U.S. patent application number 17/836994 was filed with the patent office on 2022-09-29 for metal tricarbonyl complexes comprising substituted iminodiactic acid ligands and uses as radioisotope tracers.
The applicant listed for this patent is Emory University. Invention is credited to Jeffrey Klenc, Malgorzata Lipowska, Andrew Taylor.
Application Number | 20220306663 17/836994 |
Document ID | / |
Family ID | 1000006406173 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220306663 |
Kind Code |
A1 |
Klenc; Jeffrey ; et
al. |
September 29, 2022 |
Metal Tricarbonyl Complexes Comprising Substituted Iminodiactic
Acid Ligands and Uses as Radioisotope Tracers
Abstract
This disclosure relates to compositions comprising substituted
iminodiacetic acid ligands and metal tricarbonyl complexes
containing the ligands and derivatives thereof. In certain
embodiments, the metal tricarbonyl complexes are used as
radioisotope tracers such as renal tracers. In certain embodiments,
the metal complexes comprise .sup.99mTc or Re. In certain
embodiments, the ligands are substituted with a fluorine, a
fluorine-18(F.sup.18) radioisotope, or other radionuclide.
Inventors: |
Klenc; Jeffrey; (Atlanta,
GA) ; Lipowska; Malgorzata; (Atlanta, GA) ;
Taylor; Andrew; (Atlanta, GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Emory University |
Atlanta |
GA |
US |
|
|
Family ID: |
1000006406173 |
Appl. No.: |
17/836994 |
Filed: |
June 9, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16822571 |
Mar 18, 2020 |
11384106 |
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17836994 |
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15557453 |
Sep 11, 2017 |
10633404 |
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PCT/US2016/021719 |
Mar 10, 2016 |
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16822571 |
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62130953 |
Mar 10, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 59/004 20130101;
A61B 6/4057 20130101; G01N 33/60 20130101; A61K 51/0478 20130101;
G01N 33/5088 20130101; G01N 2800/347 20130101; A61K 51/0402
20130101; C07F 13/00 20130101 |
International
Class: |
C07F 13/00 20060101
C07F013/00; A61K 51/04 20060101 A61K051/04; C07B 59/00 20060101
C07B059/00; A61B 6/00 20060101 A61B006/00; G01N 33/50 20060101
G01N033/50; G01N 33/60 20060101 G01N033/60 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under
DK038842 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. An imaging method comprising injecting into a human a
tricarbonyl complex having the formula
Re(CO).sub.3(N-(2-.sup.18fluoroethyl)iminodiacetate and imaging the
.sup.18F analog.
2. The method of claim 1, wherein the imaging is renal imaging.
3. An imaging method comprising injecting into a human a
tricarbonyl complex having formula
.sup.99mTc(CO).sub.3(N-(2-fluoroethyl)iminodiacetate) and imaging
the .sup.99mTc analog.
4. The method of claim 3, wherein the imaging is renal imaging.
5. An imaging method comprising injecting into a human a
tricarbonyl complex having the formula
Re(CO).sub.3(N-(2-.sup.18fluoroethyl)iminodiacetate and the formula
.sup.99mTc(CO).sub.3(N-(2-fluoroethyl)iminodiacetate) and imaging
the .sup.18F analog and .sup.99mTc analog.
6. The method of claim 5, wherein the imaging is renal imaging.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/822,571 filed Mar. 18, 2020, which is a continuation of U.S.
application Ser. No. 15/557,453 filed Sep. 11, 2017 that granted as
U.S. Pat. No. 10,633,404 on Apr. 28, 2020, which is the National
Stage of International Application No. PCT/US2016/021719 filed Mar.
10, 2016, which claims the benefit of U.S. Provisional Application
No. 62/130,953 filed Mar. 10, 2015. The entirety of each of these
applications is hereby incorporated by reference for all
purposes.
BACKGROUND
[0003] Radiopharmaceuticals are widely employed in nuclear medicine
for imaging and for assessing physiological function and disease.
Radioisotope renography is a form of kidney imaging involving
radioisotopes used to image the kidney, evaluate suspected renal
disease, and monitor renal function. The most common radiolabelled
pharmaceutical agent used is Tc.sup.99m-MAG.sub.3
(mercaptoacetyltriglycine). Image quality is dependent on rapid
removal of the radiotracer from the circulating plasma by the
kidney as the rate of removal provides an important measurement of
renal function. Renal plasma flow can be measured indirectly with
radioiodinated o-iodohippuran (.sup.131I-OIH) that is generally
accepted as a benchmark.
[0004] The .sup.99mTc-MAG.sub.3 tracer is eliminated via the
hepatobiliary tract which is exacerbated in patients with impaired
renal function. The clearance of
.sup.99mTc-mercaptoacetyltriglycine (.sup.99mTc-MAG.sub.3) is
50-65% when compared to .sup.131I-OIH making the tracer suboptimal
for the estimation of renal plasma flow. Thus, improved renal
tracers are need.
[0005] Klenc et al. report fac-[ReI(CO).sub.3(NTA)].sup.2- and
fac-[ReI(CO).sub.3(L)].sup.n- analogues as useful for assessing the
renal clearance. Inorg. Chem., 2015, 54 (13), pp 6281-6290. See
also Klenc et al. JNM 2015, 56, (Suppl. 3):654; Lipowska et al. J
Nucl Med. 2014; 55 (Suppl. 1):1206, and U.S. Pat. Nos. 9,061,077
and 6,926,883.
[0006] References cited herein are not an admission of prior
art.
SUMMARY
[0007] This disclosure relates to compositions comprising
substituted iminodiacetic acid ligands and metal tricarbonyl
complexes containing the ligands and derivatives thereof. In
certain embodiments, the metal tricarbonyl complexes are used as
radioisotope tracers such as renal tracers. In certain embodiments,
the metal complexes comprise .sup.99mTc and/or Re. In certain
embodiments, the ligands are substituted with a fluorine, a
fluorine-18(F.sup.18) radioisotope, or other radionuclide.
[0008] In certain embodiments, a metal tricarbonyl complex
comprises N-(2-fluoroethyl) iminodiacetic acid as a ligand, e.g., a
metal tricarbonyl complex having the formula
Re(CO).sub.3(N-(2-fluoroethyl)iminodiacetate),
Re(CO).sub.3(N-(2-.sup.18fluoroethyl)iminodiacetate),
.sup.99mTc(CO).sub.3(N-(2-fluoroethyl)iminodiacetate), mixtures or
salts thereof. In certain embodiments, a fluoro is F.sup.18.
[0009] In certain embodiments, the disclosure relates to tracer
composition comprising a mixture of
Re(CO).sub.3(N-(2-.sup.18fluoroethyl)iminodiacetate) and
.sup.99mTc(CO).sup.3(N-(2-fluoroethyl)iminodiacetate).
[0010] In certain embodiments, the disclosure relates to kits and
pharmaceutical composition comprising ligands or metal tricarbonyl
complexes disclosed herein. In certain embodiments, the disclosure
relates to kits comprising an amount of a tracer comprising a metal
tricarbonyl complex disclosed herein or precursor thereof
optionally in a sealed container, wherein the amount of the tracer
is suitable for imaging a kidney of subject. In certain
embodiments, the ligand is N-(2-fluoroethyl)iminodiacetic acid or
N-(2-((tosyl)oxy)ethyl)iminodiacetic acid, or
Re(CO).sub.3(N-(2-((tosyl)oxy)ethyl)iminodiacetate. In certain
embodiments, the kit further comprise a chelator such as a
cryptand.
[0011] In certain embodiments, the disclosure relates to the
precursor metal tricarbonyl complex
Re(CO).sub.3(N-(2-((tosyl)oxy)ethyl)iminodiacetate or derivatives.
In certain embodiments, the precursor is
N-(2-fluoroethyl)iminodiacetic acid,
N-(2-hydroxyethyl)iminodiacetic acid, or
N-(2-((tosyl)oxy)ethyl)iminodiacetic acid.
[0012] In certain embodiments, the disclosure relates to imaging
methods comprising a) administering a pharmaceutical composition
comprising a metal tricarbonyl complex disclosed herein containing
a radionuclide to a subject; b) scanning the subject for emissions;
and c) creating an image indicating a location of the metal
tricarbonyl complex containing radionuclide in the body, organ,
kidney, blood, or other area of the subject. In certain
embodiments, the imaging method comprises single photon emission
computed tomography (SPECT) and/or PET imaging
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows the HPLC chromatograms of
.sup.99mTc(CO).sub.3(FEDA) in urine at 10 min after injection.
[0014] FIG. 2 illustrates the preparation of embodiments of the
disclosure, e.g., wherein M is Re or .sup.99mTc.
