at
100 watts. The resulting solution was cooled, treated with
CF.sub.3CO.sub.2H (1.00 mL) and the microwave heating cycle
repeated. After cooling, all volatiles were removed and the residue
purified by HPLC on a Phenomenex Luna C18(2) column (250.times.10
mm, 5 micron particle size, 100 Angstrom pore size) using a
5.0%/min gradient of 0-100% MeCN containing 0.1% HCO.sub.2H acid at
a flow rate of 2.0 mL/min. The title compound was collected, all
volatiles removed, and the residue reconstituted with 10% aqueous
ethanol solution for biological experiments.
Example 35
In-Vitro Assays
Part 35A Norepinephrine Transporter Binding Assay
[0868] Individual inhibitors were dissolved in incubation buffer
(50 mM Tris-HCl, 10% sucrose, pH 7.4) at appropriate dilutions. The
inhibitor solutions were added to the wells of a microtiter plate
(40 .mu.L/well) in triplicate. Each well of test agent (and
appropriate control wells) was treated with a mixture of MDCK cell
membrane preparation (22.4 vg of membrane) expressing human
norepinephrine transporter (Bmax=3.7 pmol norepinephrine
transporter/mg protein), and [.sup.3H]desipramine (2 nM, 64.8
Ci/mmol) in a total volume of 0.2 mL. The resulting mixtures were
incubated for 2 h on ice.
[0869] A 96 well GF/C filter plate was presoaked with coating
buffer (0.5% polyvinylpyrrolidine and 0.1% Tween 20) for 2 h at
room temperature, then washed with incubation buffer (6.times.0.2
mL). The competition reactions were transferred to the coated plate
and filtered. The filter plate was washed (6.times.0.2 mL) with ice
cold wash buffer (50 mM Tris-HCl, 0.9% NaCl, pH 7.4) then dried
overnight and treated with 25 .mu.L scintillation fluid for
analysis on a plate reader (Microbeta TriLux 1450 LSC and
Luminescence counter, Perkin Elmer, Shelton Conn.).
Part 35B--Cell Preparation
[0870] Rat pheochromocytoma cell line (PC-12) were purchased from
the American Type Culture Collection (ATCC) then cultured in
collagen-coated flasks (BD Bio Coat Collagen Type 1, BD
Biosciences) using a growth media composed of F-12 K media, 2 mM
L-glutamine, 15% horse serum, 2.5% fetal bovine serum (FBS) and 1%
penicillin-streptomycin.
Part 35C--PC-12 Binding Assay
[0871] Prepared PC-12 cells were seeded into 6-well plates at a
density of 1.times.10.sup.6 cells/well with 2 mL of growth media
and maintained 24 h at 37.degree. C. under a 5% CO.sub.2
atmosphere. The media was exchanged and each well treated with 0.1
.mu.Ci test agent, with or without 1 .mu.M desipramine. The
resulting mixture was incubated for 60 min at 37.degree. C. and 5%
CO.sub.2 then centrifuged at 500.times.g for 3 min and washed with
PBS buffer. Radioactivity associated with the cells was then
measured, and total uptake determined in the wells without
desipramine; nonspecific uptake was measured in the associated
wells containing desipramine. The specific NET mediated cell uptake
is calculated as percent total uptake minus percent nonspecific
uptake.
TABLE-US-00002 TABLE 1 In-vitro association data PC-12 (% bound)
Example NET Affinity (.mu.M) Control Block 1 7.27 3.1 0.30 2 11.19
3.20 0.60 3 7.35 32.76 2.36 4 5.41 1.00 0.50 5 18.73 1.00 0.90 6
7.91 2.40 0.70 7 10.04 1.40 0.70 8 17.37 1.30 0.60 9 3.07 3.90 3.30
10 >73.5 -- -- 11 0.12 23.90 2.70 12 0.14 5.30 0.50 13 >73.5
-- -- 14 >73.5 -- -- 15 32.11 -- -- 16 >73.5 -- -- 17 59.19
-- -- 18 >73.5 -- -- 19 70.71 -- -- 20 2.06 0.10 0.10 21 1.19
0.10 0.10 22 18.97 0.00 0.00 23 6.42 1.40 0.50 24 4.86 2.10 0.90 25
>73.5 -- -- 26 >73.5 -- -- 27 1.55 -- -- 28 7.89 0.10 0.10 29
10.30 12.20 2.20 30 2.01 -- -- 31 12.96 -- -- 32 115.20 -- -- 33
3.95 2.30 1.50 34 4.10 -- --
Example 36
In vivo Tissue Distribution Assays
Part 36A--Animal Preparation
[0872] Male Sprague Dawley rats (300-500 g, Taconic), and male New
Zealand rabbits (3-4 kg, Covance) were used in accordance with our
Institutional Animal Care and Use Committee. Rats were anesthetized
with sodium pentobarbital (50 mg/kg, i.p.) and the left femoral
vein cannulated with PESO tubing for drug injection. Rabbits were
pre-sedated with acepromazine (0.75 mg/kg i.m.) then anesthetized
with ketamine (40 mg/kg, i.m.) and xylazine (8 mg/kg, i.m); the
marginal ear vein was cannulated for drug injection. Additional
doses of anesthetics were given as needed.
Part 36B--Tissue Distribution in Rats and Rabbits
[0873] After preparation, each animal received a bolus injection of
the test agent via the venous catheter. Rats and rabbits were
euthanized after the injection and samples of the blood, heart,
lung, liver, spleen, kidney, femur and muscle were collected. All
samples were weighed and counted for radioactivity (Wallac Wizard
1480, PerkinElmer Life and Analytical Sciences, Shelton, Conn.);
net radioactivity administered in each animal was determined by
subtracting the residual activity in both the syringe and venous
catheter. Tissue uptake of each agent was determined as a
percentage of the injected dose per gram tissue (% ID/g).
TABLE-US-00003 TABLE 2 In-vivo rat biodistribution data Rat (%
ID/g) Example Heart Lung Liver Blood 1 1.03 0.24 0.15 0.18 2 1.33
0.94 0.25 0.19 3 0.71 .+-. 0.24 1.12 .+-. 0.29 0.15 .+-. 0.03 0.35
.+-. 0.15 4 1.04 .+-. 0.95 0.34 .+-. 0.18 0.37 .+-. 0.24 0.13 .+-.