[0015] FIG. 3 illustrates embodiments of a renal tracer having a
mixture of metal tricarbonyl complexes.
DETAILED DESCRIPTION
[0016] Before the present disclosure is described in greater
detail, it is to be understood that this disclosure is not limited
to particular embodiments described, and as such may, of course,
vary. It is also to be understood that the terminology used herein
is for the purpose of describing particular embodiments only, and
is not intended to be limiting, since the scope of the present
disclosure will be limited only by the appended claims.
[0017] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
Although any methods and materials similar or equivalent to those
described herein can also be used in the practice or testing of the
present disclosure, the preferred methods and materials are now
described.
[0018] All publications and patents cited in this specification are
herein incorporated by reference as if each individual publication
or patent were specifically and individually indicated to be
incorporated by reference and are incorporated herein by reference
to disclose and describe the methods and/or materials in connection
with which the publications are cited. The citation of any
publication is for its disclosure prior to the filing date and
should not be construed as an admission that the present disclosure
is not entitled to antedate such publication by virtue of prior
disclosure. Further, the dates of publication provided could be
different from the actual publication dates that may need to be
independently confirmed.
[0019] As will be apparent to those of skill in the art upon
reading this disclosure, each of the individual embodiments
described and illustrated herein has discrete components and
features which may be readily separated from or combined with the
features of any of the other several embodiments without departing
from the scope or spirit of the present disclosure. Any recited
method can be carried out in the order of events recited or in any
other order that is logically possible.
[0020] Embodiments of the present disclosure will employ, unless
otherwise indicated, techniques of medicine, organic chemistry,
biochemistry, molecular biology, pharmacology, and the like, which
are within the skill of the art. Such techniques are explained
fully in the literature.
[0021] It must be noted that, as used in the specification and the
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise. In
this specification and in the claims that follow, reference will be
made to a number of terms that shall be defined to have the
following meanings unless a contrary intention is apparent. Prior
to describing the various embodiments, the following definitions
are provided and should be used unless otherwise indicated.
[0022] The term "renal scintigraphy" as used herein refers to an
imaging system including, but not limited to, a gamma camera able
to detect and form an image localizing a source of gamma radiation.
In the context of the present disclosure, the imaging system may be
for an image corresponding to the form of the labeled organ, and in
particular of a kidney underlying skin and other tissues. The
imaging system may further comprise computer-based apparatus and
software intended to produce an image in a form apparent to the
observer, and to analyze the image for information such as, but not
only, the intensity of the emitted gamma radiation as well as its
locality in the subject body. The term "dose amount" as used herein
refers to a bolus dose of a renal tracer, and in particular of the
tracer. The dose is preferred to be of an amount that, when
delivered to the kidney of an animal or human subject, will have a
gamma intensity useful for forming an image of the gamma source by
a gamma camera. The dose amount being adjusted according to the
size, weight, and shape of the recipient subject and the purpose of
the study.
[0023] As used herein, "alkyl" means a noncyclic straight chain or
branched, unsaturated or saturated hydrocarbon such as those
containing from 1 to 10 carbon atoms, typically 1 to 4 otherwise
designated C.sub.1-4alkyl. Representative saturated straight chain
alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl,
n-septyl, n-octyl, n-nonyl, and the like; while saturated branched
alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl,
isopentyl, and the like. Unsaturated alkyls contain at least one
double or triple bond between adjacent carbon atoms (referred to as
an "alkenyl" or "alkynyl", respectively). Representative straight
chain and branched alkenyls include ethylenyl, propylenyl,
1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,
3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and
the like; while representative straight chain and branched alkynyls
include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,
2-pentynyl, 3-methyl-1-butynyl, and the like.
[0024] "Alkoxy" refers to an alkyl group as defined above with the
indicated number of carbon atoms attached through an oxygen bridge.
Examples of alkoxy include, but are not limited to, methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy,
n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
"Alkoxyalkyl" refers an alkyl group as defined above with the
indicated number of carbon atoms attached through an alkyl bridge
(i.e., --CH.sub.2--O--CH.sub.2CH.sub.3).
[0025] A chelator is a molecule that contains multiple multivalent
atoms, e.g, divalent, with a lone pair of elections (multidentate).
The multivalent atoms are typically N, O, S, and mixtures thereof.
Examples of chelators include crown ethers (monocyclic) and
cryptands (bi- or polycyclic) which contain polyalkoxy or
polyethylene glycol groups.
1,10-Diaza-4,7,13,16,21,24-hexaoxabicyclo[8.8.8]hexacosane is the
[2.2.2]cryptand where the numbers [2.2.2] indicate the number of
ether oxygen atoms in each of the three bridges between the amine
nitrogen caps. Cryptands and crown ethers typically bind cations to
form salts. Chelators may be anionic if they contain a quaternary
ammonium cation.
[0026] A "linking group" refers to any variety of molecular
arrangements that can be used to bridge two molecular moieties
together. An example formula may be --R.sub.m-- wherein R is
selected individually and independently at each occurrence as:
--CR.sub.mR.sub.m--, --CHR.sub.m--, --CH--, --C--, --CH.sub.2--,
--C(OH)R.sub.n, --C(OH)(OH)--, --C(OH)H, --C(Hal)R.sub.m--,
--C(Hal)(Hal)-, --C(Hal)H--, --C(N.sub.3)R.sub.m--,
--C(CN)R.sub.n--, --C(CN)(CN)--, --C(CN)H--,
--C(N.sub.3)(N.sub.3)--, --C(N.sub.3)H--, --O--, --S--, --N--,
--NH--, --NR.sub.m--, --(C.dbd.O)--, --(C.dbd.NH)--, --(C.dbd.S)--,
--(C.dbd.CH.sub.2)--, which may contain single, double, or triple
bonds individually and independently between the R groups. If an R
is branched with an R.sub.m it may be terminated with a group such
as --CH.sub.3, --H, --CH.dbd.CH.sub.2, --CCH, --OH, --SH,
--NH.sub.2, --N.sub.3, --CN, or -Hal, or two branched Rs may form a
cyclic structure. It is contemplated that in certain instances, the
total Rs or "m" may be less than 100 or 50 or 25 or 10. Examples of
linking groups in include bridging alkyl groups and alkoxyalkyl
groups.
[0027] The term "substituted" refers to a molecule wherein at least
one hydrogen atom is replaced with a substituent. When substituted,
one or more of the groups are "substituents." The molecule may be
multiply substituted. In the case of an oxo substituent (".dbd.O"),
two hydrogen atoms are replaced. Example substituents within this
context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano,
oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl,
heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, --NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.aNR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--NR.sub.aSO.sub.2R.sub.b, --C(.dbd.O)R.sub.a, --C(.dbd.O)OR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.b, --OC(.dbd.O)NR.sub.aR.sub.b,
--OR.sub.a, --SR.sub.a, --SOR.sub.a, --S(.dbd.O).sub.2R.sub.a,
--OS(.dbd.O).sub.2R.sub.a and --S(.dbd.O).sub.2OR.sub.a. R.sub.a
and R.sub.b in this context may be the same or different and
independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl,
amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl,
heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl.
[0028] "Subject" refers any animal, preferably a human patient,
livestock, or domestic pet.
[0029] As used herein, the term "derivative" refers to a
structurally similar compound that retains sufficient functional
attributes of the identified analogue. The derivative may be
structurally similar because it is lacking one or more atoms,
substituted, a salt, in different hydration/oxidation states, or
because one or more atoms within the molecule are switched, such
as, but not limited to, replacing an oxygen atom with a sulfur or
nitrogen atom or replacing an amino group with a hydroxyl group or
vice versa. Derivatives may be prepare by any variety of synthetic
methods or appropriate adaptations presented in synthetic or
organic chemistry text books, such as those provide in March's
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,
Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in
Organic Synthesis, Wiley (2006) Lutz F. Tietze hereby incorporated
by reference.
Iminodiacetate Metal Tricarbonyl Complexes and Derivatives
[0030] The tracer .sup.99mTc(CO).sub.3(2-fluoroethyliminodiacetate)
(FEDA), i.e., .sup.99mTc(CO).sub.3 complexed with
N-(fluoroethyl)iminodiacetic acid (FEDA), showed a rapid renal
excretion in rat studies that was in significant excess of the
current clinical standard for the same purpose,
.sup.99mTc-MAG.sub.3. .sup.99mTc(CO).sub.3(FEDA) may prepared with
.sup.18F. The clearance of the .sup.99mTc-FEDA analog is comparable
to the gold standard, .sup.131I-OIH. The renal excretion exhibited
by .sup.99mTc (CO).sub.3(FEDA) was unexpected due to the
fluoroethyl pendant group being less polar and unable to form
hydrogen bonds, as the complexes that were previously evaluated
such as .sup.99mTc(CO).sub.3 complexes with
N-(2-hydroxyethyl)iminodiacetic acid (HDA) and
N-(2-acetamido)iminodiacetic acid (ADA), (.sup.99mTc(CO).sub.3(ADA)
and .sup.99mTc (CO).sub.3(HDA)).
[0031] In certain embodiments, the disclosure relates to
substituted iminodiacetate metal tricarbonyl complexes disclosed
herein, mixtures, and derivatives thereof. In certain embodiments
the metal tricarbonyl complexes disclosed herein are substituted
with one or more substituents. In certain embodiments, the metal
tricarbonyl complexes have the following formula:
##STR00001##
[0032] or salts thereof wherein [0033] M is .sup.99mTc, Re, or
other metal capable of octahedral coordination; [0034] X is alkyl,
alkoxyalkyl, or other linking group; and [0035] Y is hydroxyl,
fluoro, halogen, a leaving group, F.sup.18, or other
radionuclide.
[0036] In certain embodiments, metal tricarbonyl complexes of this
disclosure comprise N-(fluoroalkyl)iminodiacetate wherein the
fluoroalkyl is alkyl terminally substituted with fluoro, e.g.,
N-(2-fluoroethyl)iminodiacetic acid.
[0037] In certain embodiments, metal tricarbonyl complexes of this
disclosure have the formula
M(CO).sub.3(N-(fluoroalkyl)iminodiacetate),
Re(CO).sub.3(N-(fluoroalkyl)iminodiacetate) or
.sup.99mTc(CO).sub.3(N-(fluoroalkyl)iminodiacetate).
Generation of Radionuclides
[0038] The term "radionuclide" or "radioactive isotope" refers to
molecules of enriched isotopes that exhibit radioactive decay
(e.g., emitting one or more gamma rays or positrons). Such isotopes
are also referred to in the art as radioisotopes. A radionuclide
tracer does not include radioactive primordial nuclides, but does
include a naturally occurring isotopes that exhibit radioactive
decay with an isotope distribution that is enriched, e.g., is
several fold greater than natural abundance. In certain
embodiments, is contemplated that the radionuclides are limited to
those with a half live of less than 1 hour and those with a
half-life of more than 1 hour but less than 24 hours. Radioactive
isotopes are named herein using various commonly used combinations
of the name or symbol of the element and its mass number (e.g.,
.sup.18F, F-18, or fluorine-18). Elements that can be used in the
compounds of the present disclosure include: F-18; C-11; 1-125,
1-124, 1-131 and 1-123; Cl-32, Cl-33, Cl-34; Br-74, Br-75, Br-76,
Br-77, Br-78; Re-186, Re-188; Y-90, Y-86; Lu-177 and Sm-153.
Typical radioactive isotopes include I-124, F-18 fluoride, C-11,
N-13, and 0-15, which have half-lives of 4.2 days, 110 minutes, 20
minutes, 10 minutes and 2 minutes, respectively. Preferably, the
radioactive isotopes used in the present method include F-18, C-11,
I-123, I-124, I-127, 1-131, Br-76, Cu-64, Tc-99m, Y-90, Ga-67,
Cr-51, Ir-192, Mo-99, Sm-153 and Tl-201. Other radioactive isotopes
that may be employed include: As-72, As-74, Br-75, Co-55, Cu-61,
Cu-67, Ga-68, Ge-68, I-125, I-132, In-111, Mn-52, Pb-203 and
Ru-97.
[0039] Methods of preparing radiolabeled ligands are well known in
the art. Example of such methods are disclosed in, for example: 1)
Jewett, D. M. (1992) A Simple Synthesis of [.sup.11C]Methyl
Triflate Appl. Radiat. Isot. 43, 1383-1385; 2) Crouzel, C.
Langstrom, B., Pike, V. W., and Coenen, H. H. (1987)
Recommendations for a practical production of [.sup.11C]methyl
iodide Appl. Radiat. Isot. Int. J. Appl. Instrum. Part A 38,
601-603; Dannals, R. F., Ravert, H. T.; 3) Wilson, A. A. (1990)
Radiochemistry of Tracers for Neurotransmitter Receptor Studies.
In: Quantitative Imaging: Neuroreceptors, Neurotransmitters, and
Enzymes. (Edited by Frost), J. J. Wagner Jr., H. N. pp. 19-35,
Raven Press, New York; 4) Jewett, D. M., Manger, T. J., and
Watkins, G. L. (1991) Captive Solvent Methods for Fast Simple
Carbon-11 Radioalkylations. In: New Trends in Radiopharmaceutical
Synthesis, Quality Assurance and Regulatory Control (Edited by
Emran, A. M.) pp. 387-391. Plenum Press, New York; 5) Marazano, C.,
Maziere, M., Berger, G., and Comar, D. (1977) Synthesis of methyl
iodide-.sup.11C and formaldehyde-.sup.11C Appl. Radiat. Isot. 28,
49-52; 6) Watkins, G., Jewett, D., Mulholland, G., Kitbourn, M.,
and Toorongian, S. (1988) A Captive Solvent Method for Rapid
N-[.sup.11C]Methylation of Secondary Amides Application to the
Benzodiazepine, 4'-Chlorodiazepam (RO5-4864) Appl. Radiat. Isot.
39, 441-444; and 7) Wilson, A. A., DaSilva, J. N., and Houle, S.
(1996) In vivo evaluation of [.sup.11C] and [.sup.15F]-labeled
cocaine analogues as potential dopamine transporter ligands for
positron emission tomography Nucl. Med. Biol. 23, 141-146.
[0040] [.sup.18F] fluoride is typically produced by irradiation of
water (containing H.sub.2.sup.18O) with protons resulting in the
reaction .sup.18O(p,n).sup.18F. For production efficiency and
radiochemical purity, it is desirable to use water that is as
highly enriched as possible. The [.sup.18F] isotope is then
separated from water and processed for production of a
radiopharmaceutical agent. Typically fluoride recovery is based on
ion exchange resins. The recovery is carried out in two steps
(extraction and elution): first the anions (not only fluoride) are
separated from the enriched [.sup.18O] water and trapped on a resin
and then, said anions, including [.sup.18F] fluoride, are eluted
into a mixture containing water, organic solvents, a base, also
called activating agent or phase transfer agent or phase transfer
catalyst, such as for example the complex comprising a cryptand,
potassium carbonate-Kryptofix 222 (K.sub.2CO.sub.3--K.sub.222), or
a tetrabutylammonium salt. Typical labeling method uses low water
content solutions. An evaporation step follows the recovery of the
[.sup.18F]fluoride, e.g., azeotropic evaporation of acetonitrile or
other low boiling temperature organic solvent.
[0041] Alternatively the extraction process is performed by passing
the [.sup.18F] aqueous solution on a solid support as reported in
U.S. Pat. No. 8,641,903. This solid support is typically loaded
with a trapping agent, e.g., compound comprising a quaternary
amine, which is adsorbed on the solid support and allows the
[.sup.18F] activity to be trapped because of its positive charge.
The solid support is then flushed with a gas or a neutral solvent
to remove or push out most of the residual water. The [.sup.18F] is
at last eluted in an organic solvent or in a mixture of organic
solvents and is immediately usable for the labelling of precursor
compounds.
[0042] The compounds described herein could also be labeled by
bromine or iodine radionuclides through traditional labeling
procedures such as tributyltin derivatives. (See, for example,
Plisson et al, Synthesis and in vivo evaluation of fluorine-18 and
iodine-123 labeled 2beta-carbo(2-fluoroethoxy)-3beta-(4'-((Z)-2
iodoethenyl)phenyl)nortropane as a candidate serotonin transporter
imaging agent. J Med Chem, 2007, 50(19):4553-60; Plisson et al,
Synthesis, radiosynthesis, and biological evaluation of carbon-11
and iodine-123 labeled
2beta-carbomethoxy-3beta-[4'-((Z)-2-haloethenyl)phenyl]tropanes. J
Med Chem, 2004, 47(5):1122-35; Li et al, Synthesis of structurally
identical fluorine-18 and iodine isotope labeling compounds for
comparative imaging. Bioconjug Chem, 2003, 14(2):287-94; Goodman et
al., Synthesis and characterization of iodine-123 labeled
2beta-carbomethoxy-3beta-(4'-((Z)-2-iodoethenyl)phenyl) nortropane.
J Med Chem, 2003, 46(6):925-35; Maziere et al, .sup.76Br-beta-CBT,
a PET tracer for investigating dopamine neuronal uptake. Nucl Med
Biol, 1995, 22(8):993-7).