0.02 5 1.23 0.59 0.26 0.69 7 1.60 .+-. 0.13 0.80 .+-. 0.09 0.30
.+-. 0.12 0.11 .+-. 0.02 8 1.61 0.94 0.27 0.21 11 1.74 .+-. 0.27
2.71 .+-. 0.51 0.61 .+-. 0.40 0.51 .+-. 0.11 12 1.93 .+-. 0.11 2.09
.+-. 0.08 0.18 .+-. 0.01 0.37 .+-. 0.05 21 0.35 0.38 1.01 0.41 33
1.94 .+-. 0.16 0.66 .+-. 0.11 0.21 .+-. 0.04 0.10 .+-. 0.01
TABLE-US-00004 TABLE 3 In-vivo rabbit biodistribution data Rabbit
(% ID/g) Example Heart Lung Liver Blood 3 0.29 0.39 0.02 0.01 4
0.025 0.031 0.012 0.014 7 0.066 0.078 0.021 0.013 11 0.39 .+-. 0.02
0.39 .+-. 0.11 0.02 .+-. 0.00 0.04 .+-. 0.01 12 0.29 .+-. 0.09 0.28
.+-. 0.17 0.02 .+-. 0.01 0.04 .+-. 0.02
Example 37
PET Imaging
Part 37A--Image Acquisition
[0874] Cardiac PET imaging was performed in anesthetized rats and
rabbits prepared according to Part 36A. The animal was
appropriately positioned in a microPET camera (Focus220, CTI
Molecular Imaging, Inc. Knoxville, Tenn.) for cardiac imaging and
the test agent injected using the venous catheter. Complete
acquisition required 120 min.
Part 37B--Image Reconstruction and Analysis
[0875] Acquired images were reconstructed in a matrix of
256.times.256 pixels with 95 transverse slices, using the filtered
back projection algorithm, and decay corrected (microPET Manager
and ASIPro, CTI Molecular Imaging, Inc. Knoxville, Tenn.); pixel
size was 0.47 mm and slice thickness was 0.80 mm. Images were
reoriented to the cardiac axis and serial tomographic image frames
generated for every 10 min interval from 5 to 125 minutes. FIGS. 2
through 8 represent images derived using compounds described
herein. FIGS. 2 through 8 represent images derived using compounds
described herein (e.g., wherein FIG. 2 relates to a compound from
Example 1, FIG. 3 relates to a compound from Example 2, etc.).
Example 38
[0876] Introduction: Heart failure (HF) has been associated with
increased sympathetic tone and noradrenaline (NA; also referred to
herein as NE) release, and decreased neuronal NA transporter (NAT;
also referred herein as NET) function and NA concentration in the
failing heart (Rundqvist et al., Circulation. 1997; 95(1):169-75;
Bohm et al., J Am Coll Cardiol. 1995; 25(1):146-53; Liang et al., J
Clin Invest. 1989; 84(4):1267-75). The reduced cardiac NA
concentration due primarily to the impaired NAT function is usually
referred to as cardiac sympathetic denervation, even though the
sympathetic activation is elevated with increased NA spillover
(Esler, J Appl Physiol. 2010; 108(2):227-37). Cardiac sympathetic
neuronal function can be assessed by nuclear imaging. Indeed,
global cardiac sympathetic denervation associated with reduced NAT
function has been detected by cardiac imaging with a radiolabeled
substrate for NAT, such as .sup.123I-meta-iodobenzylguanidine
(MIBG), .sup.11C-meta-hydroxyephedrine (HED) and
.sup.11C-epinephrine (Bengel et al., J Nucl Cardiol. 2004;
11(5):603-16; Henneman et al., J Nucl Cardiol. 2008; 15(3):442-55;
Travin, Cardiol Clin. 2009; 27(2):311-27; Carrio, J Nucl Med. 2001;
42(7):1062-76). The imaging findings provided robust values in
prediction of cardiac events in HF patients (Jacobson et al., J Am
Coll Cardiol. 2010; 55(20):2212-21; Pietila et al., Eur J Nucl Med.
2001; 28(3):373-6). Additionally, incidence of ventricular
arrhythmia and subsequent sudden cardiac death has also been linked
to regional cardiac sympathetic dysfunction (Podrid et al.,
Circulation. 1990; 82(2 Suppl):I103-I113; Chen et al., J Cardiovasc
Electrophysiol. 2007; 18(1):123-7). Regional cardiac sympathetic
denervation (RCSD) or innervation heterogeneity identified by
cardiac imaging with .sup.123I-MIBG, .sup.11C-HED or
.sup.11C-epinephrine has shown a strong association with enhanced
probability of ventricular arrhythmia both in animals and humans
(Dae et al., Circulation. 1997; 96(4):1337-42; Mitrani et al., J Am
Coll Cardiol. 1993; 22(5):1344-53; Sasano et al., J Am Coll
Cardiol. 2008; 51(23):2266-75; Stevens et al., Circulation. 1998;
98(10):961-8) and a correlation with arrhythmia induced implantable
cardioverter defibrillator activation or cardiac death in HF
patients (Boogers et al., J Am Coll Cardiol. 2010; 55(24):2769-77).
However, the image quality of .sup.123I-MIBG is suboptimal with low
energy single-photon emission computed tomography (SPECT) imaging
and, in some patients, results in undetected regional defects
(Matsunari et al., Circ Cardiovasc Imaging. 2010; 3(5):595-603).
Positron emission tomography (PET) imaging with .sup.11C-HED has
demonstrated superiority to .sup.123I-MIBG in image quality and
detection of regional abnormalities (Matsunari et al., Circ
Cardiovasc Imaging. 2010; 3(5):595-603). However, the short
half-life of .sup.11C isotope limits its broad clinical
application.
[0877] Imaging Agent-1 has recently been studied, wherein Imaging
Agent-1 comprises the structure:
##STR00399##
or a pharmaceutically acceptable salt thereof. Imaging Agent-1 it
is a benzylguanidine analog and was designed as a NAT substrate for
evaluation of cardiac neuronal function. However, Imaging Agent-1
is radiolabeled with .sup.18F allowing PET imaging and regional
radiopharmacy production. Imaging with Imaging Agent-1 showed clear
detection of global cardiac denervation (Yu et al., Circ Cardiovasc
Imaging. 2011; 4(4):435-43). In this study, the Imaging Agent-1
imaging profile was further characterized for NAT association
in-vitro by comparison with NE, the natural NAT substrate, and
MIBG. Given the importance of regional cardiac denervation in HF
stratification, Imaging Agent-1 imaging cardiac denervation and
heart uptake kinetics in dynamic imaging were assessed in a rabbit
model of RCSD. In addition, RCSD increases the risk of cardiac
arrhythmia and treatments with antiarrhythmic drugs, such as
dofetilide, may be used in patients with cardiac denervation.
Dofetilide is a class III antiarrhythmic agent that selectively
blocks the rapid component of the delayed rectifier outward
potassium current (Lenz et al., Pharmacotherapy. 2000;
20(7):776-86). It is generally well tolerated in patients, but
torsade de pointes (TdP) may occur following the drug induced
prolongation of QTc interval. Thus, dofetilide induced changes in
QTc interval and TdP were investigated in control and RCSD rabbits
to determine the potential role of Imaging Agent-1 imaging cardiac
sympathetic denervation in antiarrhythmic drug treatment. Materials
and methods
[0878] Cell Uptake Comparison and Competition: Imaging Agent-1 cell
uptake in comparison with .sup.3H-NA and .sup.123I-MIBG was assayed
in human neuroblastoma cells (SK-N-SH, ATCC) with expression of NAT
(Buck et al., Cancer Res. 1985; 45(12 Pt 1):6366-70). Cells were
prepared in 6-well plates at a density of 1.times.10.sup.6
cells/well in 2 mL media. Imaging Agent-1, .sup.3H-NA or
.sup.123I-MIBG at 3.7 kBq was added to each well with or without
desipramine (1 .mu.M), a selective NAT inhibitor. In assay with NA,
pargyline (10 .mu.M) was included to inhibit monoamine oxidase
activity. Following incubation for 60 minutes at 37.degree. C.,
cells were washed twice with ice-cold phosphate-buffered saline,
trypsinized and centrifuged at 1000 g for 3 minutes to collect cell
pellet. Radioactivity associated with the cells was measured with a
.gamma.-(Wallac Wizard 1480, PerkinElmer) or .beta.-counter
(Microbeta TriLux 1450 LSC, PerkinElmer). Each assay was performed
in triplicate and the uptake was expressed as a percent of total
radioactivity added to the well.
[0879] For the competitive inhibition assay, Imaging Agent-1 at 3.7
kBq was incubated in SK-N-SH cells with various concentrations
(0.1, 1, 10, or 100 .mu.M) of non-radioactive NA, MIBG or
.sup.19F-Imaging Agent-1 (self) at 37.degree. C. for 60 minutes.
Similarly, following the incubation, Imaging Agent-1 cell uptake
was determined. The IC.sub.50 value of each agent was determined
using GraphPad software (v5).
[0880] Development of regional cardiac sympathetic denervation in
rabbits: Animal study protocol was approved by the Institutional
Animal Care and Use Committee. Male New Zealand rabbits (2.5-3.5
kg, Harlan) were maintained in the AAALAC-accredited Animal Care
Facility and acclimated for 7 days. The thoracotomy procedure was
similar to the method described previously (Yu et al., J Nucl
Cardiol. 2010; 17(4):631-6). Briefly, the rabbit was anesthetized
with ketamine (40 mg/kg, im) and xylazine (9 mg/kg, im) and placed
in a supine position. Under aseptic conditions, a mid-sternotomy
was performed carefully to avoid injury of parietal pleura. The
pericardial sac was exposed and incised to reveal the left
ventricular (LV) wall. Phenol (89% carbolic acid, Sigma) or saline
(sham-control group) was applied on the surface of the LV lateral
wall with a cotton-tipped applicator. The chest was then closed and
the animal allowed to recover.
[0881] Cardiac PET imaging: Cardiac PET imaging was performed in
both sham control and phenol induced RCSD rabbits at 2 and 12 weeks
after surgery. Rabbits were anesthetized and maintained with
isoflurane (0.5-2.5%) using a face mask, and positioned in a
microPET camera (Focus220, CTI Molecular Imaging, Inc).
Approximately 55.5 MBq of Imaging Agent-2, having the
structure:
##STR00400##
which is a myocardial perfusion imaging agent (Yu et al., Semin
Nucl Med. 2011; 41(4):305-13; Yu et al., J Nucl Cardiol. 2007;
14(6):789-98; Nekolla et al., Circulation. 2009; 119(17):2333-42),
was injected via a catheter in the marginal ear vein and the heart
was imaged for 60 minutes. Imaging Agent-1 and Imaging Agent-2
imaging in each rabbit was performed in a two-day interval.
[0882] Image reconstruction and analysis: Following the
acquisition, images were reconstructed in a matrix of 256.times.256
pixels with 95 transverse slices using the OSEM2D algorithm and
decay corrected (microPET Manager and ASIPro, CTI Molecular
Imaging, Inc). The pixel size was 0.47 mm and the slice thickness
was 0.80 mm. Serial tomographic cardiac images were framed in
2.times.5-, 2.times.10-, 3.times.30-, 1.times.60-, 1.times.120-,
1.times.300- and 5.times.600-second and reoriented based on cardiac
axis. Time activity curves (TAC) were generated from these
sequential images. The maximal radioactivity in the myocardium was
determined from the images acquired at 20-30 minutes using Amide
software (Amide's a Medical Image Data Examiner, v1.0.1). The
normal LV areas of sympathetic innervation and perfusion
(non-defect areas) detected by Imaging Agent-1 and Imaging Agent-2
imaging, respectively, were defined as regions with radioactivity
>50% of the maximal activity. The 50% cutoff was selected based
on published studies (Matsunari et al., J Nucl Med. 2001;
42(10):1579-85; Sherif et al., Circ Cardiovasc Imaging. 2009;
2(2):77-84; Simoes et al., Eur Heart J. 2004; 25(7):551-7). In
addition, polar map images were generated from reconstructed
cardiac short-axis images using QPS 2008 software (Cedars-Sinai
Medical Center).