Kits and Pharmaceutical Compositions
[0043] It is appreciated that the stability of metal tricarbonyl
complexes disclosed herein containing radionuclides is important to
allow for sufficient time, e.g., to complete a renal examination
minimizing the possibility of contamination due to formation of
disintegration products. Thus, in certain embodiments, metal
tricarbonyl complexes containing radionuclides may be prepared
immediately prior to conducting a kidney function diagnostic
procedure.
[0044] Thus in certain embodiments, the disclosure contemplates
kits that contain components and the chemical reagents necessary
for the preparation of a metal tricarbonyl complex disclosed herein
or mixture thereof, immediately prior to use as a
radiopharmaceutical. By means of a kit, the labeling reaction of a
ligand with a radionuclide may be carried out just prior to use in
a clinical laboratory setting. For example, it is typical that one
will have access to a molybdenum-technetium generator, from which a
desired quantity of .sup.99mTc can be obtained as a pertechnetate
solution.
[0045] F-18 derivatives are typically prepared from precursor
compounds by radiohalogenation reactions. Radiohalogenations
reactions are typically nucleophilic substitutions. Aliphatic
nucleophilic substitutions typically utilize leaving group (usually
another halogen or a sulphonic acid derivative such as mesylate,
tosylate, or triflate).
[0046] In certain embodiments, the disclosure contemplates kits for
formation of a radiopharmaceutical metal tricarbonyl complex
suitable for renal examination that comprises a precursor metal
tricarbonyl complex, e.g., .sup.99mTc(CO).sub.3(H.sub.2O).sub.3
salts and a ligand having a structure according to the formula:
##STR00002##
[0047] or salts thereof wherein [0048] X is alkyl, alkoxyalkyl, or
other linking group; and [0049] Y is hydroxyl, halogen, a leaving
group, fluoro, F.sup.18, or other radionuclide.
[0050] In certain embodiments, the kit further optionally comprises
a metal tricarbonyl complex, a reducing agent, a stabilizing agent
and/or a chelating agent, as well as instructions for use of the
reagents in the kit.
[0051] In certain embodiments, the ligand is
N-(LGalkyl)iminodiacetic acid wherein the LGalkyl is alkyl
terminally substituted with a halogen, fluroro, hydroxyl, leaving
group, or salt thereof.
[0052] In certain embodiments, the leaving group is Cl, Br, I, a
sulfonate, tosylate, mesylate, trifluoromethanesulfonate, or
sulfurate.
[0053] A .sup.99mTc-metal tricarbonyl complex may be prepared from
a kit by interacting under reducing conditions the reactants of the
kit, i.e., a ligand and a freshly prepared. .sup.99mTc solution
eluted from a molybdenum-technetium generator just prior to use.
The .sup.99mTc may be present in the form of a salt or as
technetium bound to a relatively weak chelator, in which case the
desired .sup.99mTc chelate is formed by ligand exchange. Examples
of relatively weak chelating agents known to be particularly
suitable to easily obtain a desired ligand exchange are, for
example, carboxylic acids such as citric acid, tartaric acid,
ascorbic acid, glucoheptonic acid, and derivatives thereof,
although polycarboxylic acids, hydroxycarboxylic acids and
phosphorus compounds can also be used.
[0054] Suitable reducing conditions to keep the .sup.99mTc
pertechnetate reduced can be provided by, for example, dithionite,
formamidine sulfinic acid or metallic reducing agents such as
Fe(II), Cu(I), Ti(III) or Sb(III) and, preferably, Sn(II).
[0055] The reactants of the kit may be present in liquid form, for
example, as a saline or buffer solution. However, it is preferred
that the reactants be in a dry form, e.g., a lyophilized condition.
The reactants may be stabilized by the presence of a suitable
stabilizing agent such as ascorbic acid, gentisic acid, sugar,
e.g., glucose, lactose, mannitol, inositol, and the like.
[0056] In certain embodiments, the disclosure also contemplates
kits comprising an amount of a tracer comprising a metal
tricarbonyl complex disclosed herein, or precursor, or mixtures
thereof optionally in a sealed container, wherein the amount of the
tracer is suitable for imaging a kidney of subject.
[0057] In certain embodiments, the kit further comprises a cryptand
or other anionic chelator.
[0058] In certain embodiments, the kits comprise metal tricarbonyl
complexes or mixtures having the following formula:
##STR00003##
[0059] or salts thereof wherein [0060] M is .sup.99mTc, Re, or
other metal capable of octahedral coordination; [0061] X is alkyl,
alkoxyalkyl, or other linking group; and [0062] Y is hydroxyl,
halogen, I, Br, or a leaving group.
[0063] In certain embodiment, the kit further comprises a reagent
for generating a leaving group, e.g., Y is hydroxyl and the reagent
is capable of reacting with the hydroxyl to form a leaving group
such as a tosylate or mesylate group.
[0064] In certain embodiment, the kit further comprises a precursor
compound of the formula M(CO).sub.3(N-(LGalkyl)iminodiacetate),
Re(CO).sub.3(N-(LGalkyl)iminodiacetate) or
.sup.99mTc(CO).sub.3(N-(LGalkyl)iminodiacetate) wherein LGalkyl is
an alkyl terminal substituted with a leaving group or salt
thereof.
[0065] It is contemplated that precursor metal tricarbonyl
complexes are labeled with radionuclides using methods reported
herein to provide the tracers. These tracers may be prepared at the
location of the subject near the time the subject is exposed to an
imaging device. Thus, in certain embodiments, the disclosure
contemplates kits comprising metal tricarbonyl complexes disclosed
herein or precursors (e.g., metal tricarbonyl complexes disclosed
herein that react with recently generated .sup.18F.sup.-), e.g.,
metal tricarbonyl complexes disclosed herein comprising alkyl or
alkoxy groups that are terminally substituted with tosylate and
mesylate groups.
[0066] In certain embodiments, the disclosure contemplates a kit
comprising metal tricarbonyl complexes disclosed herein or
precursors comprising alkyl or alkoxy groups terminally substituted
with halogen, hydroxyl, thiol, --O-p-toluenesulfonyl,
--O-p-bromobenzenesulfonyl, --O-- (2- or 4)-nitrobenzene sulfonyl,
--O-methanesulfonyl, --O-trifluoromethanesulfonyl,
--O-5(dimethylamino)naphthalene-1-sulfonyl, --S-p-toluenesulfonyl,
--S-p-bromobenzenesulfonyl, --S-(2- or 4)-nitrobenzene sulfonyl,
--S-methanesulfonyl, --S-trifluoromethanesulfonyl,
--S-5(dimethylamino)naphthalene-1-sulfonyl. In certain embodiments,
the kit may further comprise a metal tricarbonyl complex disclosed
herein having a terminal hydroxy or thiol and an activating agent
such as p-toluenesulfonyl chloride, p-bromobenzenesulfonyl
chloride, (2- or 4)-nitrobenzene sulfonyl chloride, methanesulfonyl
chloride, trifluoromethanesulfonyl chloroide,
5(dimethylamino)naphthalene-1-sulfonyl chloride,
dicyclohexylcarbodiimide, bromo-tripyrrolidino-phosphonium
hexafluorophosphate, bromotris(dimethylamino) phosphonium
hexafluorophosphate,
2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminium
hexafluorophosphate,
N-[(5-Chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium
hexafluorophosphate N-oxide, tetramethylfluoro formamidinium
hexa-fluorophosphate,
1-[1-(Cyano-2-ethoxy-2-oxoethylidene-aminooxy)-dimethylamino-morpholino]--
uronium hexafluorophosphate,
2-(1-oxy-pyridin-2-yl)-1,1,3,3-tetramethyl-isothiouronium
tetrafluoroborate].
[0067] In certain embodiments, the kit comprise a solid support
comprising .sup.18F salts.
[0068] In some embodiments, the solid support is selected from the
group of solid phase extraction resins or liquid chromatography
resins, e.g., silica (oxide) based or non-silica (metal oxide or
polymers) based particles optionally functionalized (e.g., by
organosilanization) with alkyl chains for example C4, C8, C18, C18,
C30 or other functional groups, e.g., polar groups (amide,
carbamate, sulfamide, and ureas) embedded within alkyl chains or
branched alkyl groups or polymeric packings. Polymeric column
packing refers to particles made by the process of reacting silica
surface silanol groups with halogenated di or trifunctional
silanes.