[0883] Assessment of cardiac regional denervation on dofetilide
treatment. Dofetilide is an antiarrhythmic drug used clinically and
known to cause QTc prolongation and possible TdP. The role of
cardiac denervation in dofetilide induced changes in QTc interval,
premature ventricular contraction (PVC) and TdP was assessed in
sham control and RCSD rabbits at 3 weeks after surgery. Rabbits
were anesthetized with ketamine (40 mg/kg, im) and xylazine (9
mg/kg, im), and dofetilide (1 and 4 .mu.g/kg/min, Haorui
Pharma-Chem Inc. Edison, N.J.) was infused for 10 minutes via a
catheter in the marginal ear vein. Electrocardiogram (ECG) in lead
II configuration was recorded with Ponemah system (v4.3, Data
Science International) before and during the drug infusion. Heart
rate (HR) and QT interval were derived from ECG waveforms. The QT
interval was corrected by Fridericia method
(QT.sub.ct=QT/RR.sup.1/3).
[0884] Radiopharmaceutical agents: Imaging Agent-1 and Imaging
Agent-2 were radiosynthesized as previously described (Yu et al.,
Circ Cardiovasc Imaging. 2011; 4(4):435-43; Yu et al., J Nucl
Cardiol. 2007; 14(6):789-98). The radiochemical purity of each
imaging agent was consistently >99% and specific activity was
>148000 GBq/mmol. Both agents were formulated in 5% ethanol
(v/v) and 50 mg/ml ascorbic acid in water for injection.
[0885] Data analysis: Values are expressed as mean.+-.SD.
Comparisons were performed after data passed normality and variance
homogeneity tests with or without simple data transformation using
SigmaPlot software (v12). One-way ANOVA was used in comparison of
cell uptake of radioactive agents and the non-defect LV volume
detected by cardiac imaging, while two-way repeated measures ANOVA
was used in analyzing changes in QT.sub.cf interval between control
and denervated rabbits at various time points. The post hoc
comparisons were performed with the Bonferroni test. Dofetilide
induced frequencies of PVC and TdP between control and denervated
rabbits were compared by Fisher Exact Test. p<0.05 was
considered statistically significant.
Results:
[0886] Comparison of Imaging Agent-1 NAT association with NA and
MIBG: As shown in FIG. 9, Imaging Agent-1 uptake in SK-N-SH cells
was 24.6.+-.9% (n=50), comparable to .sup.123I-MIBG and higher than
.sup.3H-NA (n=8/each). Blockade of NAT with desipramine achieved
>90% inhibition of cell uptake for Imaging Agent-1 (90.+-.3%),
.sup.123I-MIBG (94.+-.2%) and .sup.3H-NA (97.+-.2%).
[0887] FIG. 9 shows Imaging Agent-1 uptake (n=50) in comparison
with .sup.3H-noradrenaline (NA, n=8) and .sup.123I-MIBG (n=8) in
SK-N-SH cells with and without desipramine to block noradrenaline
transporter (NAT). Similarly, NAT blockade inhibited over 90% cell
uptake of Imaging Agent-1, NE and MIBG. * indicates p<0.05 vs.
control. In competitive inhibition assay (FIG. 10), non-radioactive
NA, MIBG and self (n=4/each) inhibited Imaging Agent-1 cell uptake
in a concentration-dependent fashion. The IC.sub.50 values were
1.09, 0.21 and 0.90 .mu.M for NA, MIBG and .sup.19F-Imaging
Agent-1, respectively.
[0888] FIG. 10 shows dose-response curves of Imaging Agent-1 uptake
in SK-N-SH cells in the presence of increasing concentrations of
non-radioactive compounds: noradrenaline (NA, n=4), MIBG (n=4,
concentration at 100 .mu.M was not tested) or .sup.19F-Imaging
Agent-1 (n=4). Results are expressed as percent of control Imaging
Agent-1 uptake at each concentration of the compound. NA, MIBG and
.sup.19F-Imaging Agent-1 inhibited Imaging Agent-1 cell uptake
concentration-dependently with IC.sub.50 values in a 0.2-1.1 .mu.M
range.
[0889] Assessment of cardiac denervation by imaging with Imaging
Agent-1 and Imaging Agent-2: Cardiac sympathetic innervation and
myocardial perfusion were assessed by imaging with Imaging Agent-1
and Imaging Agent-2, respectively. In control rabbits (n=3-5, FIG.
11), the images of both agents showed well delineated myocardium
with homogeneous activity distribution. The radioactivity in
adjacent organs, like the blood, liver and lung, was low. In
cardiac phenol denervated rabbits (n=8-14, FIG. 12), Imaging
Agent-2 imaging showed well perfused myocardium, similar to that in
the control. In contrast, in the same rabbit, cardiac neuronal
imaging with Imaging Agent-1 revealed denervated regions in the LV
wall. The denervated area was observed in the views of both cardiac
short- and long-axis and polar map. Additionally, the denervated
area reduced in Imaging Agent-1 images from 2 to 12 weeks after
phenol denervation.
[0890] FIG. 11 shows representative cardiac images and polar maps
of Imaging Agent-1 and Imaging Agent-2, a PET myocardial perfusion
imaging agent, from a control rabbit (same rabbit imaged 2 times).
The images were acquired at 20-30 min after injection. The
myocardium was clearly delineated with homogeneous activity
distribution in the left ventricle. Radioactivity levels in the
adjacent organs were low. FIG. 12 shows representative cardiac
images and polar maps of Imaging Agent-1 and Imaging Agent-2, a PET
myocardial perfusion imaging agent, from a regional cardiac
denervated rabbit (same rabbit imaged 3 times). The images were
acquired at 20-30 min after injection. The regional denervation was
detected by Imaging Agent-1 imaging at 2 weeks after phenol
denervation and the defect was not due to reduced perfusion (normal
Imaging Agent-2 images). The denervated area observed in Imaging
Agent-1 images was reduced from 2 to 12 weeks post denervation,
indicating re-innervation in the previous denervated area.