[0069] In some embodiments, the solid support is selected from the
group consisting of solid phase extraction resins and liquid
chromatography resins resulting from the copolymerization of
divinylbenzene and/or styrene, or by the copolymerization with
vinylpyrrolidone, vinylacetate, (methacryloyloxymethyl)naphtalene,
4,4'-bis(maleimido)diphenylmethane, p,p'-dihydroxydiphenylmethane
diglycidylmethacrylic ester, p,p'-dihydroxydiphenylpropane
diglycidylmethacrylic ester, 2-hydroxyethylmethacrylate (HEMA),
2,2-dimethylaminoethylmethacrylate (DMAEMA), ethylenedimethacrylate
glycidylmethacrylate, N-vinylcarbazole, acrylonitrile,
vinylpyridine, N-methyl-N-vinylacetamide, aminostyrene,
methylacrylate, ethylacrylate, methylmethacrylate,
N-vinylcaprolactam, N-methyl-N-vinylacetamide.
[0070] In some embodiments, the solid support comprises or is
functionalized with or preconditioned with quaternary ammonium
salts, e.g., tetraethylammonium carbonate, tetrabutylammonium
carbonate or potassium carbonate cryptands such as
1,4,10-Trioxa-7,13-diaza-cyclopentadecane,
4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane,
4,7,13,16,21-Pentaoxa-1,10-diazabicyclo[8.8.5]tricosane,
4,7,13,18-Tetraoxa-1,10-diazabicyclo[8.5.5]eicosane,
5,6-Benzo-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacos-5-ene;
the group of glymes including crown ethers such as for example
4'-Aminobenzo-15-crown-5, 4'-Aminobenzo-15-crown-5,
4'-Aminobenzo-15-crown-5 hydrochloride, 4'-Aminobenzo-18-crown-6,
4'-Aminodibenzo-18-crown-6, 2-Aminomethyl-15-crown-5,
2-Aminomethyl-15-crown-5, 2-Aminomethyl-18-crown-6,
4'-Amino-5'-nitrobenzo-15-crown-5,
4'-Amino-5'-nitrobenzo-15-crown-5, 1-Aza-12-crown-4,
1-Aza-15-crown-5, 1-Aza-15-crown-5, 1-Aza-18-crown-6,
1-Aza-18-crown-6, Benzo-12-crown-4,
5,6-Benzo-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacos-5-ene,
1-Benzyl-1-aza-12-crown-4,
Bis[(benzo-15-crown-5)-15-ylmethyl]pimelate,
4'-Bromobenzo-15-crown-5, 4-tert-Butylbenzo-15-crown-5,
4-tert-Butylcyclohexano-15-crown-5, 4'-Carboxybenzo-15-crown-5,
polyethylene glycols (PEG), polyethylene oxides (PEO); the group of
calixarenes such as for example 4-tert-Butylcalix[4]arene,
4-tert-Butylcalix[4]arene, 4-tert-Butylcalix[4]arene,
4-tert-Butylcalix[5]arene, 4-tert-Butylcalix[6]arene,
4-tert-Butylcalix[6]arene, 4-tert-Butylcalix[6]arene,
4-tert-Butylcalix[8]arene, 4-tert-Butylcalix[8]arene,
4-tert-Butylcalix[4]arene-tetraacetic acid tetraethyl ester,
4-tert-Butylcalix[4]arenetetraacetic acid tetraethyl ester,
4-tert-Butylcalix[4]arene-tetraacetic acid triethyl ester,
Calix[4]arene, Calix[6]arene, Calix[8]arene,
4-(Chloromethyl)calix[4]arene, 4-Isopropylcalix[4]arene,
C-Methylcalix[4]resorcinarene, C-Methylcalix[4]resorcinarene,
meso-Octamethylcalix(4)pyrrole, 4-Sulfocalix[4]arene,
4-Sulfocalix[4]arene sodium salt, C-Undecylcalix[4]resorcinarene
monohydrate, C-Undecylcalix[4]resorcinarene monohydrate, the group
of cyclodextrines such as .alpha.-Cyclodextrin,
.beta.-Cyclodextrin, .gamma.-Cyclodextrin,
(2,6-Di-O-)ethyl-.beta.-cyclodextrin,
6-O-.alpha.-D-Glucosyl-.beta.-cyclodextrin,
Heptakis(6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-.beta.-cyclodextrin,
Heptakis(2,6-di-O-methyl)-.beta.-cyclodextrin,
Heptakis(2,3,6-tri-O-acetyl)-.beta.-cyclodextrin,
Heptakis(2,3,6-tri-O-benzoyl)-.beta.-cyclodextrin, Hexakis
(6-O-tertbutyl-dimethylsilyl)-.alpha.-cyclodextrin, Hexakis
(2,3,6-tri-O-acetyl)-.alpha.-cyclodextrin, Hexakis
(2,3,6-tri-O-methyl)-.alpha.-cyclodextrin,
(2-Hydroxyethyl)-.beta.-cyclodextrin,
6-O-.alpha.-Maltosyl-.beta.-cyclodextrin hydrate,
Methyl-.beta.-cyclodextrin,
6-Monodeoxy-6-monoamino-.beta.-cyclodextrin, Octakis
(6-O-t-butyldimethylsilyl)-T-cyclodextrin,
Sulfopropyl-.beta.-cyclodextrin, Triacetyl-.alpha.-cyclodextrin,
Triacetyl-.beta.-cyclodextrin; and the group of EDTA and
derivatives such as for example Ethylenediamine-N,N'-diacetic acid,
2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid,
trans-1,2-Diaminocyclohexane-N,N,N',N'-tetraacetic acid
monohydrate, trans-1,2-Diaminocyclohexane-N,N,N',N'-tetraacetic
acid monohydrate,
1,3-Diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid,
1,2-Diaminopropane-N,N,N',N'-tetraacetic acid,
1,3-Diaminopropane-N,N,N',N'-tetraacetic acid,
1,3-Diamino-2-propanol-N,N,N',N'-tetraacetic acid,
Diethylenetriamine-pentaacetic acid calcium trisodium salt hydrate,
N-(2-Hydroxyethyl)ethylenediaminetriacetic acid trisodium salt
hydrate, N-(2-Hydroxyethyl)ethylenediamine-N,N',N'-triacetic
acid.
[0071] Another aspect of the present disclosure provides kits
comprising: an amount of a ligand or metal tricarbonyl complex
disclosed herein in a sealed container, wherein the amount is
suitable for imaging a kidney of an animal or human subject, and
instructions for the use thereof in imaging said kidney and
optionally for determining renal function in the animal or human
subject.
[0072] In certain embodiments, the instructions comprise the steps
of: administering to an animal or human subject an amount of a
renal tracer, where the renal tracer comprises a metal tricarbonyl
complex disclosed herein or mixtures; detecting the tracer in the
kidney of the animal or human subject with a gamma camera; and
obtaining at least one image of the kidney of the animal or human
subject, wherein the image is obtained as a data output from a
gamma camera. In another embodiment of this aspect of the
disclosure, the instructions comprise steps for the use of the
tracer in measuring renal function, the instructions comprising the
steps of: administering to an animal or human subject an amount of
a renal tracer; obtaining at least one image of a kidney of the
animal or human subject, wherein the image is obtained as a data
output from a gamma camera; and analyzing the data output from the
gamma camera, wherein the data analysis provides a measurement of
the effective renal plasma flow of the animal or human subject.
[0073] In certain embodiments, the instructions for the use of the
tracer in measuring renal function comprise the steps of:
administering to an animal or human subject an amount of a renal
tracer or mixtures; isolating a plurality of biological samples
from the animal or human subject after administering the renal
tracer; quantitatively measuring the amount of the renal tracer in
the isolated biological samples; and determining the effective
renal plasma flow of the animal or human subject.
[0074] Pharmaceutical compositions for use in the present
disclosure typically comprise an effective amount of a metal
tricarbonyl complex or mixtures and a suitable pharmaceutical
acceptable carrier. The preparations may be prepared in a manner
known per se, which usually involves mixing the at least one
compound according to the disclosure with the one or more
pharmaceutically acceptable carriers, and, if desired, in
combination with other pharmaceutical active compounds, when
necessary under aseptic conditions. Reference is again made to U.S.
Pat. Nos. 6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the
further references mentioned above, as well as to the standard
handbooks, such as the latest edition of Remington's Pharmaceutical
Sciences.
[0075] In certain embodiments, the disclosure relates to
pharmaceutical composition comprising a metal tricarbonyl complex
disclosed herein or mixture thereof. The radioactive diagnostic
composition of the invention may be formulated in any appropriate
preparation form such as powder, lyophilized powder or solution.
Further, it may comprise, in addition to said essential components,
any auxiliary agent such as a pH regulating agent (e.g. acid,
base), an isotonic agent (e.g. sodium chloride), a preservative
(e.g. benzyl alcohol) or the like.