[0891] As shown in the injected dose corrected TACs (FIG. 13),
radioactivity in the blood cleared similarly for Imaging Agent-1
and Imaging Agent-2 in control rabbits: reaching a peak immediately
after iv administration, then decreasing rapidly with time. In the
heart, the activity levels for Imaging Agent-1 exhibited a quick
washout after the initial peak and then plateaued (FIG. 13b). This
differed from Imaging Agent-2 (FIG. 13a), where the plateau was
reached without marked washout following the initial activity peak
in the heart. However, a small and slow decrease in Imaging Agent-2
levels was observed between 5 to 25 minutes in the rabbit heart.
Radioactivity levels in the liver cleared rapidly after injection
of both imaging agents. In RCSD rabbits (FIG. 13c), Imaging Agent-1
was delivered to the denervated region initially and then washed
out to a plateau, lower than that in the innervated region.
[0892] FIG. 13 shows representative time-activity curves (TAC)
derived from Imaging Agent-2 and Imaging Agent-1 images in the same
control rabbit (a and b) as shown in FIG. 11, and from Imaging
Agent-1 images in the denervated rabbit (c) as shown in FIG. 12.
Regions of interest were selected from the anterior wall of the LV
(heart), liver and LV chamber (blood) in the control rabbit, and
from the non-defect area of the LV anterior wall (innervated
region) and the defect area (denervated region). TACs were
expressed as video intensity unit corrected by injected dose (MBq).
For visual simplicity, only TACs of the heart and blood were shown
in the first 2 minutes. Unlike Imaging Agent-2 which reached an
uptake plateau phase immediately after injection, Imaging Agent-1
washed quickly from the heart initially and them reached a plateau
phase.
[0893] Comparison of non-defect LV Areas detected by Imaging
Agent-1 and Imaging Agent-2: The innervated and perfused LV areas,
which were defined as total LV volume with radioactive intensity
>50% of the maximal activity in cardiac images of Imaging
Agent-1 and Imaging Agent-2, were compared between sham control
(n=3-5) and RCSD (n=8-14) rabbits (FIG. 14). The perfused LV region
detected by Imaging Agent-2 imaging was 21594.+-.1805 voxels in
control rabbits, similar to the perfused area detected in RCSD
rabbits. However, Imaging Agent-1 imaging revealed the denervated
region in RCSD rabbits, and the innervated area (non-defect area)
decreased by 48% compared to the control at 2 weeks (Early) post
cardiac phenol denervation. Following the recovery from 2 to 12
weeks (Late), the denervated area recovered partially and the
innervated area increased by 37%, significantly larger than that at
2 weeks but still less than in sham control rabbits.
[0894] FIG. 14 shows image quantification to assess non-defect left
ventricular areas (normal perfused and innervated areas detected by
Imaging Agent-2 and Imaging Agent-1 imaging respectively) in
rabbits of control (n=3-5), and 2 weeks (Early, n=11-14) and 12
weeks (Late, n=8) post denervation. Regional phenol denervation did
not impair myocardial perfusion, but reduced the innervated area
detected by Imaging Agent-1 at 2 weeks post denervation. The
innervated area increased at 12 weeks, indicating re-innervation. *
indicates p<0.05 vs. control and +indicates p<0.05 vs. early
time point.
[0895] Effect of regional cardiac denervation on dofetilide induced
ECG changes: Changes in ECG induced by iv infusion of dofetilide,
an antiarrhythmic drug, were investigated in sham control (n=6) and
RCSD (n=8) rabbits at 3 weeks after surgery. ECG waveform was
normal with regular cardiac rhythm (FIG. 15a) and baseline values
of HR and QT.sub.cf were comparable (Table 4) in the two groups
before drug infusion. Intravenous administration of dofetilide
induced bradycardia and QT prolongation. Dofetilide induced
bradycardia was similar in the two rabbit groups at doses of both 1
and 4 .mu.g/kg/min (FIG. 15b). In contrast, dofetilide at a dose of
4 .mu.g/kg/min increased QT.sub.cf interval to a greater extent
than at 1 .mu.g/kg/min, and the QT.sub.cf prolongation was
significantly more severe in RCSD rabbits than the control at both
dose levels (FIG. 15c). In addition, dofetilide (4 .mu.g/kg/min)
induced PVC and TdP, and the frequency of these events in RCSD
rabbits was high, but did not reach statistical significance
compared to the sham control (Table 4).
[0896] FIG. 15 shows: a) Examples of ECG tracings in rabbits before
and during dofetilide infusion. Before infusion (Control), ECG was
normal with regular rhythm. During the infusion, arrhythmia was
observed with premature ventricular contractions (PVC) and torsade
de pointes (TdP). b and c) Comparison of changes in heart rate (HR)
and QT.sub.cf interval (corrected by Fridericia method) between
sham control (n=6) and regional cardiac denervated (n=8) rabbits iv
infused with dofetilide at doses of 1 and 4 .mu.g/kg/min for 10
minutes. Dofetilide infusion induced bradycardia and QT.sub.cf
prolongation. In contrast to changes in HR (similar between control
and denervated groups), dofetilide increased QT.sub.cf interval
more in denervated than in control rabbits at both doses.
Control-D1 and -D4: control rabbits infused with dofetilide at 1
and 4 .mu.g/kg/min; Denervated-D1 and D4: denervated rabbits with
dofetilide at 1 and 4 .mu.g/kg/min. * indicates p<0.05.
DISCUSSION
[0897] Increased NA release and reduced neuronal NAT function in
the heart are associated with HF. Imaging with a NAT substrate,
such as .sup.123I-MIBG or .sup.11C-HED, to assess cardiac neuronal
function has demonstrated robust values in predication of cardiac
events and treatment stratification in HF patients (Carrio, J Nucl
Med. 2001; 42(7):1062-76; Jacobson et al., J Am Coll Cardiol. 2010;
55(20):2212-21; Pietila et al., Eur J Nucl Med. 2001; 28(3):373-6;
Boogers et al., J Am Coll Cardiol. 2010; 55(24):2769-77). In the
present study, the NAT association of Imaging Agent-1, an MIBG
analog designed also as a NAT substrate, was investigated in cells
with NAT expression. These cells have been used previously for
evaluation of MIBG and its analogs (Vaidyanathan et al., J Nucl
Med. 1997; 38(2):330-4; Ko et al., Eur J Nucl Med Mol Imaging.