[0076] In certain embodiments, the disclosure contemplates
pharmaceutical compositions comprising a pharmaceutically
acceptable excipient and a compound disclosed herein. In certain
embodiments, the pharmaceutical composition is in the form of a
tablet, capsule, pill, aerosol, or aqueous buffer, such as a saline
or phosphate buffer.
[0077] The pharmaceutical composition may contain a water-soluble
stabilizer, water-soluble reducing agent such as chloride, stannous
fluoride, stannous sulfate, stannous nitrate, stannous acetate,
stannous citrate, stannous tartrate, ascorbic acid or erythrobic
acid, or any pharmaceutically acceptable salt or ester thereof.
Imaging Methods
[0078] Instruments for detecting and monitoring by radionuclide
imaging the location of a tracer in the body of a subject include
positron emission tomography (PET) and single photon emission
computed tomography (SPECT) scanners. These may be combined with
other methods such as computerized tomography (CT) scans and MRI. A
CT scan combines a series of X-ray images taken from different
angles and uses computer processing to create cross-sectional
images, or slices, of the bones, blood vessels and soft tissues
inside your body. These scans or associated data can be used to
create computerized images that take place in tissue or the blood
stream. A scanner records data that a computer constructs into two-
or three-dimensional images. In a typical method, radioactive drug
is injected into the subject, e.g., a vein, and a scanner is used
to make detailed images of areas inside the body where the
radioactive material is taken up by the cells, tissue, fluids, or
organs.
[0079] Single photon emission computed tomography (SPECT) is a
nuclear medicine imaging technique using gamma rays. It may be used
with any gamma-emitting isotope, including Tc-99m (.sup.99mTc). In
the use of technetium-99m, the radioisotope is administered to the
patient and the escaping gamma rays are incident upon a moving
gamma camera which computes and processes the image. To acquire
SPECT images, the gamma camera is typically rotated around the
patient. Projections are acquired at defined points during the
rotation, typically every three to six degrees. In most cases, a
full 360.degree. rotation is used to obtain an optimal
reconstruction. SPECT is widely used to obtain clinically
significant information about analog binding, localization and
clearance rates.
[0080] Positron Emission Tomography (PET) involves detection of
pairs of gamma rays emitted indirectly by a positron-emitting
radionuclide (tracer), which is introduced into the body on a
biologically active molecule. Images of tracer concentration in the
body are then reconstructed by computer analysis. Two or
three-dimensional images of tracer concentration within the area
are then constructed by computer analysis. A radioactive tracer is
administered to a subject e.g., into blood circulation. Typically
there is a waiting period while tracer becomes concentrated in
areas of interest; then the subject is placed in the imaging
scanner. As the radionuclide undergoes positron emission decay, it
emits a positron, an antiparticle of the electron with opposite
charge, until it decelerates to a point where it can interact with
an electron, producing a pair of (gamma) photons moving in
approximately opposite directions. These are detected in the
scanning device. The technique typically utilizes simultaneous or
coincident detection of the pair of photons moving in approximately
opposite direction (the scanner typically has a built-in slight
direction-error tolerance). Photons that do not arrive in pairs
(i.e. within a timing-window) are typically ignored. One typically
localizes the source of the photons along a straight line of
coincidence (also called the line of response, or LOR). This data
is used to generate an image.
[0081] The term "radionuclide" or "radioactive isotope" refers to
molecules of enriched isotopes that exhibit radioactive decay
(e.g., emitting positrons). Such isotopes are also referred to in
the art as radioisotopes. A radionuclide tracer does not include
radioactive primordial nuclides, but does include a naturally
occurring isotopes that exhibit radioactive decay with an isotope
distribution that is enriched, e.g., is several fold greater than
natural abundance. In certain embodiments, is contemplated that the
radionuclides are limited to those with a half live of less than 1
hour and those with a half-life of more than 1 hour but less than
24 hours. Radioactive isotopes are named herein using various
commonly used combinations of the name or symbol of the element and
its mass number (e.g., .sup.18F, F-18, or fluorine-18). Elements
that can be used in the compounds of the present disclosure
include: F-18; C-11; 1-125, 1-124, 1-131 and 1-123; Cl-32, Cl-33,
Cl-34; Br-74, Br-75, Br-76, Br-77, Br-78; Re-186, Re-188; Y-90,
Y-86; Lu-177 and Sm-153. Typical radioactive isotopes include
I-124, F-18 fluoride, C-11, N-13, and 0-15, which have half-lives
of 4.2 days, 110 minutes, 20 minutes, 10 minutes and 2 minutes,
respectively. Preferably, the radioactive isotopes used in the
present method include F-18, C-11, I-123, I-124, I-127, 1-131,
Br-76, Cu-64, Tc-99m, Y-90, Ga-67, Cr-51, Ir-192, Mo-99, Sm-153 and
Tl-201. Other radioactive isotopes that may be employed include:
As-72, As-74, Br-75, Co-55, Cu-61, Cu-67, Ga-68, Ge-68, I-125,
I-132, In-111, Mn-52, Pb-203 and Ru-97.
[0082] Methods of preparing radiolabeled ligands are well known in
the art. Example of such methods are disclosed in, for example: 1)
Jewett, D. M. (1992) A Simple Synthesis of [.sup.11C]Methyl
Triflate Appl. Radiat. Isot. 43, 1383-1385; 2) Crouzel, C.
Langstrom, B., Pike, V. W., and Coenen, H. H. (1987)
Recommendations for a practical production of [.sup.11C]methyl
iodide Appl. Radiat. Isot. Int. J. Appl. Instrum. Part A 38,
601-603; Dannals, R. F., Ravert, H. T.; 3) Wilson, A. A. (1990)
Radiochemistry of Tracers for Neurotransmitter Receptor Studies.
In: Quantitative Imaging: Neuroreceptors, Neurotransmitters, and
Enzymes. (Edited by Frost), J. J. Wagner Jr., H. N. pp. 19-35,
Raven Press, New York; 4) Jewett, D. M., Manger, T. J., and
Watkins, G. L. (1991) Captive Solvent Methods for Fast Simple
Carbon-11 Radioalkylations. In: New Trends in Radiopharmaceutical
Synthesis, Quality Assurance and Regulatory Control (Edited by
Emran, A. M.) pp. 387-391. Plenum Press, New York; 5) Marazano, C.,
Maziere, M., Berger, G., and Comar, D. (1977) Synthesis of methyl
iodide-.sup.11C and formaldehyde-.sup.11C Appl. Radiat. Isot. 28,
49-52; 6) Watkins, G., Jewett, D., Mulholland, G., Kitbourn, M.,
and Toorongian, S. (1988) A Captive Solvent Method for Rapid
N-[.sup.11C]Methylation of Secondary Amides Application to the
Benzodiazepine, 4'-Chlorodiazepam (RO5-4864) Appl. Radiat. Isot.
39, 441-444; and 7) Wilson, A. A., DaSilva, J. N., and Houle, S.
(1996) In vivo evaluation of [.sup.11C] and [.sup.1F]-labeled
cocaine analogues as potential dopamine transporter ligands for
positron emission tomography Nucl. Med. Biol. 23, 141-146.
[0083] It is also contemplated that, besides images over the renal
area, static images may also be taken of the pre-injection dose
syringe, post-imaging empty dose syringe, the pre-voided bladder,
the post-void-bladder, the post-void kidneys, and the injection
site. The syringe images are necessary for calculation of renal
clearance by the camera-based method. Bladder images are necessary
in order to obtain urine flow rate and residual urine volume. The
post-void kidney image is a visual indicator of the emptying of
urine from the renal collecting systems (since the patient will
usually have gotten up from the scan table in order to void). This
image also provides kidney counts, from whole kidney regions of
interest, which allow calculation of important ratios relevant to
the excretory function of the kidneys. The injection site image is
a quality control element for the radiopharmaceutical injection,
since a significant quantity of the dose outside the vein will
invalidate the study.
[0084] The baseline study may be analyzed quantitatively and the
results reviewed by a physician. If the patient was referred for
evaluation of possible obstruction, adequate clearance of the
radiopharmaceutical should be seen and, if it is not, an
intravenous dose of furosemide, a diuretic, can be administered. An
additional dynamic image set is then acquired. In certain
embodiments or the present disclosure, therefore provides methods
of imaging a kidney in an animal or human subject, the method
comprising: (a) administering to an animal or human subject an
amount of a renal tracer, where the renal tracer comprises a metal
tricarbonyl complex disclosed herein in the kidney of the animal or
human subject with a gamma camera; and (c) obtaining at least one
image of the kidney of the animal or human subject, where the image
is obtained as a data output from a gamma camera.
[0085] In certain embodiments the present disclosure encompasses
methods of measuring renal function in an animal or human subject
using renal scintigraphy, comprising: (a) administering to an
animal or human subject an amount of a renal tracer, where the
renal tracer comprises a metal tricarbonyl complex disclosed herein
or mixtures; (b) obtaining at least one image of a kidney of the
animal or human subject, wherein the image is obtained as a data
output from a gamma camera; and (c) analyzing the data output from
the gamma camera, wherein the data analysis provides a measurement
of the effective renal plasma flow of the animal or human
subject.
[0086] In certain embodiments of the disclosure, the methods may
further comprise repeating the steps (a)-(c), thereby providing a
time-dependent analysis of the urinary tract function of an animal
or human subject, wherein the analysis is selected from the group
consisting of: the EPRF of a kidney, the ability of a kidney to
extract the tracer from the blood, the ability of subject human or
animal to excrete the tracer into the collecting system of a
kidney, monitoring of drainage of the tracer from the collecting
system (calyces and pelvis) to the bladder, and to quantify the
ability of the bladder to empty.
[0087] In other embodiments of the disclosure, the methods may
further comprise repeating the steps (a)-(c) at least once, thereby
providing a series of images and a time-dependent analysis of renal
efficiency of the animal or human subject.
[0088] In another embodiment of the disclosure, the methods may
further comprise repeating the steps (b) and (c) after a single
amount of the renal tracer obtaining a series of images of the
kidney or kidneys of the animal or human subject, and analyzing the
data output from the gamma camera, wherein the data analysis
provides a measurement of the effective renal plasma flow of the
animal or human subject.
[0089] In one embodiment of this aspect of the disclosure, the
steps (a)-(c) may be repeated at time intervals over a period of
about 2 mins to 60 mins, thereby providing a time-dependent series
of images.
[0090] In another embodiment, the steps (a)-(c) are repeated at
time intervals over a period of about 3 mins to 30 mins, thereby
providing a time-dependent series of images.
[0091] In certain embodiments, the disclosure contemplates method
of measuring effective renal plasma flow in an animal or human
subject, comprising administering to an animal or human subject an
amount of a renal tracer, wherein the renal tracer comprises a
metal tricarbonyl complex disclosed herein or mixtures, isolating a
series of biological samples from the animal or human subject after
administering the renal tracer, quantitatively detecting the amount
of the renal tracer in the biological samples, and determining the
effective renal plasma flow of the animal or human subject.
[0092] In certain embodiments, the disclosure relates to imaging
methods comprising a) administering a metal tricarbonyl complex
comprising a radionuclide or positron-emitting radionuclide
disclosed herein or mixtures to a subject; and b) scanning the
subject for the emission, positron-emissions or other
gamma-emissions.
[0093] The methods typically further comprise the steps of
detecting the emissions and creating an image of an area of the
subject indicating or highlighting the location of the metal
tricarbonyl complex containing radionuclide or mixtures in the
subject. In certain embodiments, the area of the subject is the
lymph nodes, groin, axilla, neck, lungs, liver, kidney, pancreas,
stomach, balder, intestines, circulatory system, breast, prostate,
gallbladder, or brain.
[0094] The metal tricarbonyl complexes of the present disclosure
may be labeled with one or more radionuclides, such as .sup.11C,
.sup.18F, .sup.76Br, .sup.123I, .sup.124I, .sup.131J .sup.13N, or
.sup.15O. Radionuclides used in PET scanning are typically
positron-emitting isotopes with short half-lives such as carbon-11
(approximately 20 min), nitrogen-13 (approximately 10 min),
oxygen-15 (approximately 2 min), and fluorine-18 (approximately 110
min). The metal tricarbonyl complex may be administered by any
suitable technique known in the art, such as direct injection.
Injection may be intravenous (IV). Administration may be general or
local to the site of interest. The compound may be used in
conjunction with another probe. The two (or more) probes may be
administered together, separately or sequentially. The metal
tricarbonyl complexes of the present disclosure may be used to
diagnose, assess or monitor the progression or treatment of a
disease or condition.
[0095] The metal complexes of the disclosure are useful as tracer
compounds for kidney functioning and blood circulating imaging
techniques, including PET and SPECT imaging. Particularly useful as
an imaging agent are those compounds labeled with F-18 since F-18
has a half-life of 110 minutes, which allows sufficient time for
incorporation into a radio-labeled tracer, for purification and for
administration into a human or animal subject. In addition,
facilities more remote from a cyclotron, up to about a 200 mile,
radius can make use of F-18 labeled compounds.
[0096] Other halogen isotopes can serve for PET or SPECT imaging,
or for conventional tracer labeling. These include .sup.75Br,
.sup.76Br, .sup.77Br and .sup.82Br as having usable half-lives and
emission characteristics. In general, the chemical means exist to
substitute any halogen moiety for the described isotopes. Astatine
can be substituted for other halogen isotopes, [.sup.210At] emits
alpha particles with a half-life of 8.3 h. At-substituted compounds
are therefore useful for tumor therapy where binding is
sufficiently tumor-specific.
[0097] In certain embodiments, the disclosure provides methods for
kidney imaging using PET and SPECT. The methods entail
administering to a subject (which can be human or animal, for
experimental and/or diagnostic purposes) an image-generating amount
of a metal tricarbonyl complex of the disclosure or mixtures,
labeled with the appropriate isotope and then measuring the
distribution of the metal tricarbonyl complex by PET if [.sup.18F]
or other positron emitter is employed, or SPECT if [.sup.99mTc] or
other gamma emitter is employed. An image-generating amount is that
amount which is at least able to provide an image in a PET or SPECT
scanner, taking into account the detection sensitivity and noise
level of the scanner, the age of the isotope, the body size of the
subject and route of administration.
[0098] It will be understood that compounds of the disclosure can
be labeled with an isotope of any atom or combination of atoms in
the structure. While [.sup.18F], [.sup.99mTc] and have been
emphasized herein as being particularly useful for PET, SPECT and
tracer analysis, other uses are contemplated including those
flowing from physiological or pharmacological properties of stable
isotope homologs and will be apparent to those skilled in the
art.
[0099] Methods of use of the imaging agents provided herein
include, but are not limited to: methods of imaging kidney tissue;
methods of imaging kidney function; methods of diagnosing kidney
function; methods of monitoring the progress of kidney issue
degeneration; methods of imaging abnormal kidney tissue, and the
like. The methods can be used to detect, study, monitor, evaluate,
and/or screen, biological events in vivo or in vitro.
[0100] In diagnosing and/or monitoring pharmaceutical compositions
comprising the metal tricarbonyl complexes disclosed herein or
mixtures are administered to the subject in an amount effective to
result in uptake of the complex into the blood stream. After
administration of the complexes, the complexes are detected using
PET or SPECT imaging. Embodiments of the present disclosure can
non-invasively image the presence of the complexes in the blood and
tissue throughout an animal or patient.
[0101] In preferred methods of the present disclosure, the metal
tricarbonyl complexes of the present disclosure are excreted from
tissues of the body quickly to prevent prolonged exposure to the
radiation of the radiolabeled complexes administered to the
patient. In particular embodiment, the radionuclide labeled
complexes provided herein can be used on an outpatient basis.
Typically metal complexes of the present disclosure are eliminated
from the body in less than about 24 hours. More preferably,
complexes of the present disclosure are eliminated from the body in
less than about 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2
hours, 90 minutes, or 60 minutes.
[0102] The spatial distribution of the complexed disclosed herein
may be measured using any imaging apparatus suitable for the
particular label, for example, a gamma camera, a PET apparatus, a
SPECT apparatus, MRS, MRI or optical imaging apparatus, and the
like. The extent of accumulation of the imaging agent may be
quantified using known methods for quantifying radioactive
emissions. A particularly useful imaging approach employs more than
one imaging agent to perform simultaneous studies. Alternatively,
the imaging method may be carried out a plurality of times with
increasing administered dose of the pharmaceutically acceptable
imaging composition of the present disclosure to perform successive
studies using the split-dose image subtraction method, as are known
to those of skill in the art.
[0103] Preferably, an amount of the imaging agent effective for
imaging kidney function is administered to a subject. An effective
amount of the imaging agent may be administered in more than one
injection. The effective amount of the imaging agent can vary
according to factors such as the degree of susceptibility of the
individual, the age, sex, and weight of the individual,
idiosyncratic responses of the individual, the dosimetry, and the
like. Effective amounts of the imaging agent can also vary
according to instrument and film-related factors.
EXAMPLES
[0104] Evaluation of .sup.99mTc(CO).sub.3(FEDA): A Dual-Purpose
.sup.99mTc/.sup.18F Renal Imaging Agent
[0105] N-(2-fluoroethyl)iminodiacetic acid (FEDA) was prepared by
the reaction of 1-bromo-2-fluoroethane with dimethyl
2,2'-iminodiacetate, followed by an alkaline hydrolysis of methyl
esters. FEDA was labeled using an IsoLink kit and purified by HPLC.