2008; 35(3):554-61). Imaging Agent-1 cell uptake was inhibited by
non-radioactive MIBG, NA or self in a concentration-dependent
fashion with comparable IC.sub.50 values in a low .mu.M range,
similar to our previously reported K.sub.m values of
.sup.19F-Imaging Agent-1 and NA (Yu et al., Circ Cardiovasc
Imaging. 2011; 4(4):435-43). Furthermore, blockade of NAT with
desipramine reduced the uptake of all these test agents by more
than 90%. These findings suggest that Imaging Agent-1, NA and MIBG
share the same transporter, NAT, and possess similar NAT
association at least in NAT expressing cells.
[0898] Imaging Agent-1 radiolabeled with .sup.18F is a PET imaging
agent. It has demonstrated better uptake ratio of the heart to
liver and quicker liver clearance than .sup.123I-MIBG in rats and
nonhuman primates (NHP) (Yu et al., Circ Cardiovasc Imaging. 2011;
4(4):435-43). Consistently in this study, cardiac image quality of
Imaging Agent-1 was excellent with low activity in adjacent organs
(FIG. 11). Immediately after the initial Imaging Agent-1 heart
uptake in rabbits, a quick, transit washout phase was observed and
the retention reached a plateau phase (FIG. 13b). This kinetics
profile is similar to the observations of Imaging Agent-1 in NHPs
(Yu et al., Circ Cardiovasc Imaging. 2011; 4(4):435-43), but seems
to differ from .sup.11C-HED where the cardiac uptake plateaus after
the initial uptake (Raffel et al., J Med Chem. 2007; 50(9):2078-88;
Munch et al., Circulation. 2000; 101(5):516-23). This may be due to
the uptake kinetics of each imaging agent: integration of various
k.sub.1, k.sub.2 and k.sub.3 (rate constants for imaging agent
distribution into extracellular space, washout from extracellular
space back into the blood and transportation into the neuron via
the NAT from the extracellular space, respectively). In a kinetics
study comparing phenethylguanidine analogs, Raffel et al suggested
that an analog with rate-limited neuronal uptake
(k.sub.3<<k.sub.2, depending more on NAT function) is
superior to no rate-limited uptake (k.sub.3>>k.sub.2,
depending more on flow, such as Imaging Agent-2 (Nekolla et al.,
Circulation. 2009; 119(17):2333-42) in evaluation of cardiac
neuronal function (Raffel et al., J Med Chem. 2007; 50(9):2078-88).
The TACs generated in rabbits, together with our previous
observation in NHPs (high initial cardiac activity followed by a
quick washout), support the notion that Imaging Agent-1 cardiac
uptake may be rate limited (k.sub.3<<k.sub.2), depending more
on neuronal function than flow. However, based on the instantaneous
MIBG heart extraction fraction measured within 40 seconds after
injection and flow increased by infusion of dipyridamole in pigs,
Glowniak et al demonstrated that MIBG heart uptake is flow
dependent (Glowniak et al., J Nucl Med. 1992; 33(5):716-23). In
contrast to Imaging Agent-1 initial rapid washout, myocardial TACs
of Imaging Agent-2 showed a rapid uptake to a plateau (FIG. 13a),
supporting the findings that Imaging Agent-2 myocardial uptake may
depend on changes in flow at a large range of flow rates (Yu et
al., J Nucl Cardiol. 2007; 14(6):789-98; Nekolla et al.,
Circulation. 2009; 119(17):2333-42). A small and slow myocardial
Imaging Agent-2 washout was seen from 5 to 25 minutes post
injection, which differs from our observations in other species:
rats, pigs, NHPs and humans (Yu et al., J Nucl Cardiol. 2007;
14(6):789-98; Nekolla et al., Circulation. 2009; 119(17):2333-42;
Sherif et al., Circ Cardiovasc Imaging. 2009; 2(2):77-84; Maddahi
et al., J Nucl Med. 2011; 52(9):1490-8). This could be due to
species variation.
[0899] Moreover, in this study, Imaging Agent-1 imaging
demonstrated clear detection of regional sympathetic denervation in
the heart. Animal models of sympathetic denervation induced by
local phenol application on the myocardial surface have been widely
utilized in assessment of regional sympathetic denervation
previously (Minardo et al., Circulation. 1988; 78(4):1008-19;
Rimoldi et al., Eur J Nucl Med Mol Imaging. 2007; 34(2):197-205).
Imaging with .sup.123I-MIBG or .sup.11C-HED detected the denervated
area in the heart. This model differs from the coronary ligation
induced myocardial infarction model in that there is minimal flow
interruption and regional cardiac retention of an imaging agent is
little affected by flow. A similar scenario of regional sympathetic
denervation is seen clinically in patients with non-ischemic
cardiomyopathy, such as diabetes (Scholte et al., Eur J Nucl Med
Mol Imaging. 2010; 37(9):1698-705). In agreement with
.sup.123I-MIBG and .sup.11C-HED, Imaging Agent-1 imaging identified
the denervated region corresponding to the area that phenol had
been applied. The reduced local Imaging Agent-1 uptake was not the
consequence of myocardial perfusion interruption as Imaging Agent-2
imaging showed normal uptake in the denervated area (FIG. 12).
Additionally, myocardial TACs in the RCSD rabbit (FIG. 13c) also
confirmed that Imaging Agent-1 was initially delivered by blood to
the denervated region, similar to the innervated area, and then
quickly cleared from that region to a lower level consistent with
reduced NAT function (low k.sub.3) associated with the denervation.
Cardiac imaging detection of regional sympathetic neuronal
dysfunction has been suggested to predict ventricular tachycardia,
arrhythmia and increased risk of cardiac death (Dae et al.,
Circulation. 1997; 96(4):1337-42; Mitrani et al., J Am Coll
Cardiol. 1993; 22(5):1344-53; Sasano et al., J Am Coll Cardiol.
2008; 51(23):2266-75; Stevens et al., Circulation. 1998;
98(10):961-8; Boogers et al., J Am Coll Cardiol. 2010;
55(24):2769-77; Minardo et al., Circulation. 1988; 78(4):1008-19;
Calkins et al., Circulation. 1993; 88(1):172-9). However, clinical
assessment of cardiac neuronal function is not performed routinely.