.sup.99mTc-tricarbonyl ([.sup.99mTc(CO).sub.3].sup.+) is produced
in the form of its aqua ion
[.sup.99mTc(CO).sub.3(H.sub.2O).sup.3].sup.+ in a one-step reaction
by reduction of the generator-eluted form of .sup.99mTc, sodium
pertechnetate ([.sup.99mTcO.sub.4].sup.-). See Waibel et al. Nat
Biotechnol 1999, 17: 897-901.
[0106] .sup.99mTc(CO).sup.3(FEDA) was evaluated in rats using
.sup.131I-OIH as an internal control; urine was analyzed for
metabolites. Plasma protein binding (PPB) and erythrocyte uptake
(RCB) were determined from the 10 min blood samples. The
Re(CO).sub.3 analog was prepared for structural
characterization.
[0107] .sup.99mTc(CO).sub.3(FEDA) was efficiently prepared as a
single species with high radiochemical purity (>99%), and was
stable through 24 h at physiological pH. It showed rapid blood
clearance, high specificity for renal excretion and lack of
significant uptake in other organs. The % injected dose in the
urine was 100% and 99% that of .sup.131I-OIH at 10 and 60 min,
respectively. The tracer was secreted intact in the urine; PPB was
61% and RCB was 20%.
Dimethyl N-(2-fluoroethyl)iminodiacetate (1):
##STR00004##
[0108] Dimethyl iminodiacetate hydrochloride (1 g, 5.0 mmol) and
1-bromo-2-fluoroethane (0.63 g, 5.0 mmol) were combined with 5 mL
MeCN and diisopropylamine (1.2 mL, 11 mmol) in an oven-dried 10 mL
sealed tube. The tube was heated in an oil bath at 90.degree. C.
for 3 d. The reaction mixture was concentrated, and the crude
yellow solid was purified by flash chromatography (97% CHCl.sub.3,
3% MeOH; 10 mL fractions). Fractions 6-20 yielded the product as a
slightly yellow oil (0.77 g, 3.7 mmol, 74%), sufficiently pure for
subsequent reactions. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
4.58 (doublet of triplets, 2H, J.sub.FH=48 Hz, J.sub.HH=5.6 Hz),
3.71 (s, 6H), 3.64 (s, 4H), 3.10 (doublet of triplets, 2H,
J.sub.F-H=28 Hz, J.sub.H-H=5.6 Hz). .sup.19F NMR (400 MHz,
CDCl.sub.3, TFA reference) .delta.: 222.41 ppm. HRMS (M.sup.+, ESI)
Calc'd for C.sub.8H.sub.14O.sub.4NFNa: 230.07991, found: 230.07986
(.DELTA.=-0.05 mmu, -0.21 ppm).
N-(2-fluoroethyl)iminodiacetic acid (2, FEDA):
##STR00005##
[0109] Compound 1 (0.12 g, 0.5 mmol) was dissolved in 4 mL methanol
before the addition of 2M NaOH (2 mL). The solution was stirred at
room temperature for 24 h, neutralized with 1M HCl. The reaction
mixture was evaporated and the crude product was desalted on a
Sephadex G-15 column, into 3 min fractions. A TLC plate was spotted
with each fraction and those containing the product were identified
by a basic permanganate stain. Appropriate fractions were
concentrated to yield 2 as a colorless oil (76 mg, 0.42 mmol, 84%).
.sup.1H NMR (400 MHz, D.sub.2O, pH9) .delta.: 4.58 (doublet of
triplets, 2H, J.sub.FH=48 Hz, J.sub.HH=4.8 Hz), 3.33 (s, 4H), 3.01
(doublet of triplets, 2H, J.sub.F-H=28 Hz, J.sub.H-H=4.8 Hz).
.sup.19F NMR (400 MHz, CDCl.sub.3, TFA reference) .delta.: 221.2
ppm. HRMS (M.sup.+, ESI) Calc'd for C.sub.6H.sub.10O.sub.4NFNa:
202.04970, found: 202.04906 (.DELTA.=-0.64 mmu, -3.19 ppm).
Re(CO).sub.3(FEDA) (3):
##STR00006##
[0111] An aqueous solution of 2 (25 mg, 0.12 mmol) was combined
with a stirred solution of 0.1 M [Re(CO).sub.3(H.sub.2O).sub.3]OTf
(0.12 mL, 0.12 mmol). The pH of the reaction mixture was
immediately adjusted to 6 using 1 M NaOH and monitored by HPLC. A
small aliquot was heated at 70.degree. C. for 5 min and examined by
HPLC; the reaction was complete. The remainder of the reaction
proceeded to completion within 90 min at room temperature. HPLC
analysis revealed the major product peak with a retention time of
16.5 min. The reaction mixture was concentrated to 1 mL and
purified over Sephadex G-15 gel. UV active fractions were analyzed
by HPLC and combined to yield the product in >90% purity by
HPLC. %). .sup.1H NMR (400 MHz, D.sub.2O, pH 7) .delta.: 4.75
(doublet of triplets, 2H, J.sub.FH=48 Hz, J.sub.HH=4.8 Hz), 3.94
(d, 2H, J=16.4 Hz), 3.79 (doublet of triplets, 2H, J.sub.F-H=28 Hz,
J.sub.H-H=4.8 Hz), 3.73 (d, 2H, J=16.4 Hz). .sup.19F NMR (400 MHz,
CDCl.sub.3, TFA reference) .delta.: 217.61 ppm. HRMS (M.sup.-, ESI)
Calc'd for C.sub.9H.sub.8O.sub.7NF.sup.187Re: 447.98478, found:
447.98438 (.DELTA.=-0.40 mmu, -0.89 ppm).
##STR00007##
[0112] Re(CO).sub.3(HDA), prepared from 2-hydroxyethyl
iminodiacetic acid and Re(CO).sub.3(H.sub.2O).sub.3[OTf], was
dissolved in THE and stirred in an oil bath at room temperature
with p-toluenesulfonyl chloride (29 mg, 0.15 mmol), triethylamine
(21 .mu.L, 0.15 mmol) and a catalytic amount of
dimethylaminopyridine (3 mg) overnight. The starting material was
consumed, giving rise to a single product peak with a retention
time of 23 min. The crude product was purified over silica using a
water:isopropanol:ethylacetate (7:2:1) mobile phase. UV active
fractions were combined and concentrated to yield the product 4 as
a white powder (10 mg, 0.02 mmol, 20%).
.sup.18F-Re(CO).sub.3(FEDA) (3) from .sup.18F-labeling precursor,
(4) Re(CO).sub.3(.sup.18FFEDA) (3) was prepared by reacting the
corresponding tosyl precursor, rheniumtricarbonyl-N-ethyltosylate
iminodiacetate, Re(CO).sub.3(TsDA), with [18F]fluoride ion
(.sup.18F) in anhydrous acetonitrile in the presence of
K.sub.2CO.sub.3 and Kryptofix 222 at 110.degree. C. for 20 min in a
chemical processing control unit (CPCU). The resulting radiolabeled
product was purified by semi-preparative high performance liquid
chromatography (HPLC) using a Waters XTerra Prep RP 18 column (5 m,
19.times.100 mm) and eluted with a mobile phase of 0.05 M
triethylammonium phosphate (TEAP) buffer (pH=7)/ethanol (80:20 v/v)
at a flow rate of 6 mL/min. The solution of the .sup.18F
radiotracer (pH 7) was analyzed by HPLC for stability for up to 23
h.
[0113] Re(CO).sub.3(.sup.18FFEDA) was obtained by the nucleophilic
substitution fluorination in the decay corrected radiochemical
yield of 18% in a total synthesis time of 120 min from end of
bombardment. The purified filtered final radiotracer was formulated
in a 0.05 M TEAP solution containing 10% ethanol. Quality control
showed radiochemical and chemical purities above 99%. Coinjection
with the standard Re(CO).sub.3(FEDA) confirmed the identity of the
radiolabeled product. The HPLC analysis of an aliquot of
Re(CO).sub.3(.sup.18FFEDA) incubated for 23 hours revealed only
intact .sup.18F radiotracer confirming its stability.
.sup.99mTc(CO).sub.3(FEDA) (5):
##STR00008##
[0114] The ligand 2 was heated with the labeling precursor
[.sup.99mTc(CO).sub.3(H.sub.2O).sub.3]OTf for 30 min before
purifying by HPLC. Coinjection with the cold standard showed the
product 5 was isolated in high purity. The tracer 5 was stable
under physiological conditions for at least 1 d and used in animal
studies.
* * * * *