One of the possible reasons may be associated with the lack of an
ideal neuronal imaging agent for tomographic imaging. Cardiac PET
neuronal imaging has been shown to be superior to SPECT in image
quality and identification of neuronal abnormalities (Matsunari et
al., Circ Cardiovasc Imaging. 2010; 3(5):595-603). Imaging Agent-1
PET imaging showed high image quality and allowed quantification of
regional sympathetic innervation/denervation. The innervated region
increased over time following phenol denervation in the heart
(FIGS. 12 and 14), consistent with reinnervation occurring over
time (Odaka et al., J Nucl Med. 2001; 42(7):1011-6).
[0900] Regional denervated myocardium has been suggested to exhibit
comparable effective refractory period (ERP) to normal innervated
area but increased sensitivity to NA induced ERP shortening
(Minardo et al., Circulation. 1988; 78(4):1008-19) or increased ERP
but similar sensitivity to NA induced ERP shortening (Calkins et
al., Circulation. 1993; 88(1):172-9). Regardless of the different
findings, heterogeneity of sympathetic innervation may render the
heart abnormal electrophysiologically and increase sensitivity to
drugs which interact with cardiac ion channel conductance, such as
antiarrhythmic drugs (Nattel, J Cardiovasc Electrophysiol. 1999;
10(2):272-82). In this study, we observed a marked increase in QTc
prolongation in regional cardiac denervated rabbits during
dofetilide infusion, even though the baseline values of HR and QTc
interval were comparable to the sham control. The dose of
dofetilide used in this study is in a range of clinical doses (500
.mu.g twice a day with >90% bioavailability in humans, Package
Insert). Dofetilide is known to increases ERP (Lenz et al.,
Pharmacotherapy. 2000; 20(7):776-86) and this action seems to be
potentiated by regional denervation or innervation heterogeneity.
Similarly, in humans, an antiarrhythmic drug (ibutilide) induced QT
prolongation, not changes in HR, was exaggerated when the autonomic
system was impaired (Smith et al., J Cardiovasc Electrophysiol.
2007; 18(9):960-4). These findings suggested that denervation in
the heart enhances cardiac risk to some antiarrhythmic drug
treatments, and this risk associated with innervation dysfunction
can potentially be assessed by Imaging Agent-1 imaging.
Conclusion:
[0901] Imaging Agent-1 was designed as an .sup.18F labeled NAT
substrate for cardiac sympathetic neuronal imaging. It exhibits
high association with NAT and its neuronal uptake may be NAT
mediated. Cardiac imaging demonstrates high image quality with
homogeneous heart uptake and rapid blood and liver clearance in
controls, and clear detection and quantification of regional
denervated areas in cardiac denervated animals. Since cardiac
denervation increased the sensitivity to dofetilide induced
electrophysiological changes, Imaging Agent-1 cardiac imaging may
provide a means to identify patients with enhanced risk to
dofetilide-like antiarrhythmic agents.
TABLE-US-00005 TABLE 4 Control values and dofetilide induced events
in control and regional cardiac denervated rabbits Control value
(Before dofetilide infusion) Dofetilide induced events HR QT.sub.cf
(4 .mu.g/kg/min iv infusion) (beat/min) (msec) PVC TdP Sham 158
.+-. 10 236 .+-. 5 3 (50%) 1 (17%) (n = 6) Denervated 169 .+-. 7
246 .+-. 8 5 (63%) 2 (25%) (n = 8) HR: heart rate, QT.sub.cf: QT
interval corrected by Fridericia method, PVC: premature ventricular
contraction, TdP: torsade de pointes.
Example 39
[0902] The following example describes studies completed on rabbits
to assess cardiac perfusion and innervation mismatch following
myocardial infarction. The imaging agent employed for determining
innervation was Imaging Agent-1 or a salt thereof. The imaging
agent employed for imaging cardiac perfusion was Imaging
Agent-2.
[0903] In this example, the rabbit model of myocardial infarction
(MI) comprises a surgical 30-min left coronary temporary occlusion
followed by reperfusion. The rabbits recovered from the
surgery.
[0904] For cardiac PET imaging with Imaging Agent-1 and Imaging
Agent-2, the imaging was performed in a 2-day interval. The MI
rabbits were assessed at 4, 13, and 46 weeks post
ischemia-reperfusion injury. The innervation defect (e.g.,
denervation) was determined from the Imaging Agent-1 images whereas
that of the perfusion defect was determined from the Imaging
Agent-2 images. The images were analyzed using the MunichHeart.TM.
software package. The defect area is defined as a percentage of
left ventricle (% LV) area with radioactivity levels <50% of the
maximum radioactivity in the LV.
[0905] FIG. 16A shows images of a heart of a control rabbit using
both Imaging Agent-1 and Imaging Agent-2. As can be observed in the
images, the areas of uptake in the heart of the imaging agents are
approximately equal for both agents. In contrast, FIGS. 16B and 16C
shows images of a heart of rabbits having global denervation and
regional denervation, respectively. As can be observed in the
images, the areas of uptake of Imaging Agent-1 in the heart is less
than the areas of uptake of Imaging Agent-2, indicating a mismatch
between innervation and perfusion.
[0906] FIG. 17 shows images of a heart of a control rabbit using
both Imaging Agent-1 and Imaging Agent-2, as well as the
corresponding polar maps. As can be observed in the images and the
polar maps, the areas of uptake in the heart of the imaging agents
is approximately equal for both agents. FIGS. 18A-18C show images
of a heart of a rabbit 4, 13, and 46 weeks following the
ischemia-reperfusion injury using both Imaging Agent-1 and Imaging
Agent-2, as well as their corresponding polar maps. As can be
observed in the images and the polar maps, the areas of uptake of
Imaging Agent-1 in the heart is less than the areas of uptake of
Imaging Agent-2, indicating a mismatch between innervation and
perfusion. The mismatch decreased with time, indicating
reinnervation. FIG. 18D shows a plot of the % LV defect versus time
for the images shown in FIGS. 18A-18C. Accordingly, it may be
beneficial to evaluate the mismatch at an early time point
following acute MI.
Example 40
[0907] In imaging, noise filtration (NF) is preferred so that noise
does not negatively impact diagnostic information contained in the
image. NF with optimized filter parameters (OFP) may minimize
count-related uncertainty while preserving diagnostic information.
A method is described using a cardiac phantom to determine the OFP
for the Phase 3 study of Imaging Agent-2 injection.
[0908] Based on Standardized Uptake Values (SUVs) in normal patient
myocardium, a cardiac phantom fitted with a 45.degree. defect
insert was loaded with 12.3 uCi/ml in the myocardium and 3.1 uCi/ml
in the defect to simulate a 70 kg patient injected with midpoint
doses for imaging at rest of 2.75 mCi, during pharmacological
stress of 6.25 mCi, and during exercise stress of 9.25 mCi. A GE
Discovery ST PET/CT was then employed to scan the phantom in both
3D and 2D modes. Multiple PET image data sets were first
reconstructed from the listmode rebinning to generate realistic 3D
perfusion images (3D-PI) and 2D ECG-gated images (2D-GI), then
filtered with a 3D Gaussian filter (FWHM=4-20 mm). Defect contrast
(DC) was then calculated to determine OFP for 3D-PI with <5% DC
degradation. Left ventricular volume (LVV) was quantified with the
QGS cardiac tool to determine OFP for 2D-GI while maintaining
>90% accuracy of LVV. The signal-to-noise (SNR), as the mean/SD
in normal myocardium was assessed with respect to the degree of
filtering. Finally, in order to test OFP adequacy in a clinical
setting, 10 patient images generated on a GE Discovery ST PET/CT
were processed with the appropriate OFP value then visually
assessed using an image quality score (IQS) (excellent=3, good=2,
fair=1, poor=0). The imaging parameters applied are set forth in
Table 5 and the results presented in Table 6.
TABLE-US-00006 TABLE 5 Imaging Parameters Rest Pharmacological
Exercise Normal Myocardial SUV 4.8 11.1 6.7 from Phase II Mean
Phase III Dose (mCi) 2.75 (2.5-3.0) 6.25 (6.0-6.5) 9.25 (9.0-9.5)
Assumed Patient Weight (kg) 70 70 70 F18 Activity Concentration in
0.184 0.984 0.880 Myocardial Wall (uCi/ml) Defect Severity 75% 75%
75% Imaging Duration for 3D 600 600 600 Perfusion (sec) Imaging
Duration for 2D 600 600 600 Gated (sec)
TABLE-US-00007 TABLE 6 Results FWHM (mm), DC Degradation (%), SNR
Rest 4, 1.6, 7.25 6, 3.1, 7.8 8, 4.9, 8.0 10, 7.8, 8.2 12, 11.7,
8.2 15, 19.1, 8.0 20, 33.2, 7.5 Pharm 4, 3.1, 8.1 6, 3.1, 8.3 8,
4.4, 8.5 10, 7.1, 8.8 12, 11.1, 8.7 15, 18.8, 8.4 20, 33.0, 7.6
Exercise 4, 0.4, 8.1 6, 2.7, 8.3 8, 3.2, 8.5 10, 7.2, 8.7 12, 12.2,
8.6 15, 21.1, 8.3 20, 35.7, 7.6 FWHM (mm), LVV Accuracy (%) Rest 4,
50.sup. 6, 55.sup. 8, 65.sup. 10, 70.sup. 12, 78.3 15, 93.3 20,
65.2 Pharm 4, 66.7 6, 71.7 8, 76.7 10, 83.3 12, 93.3 15, 91.7 20,
74.3 Exercise 4, 65.1 6, 72.2 8, 77.1 10, 84.2 12, 92.7 15, 91.2
20, 72.5
[0909] Using preferred SNR and DC degradation (<5%) settings,
the optimal filter parameters (OFP) for rest, and pharmacological
and exercise induced stress 3D perfusion imaging, were found to be
FWHM=8.0 mm, while the OFP for rest and pharmacological and
exercise inducedstress 2D gated imaging were found to be 15.0 mm
and 12.0 mm, respectively. The mean IQS for the 3D erfusion images
were 2.6.+-.0.7 while that for the 2D gated images were 2.2.+-.0.6
(data not shown).
[0910] A cardiac phantom simulation using known patient myocardial
SUVs is an effective method to determine an optimal noise filter
parameter set that can produce high-quality diagnostic images when
using an Imaging Agent-2 injection.
Terms and Equivalents
[0911] While several embodiments of the present invention have been
described and illustrated herein, those of ordinary skill in the
art will readily envision a variety of other means and/or
structures for performing the functions and/or obtaining the
results and/or one or more of the advantages described herein, and
each of such variations and/or modifications is deemed to be within
the scope of the present invention. More generally, those skilled
in the art will readily appreciate that all parameters, dimensions,
materials, and configurations described herein are meant to be
exemplary and that the actual parameters, dimensions, materials,
and/or configurations will depend upon the specific application or
applications for which the teachings of the present invention
is/are used. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. It is, therefore, to be understood that the foregoing
embodiments are presented by way of example only and that, within
the scope of the appended claims and equivalents thereto, the
invention may be practiced otherwise than as specifically described
and claimed. The present invention is directed to each individual
feature, system, article, material, kit, and/or method described
herein. In addition, any combination of two or more such features,
systems, articles, materials, kits, and/or methods, if such
features, systems, articles, materials, kits, and/or methods are
not mutually inconsistent, is included within the scope of the
present invention.
[0912] The indefinite articles "a" and "an," as used herein in the
specification and in the claims, unless clearly indicated to the
contrary, should be understood to mean "at least one."
[0913] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified unless clearly
indicated to the contrary. Thus, as a non-limiting example, a
reference to "A and/or B," when used in conjunction with open-ended
language such as "comprising" can refer, in one embodiment, to A
without B (optionally including elements other than B); in another
embodiment, to B without A (optionally including elements other
than A); in yet another embodiment, to both A and B (optionally
including other elements); etc.
[0914] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e. "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of." "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0915] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0916] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," and the like are to
be understood to be open-ended, i.e., to mean including but not
limited to. Only the transitional phrases "consisting of" and
"consisting essentially of" shall be closed or semi-closed
transitional phrases, respectively, as set forth in the United
States Patent Office Manual of Patent Examining Procedures, Section
2111.03.
* * * * *