U.S. patent application number 12/683851 was filed with the patent office on 2010-05-06 for luminescent metal complexes for monitoring renal function.
This patent application is currently assigned to Mallinckrodt Inc.. Invention is credited to Richard B. Dorshow, Dennis A. Moore, Raghavan Rajagopalan.
Application Number | 20100113756 12/683851 |
Document ID | / |
Family ID | 35229727 |
Filed Date | 2010-05-06 |
United States Patent
Application |
20100113756 |
Kind Code |
A1 |
Rajagopalan; Raghavan ; et
al. |
May 6, 2010 |
LUMINESCENT METAL COMPLEXES FOR MONITORING RENAL FUNCTION
Abstract
Some embodiments of the present invention may be said to be
directed to metal complexes of Formula I wherein at least one of
X.sup.1, X.sup.2, X.sup.3, R.sup.1, R.sup.2, R.sup.3, R.sup.4 or
R.sup.5 is what may be characterized as an antenna capable of
providing (e.g., absorbing and/or emitting) an appropriate
electromagnetic signal. Some embodiments of the present invention
are directed to ligands corresponding to metal complexes of Formula
I. Some embodiments of the invention are directed to methods of
determining renal function using at least one metal complex of
Formula I. ##STR00001##
Inventors: |
Rajagopalan; Raghavan;
(Solon, OH) ; Dorshow; Richard B.; (St. Louis,
MO) ; Moore; Dennis A.; (St. Louis, MO) |
Correspondence
Address: |
THOMPSON HINE L.L.P.;Intellectual Property Group
P.O. BOX 8801
DAYTON
OH
45401-8801
US
|
Assignee: |
Mallinckrodt Inc.
St. Louis
MO
|
Family ID: |
35229727 |
Appl. No.: |
12/683851 |
Filed: |
January 7, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11572920 |
Jan 30, 2007 |
7674902 |
|
|
PCT/US2005/027486 |
Aug 3, 2005 |
|
|
|
12683851 |
|
|
|
|
60604573 |
Aug 26, 2004 |
|
|
|
Current U.S.
Class: |
534/10 |
Current CPC
Class: |
C09K 11/06 20130101;
A61K 49/0013 20130101; C07C 237/02 20130101; C09K 2211/188
20130101; C07C 237/12 20130101 |
Class at
Publication: |
534/10 |
International
Class: |
C07F 5/00 20060101
C07F005/00 |
Claims
1. A metal complex of Formula I, ##STR00005## wherein M is a metal
ion that exhibits spectral absorption and emission in the visible
and/or NIR regions; each of X.sup.1, X.sup.2, and X.sup.3 is
independently selected from Ar.sup.1--Z.sup.1--, --O.sup.-,
--NH(CH.sub.2).sub.aOH, --NH(CH.sub.2).sub.aCO.sub.2H,
--NH(CH.sub.2).sub.aSO.sub.3.sup.-,
--NH(CH.sub.2).sub.aOSO.sub.3.sup.-,--NH(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--O(CH.sub.2).sub.aSO.sub.3.sup.-,
--O(CH.sub.2).sub.aOSO.sub.3.sup.-,
--O(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--NH(CH.sub.2).sub.aPO.sub.3H.sup.-,
--NH(CH.sub.2).sub.aPO.sub.3.sup.=,
--NH(CH.sub.2).sub.aOPO.sub.3H.sup.-,
--NH(CH.sub.2).sub.aOPO.sub.3.sup.=,
--NH(CH.sub.2).sub.aNHPO.sub.3H.sup.-,
--NH(CH.sub.2).sub.aNHPO.sub.2H.sup.-,
--NH(CH.sub.2).sub.aNHPO.sub.3.sup.=,
--O(CH.sub.2).sub.aPO.sub.3H.sup.-,
--O(CH.sub.2).sub.aPO.sub.3.sup.=,
--O(CH.sub.2).sub.aOPO.sub.3H.sup.-,
--O(CH.sub.2).sub.aOPO.sub.3.sup.=,
--O(CH.sub.2).sub.aNHPO.sub.3H.sup.-, and
--O(CH.sub.2).sub.aNHPO.sub.3.sup.=; each of Y.sup.1 and Y.sup.2 is
independently selected from a single bond, --(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mOCO--,
--(CH.sub.2).sub.mCO.sub.2--, --(CH.sub.2).sub.mOCNH--,
--(CH.sub.2).sub.mOCO.sub.2--, --(CH.sub.2).sub.mNHCO--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2, --,
--(CH.sub.2).sub.mNHSO.sub.2--, and --(CH.sub.2).sub.mSO.sub.2NH--;
Z.sup.1 is --NH--, --O--, --NH(CH.sub.2).sub.m--, or
--O(CH.sub.2).sub.m--; Ar.sup.1 is a bicyclic heteroaromatic
radical having a base ring structure containing 5 to 10 carbon
atoms; each of R1 to R5 is independently selected from
Ar.sup.2--Z.sup.2--, hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl,
C1-C10 polyhydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, C1-C10
alkoxyalkyl, --(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bOSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bCO.sub.2(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHCONH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHCSNH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCONH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bPO.sub.3H.sup.-,
--(CH.sub.2).sub.bPO.sub.3.sup.=,
--(CH.sub.2).sub.bOPO.sub.2H.sup.-,
--(CH.sub.2).sub.bOPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHPO.sub.3.sup.=,
--(CH.sub.2).sub.bCO.sub.2(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bCO.sub.2(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cPO.sub.3H.sup.-m
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHCONH(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHCONH(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHCSNH(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHCSNH(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bOCONH(CH.sub.2).sub.cPO.sub.3H.sup.-, or
--(CH.sub.2).sub.bOCONH(CH.sub.2).sub.cPO.sub.3.sup.=; Z.sup.2 is a
single bond; Ar.sup.2 is a bicyclic heteroaromatic radical having a
base ring structure containing 5 to 10 carbon atoms; a, b, and c
are independently 1 to 6; m is 1 to 10; and n is 1 to 5; with the
proviso that at least one of X.sup.1 to X.sup.3 is
Ar.sup.1--Z.sup.1-- or at least one of R.sup.1 to R.sup.5 is
Ar.sup.2--Z.sup.2--.
2. The complex of claim 1, wherein Ar.sup.1--Z.sup.1-- is an
aromatic or heteroaromatic chromophore derived from an
unsubstituted or substituted aromatic or heteroaromatic
compound.
3. The complex of claim 2, wherein the aromatic or heteroaromatic
compound is represented by the formula Ar.sup.1--Z.sup.1-- where
Ar.sup.1 is a monocyclic or bicyclic ring structure of 5 to 10
carbon atoms, and Z.sup.1 is selected from amino, hydroxyl,
carboxyl, carboxylate, acid halide, alkyl halides, alkyl
sulfonates, sulfonyl halide, phosphoryl chloride, N-succinimido
ester, chloroformate, isocyanate, acyl azide, and
isothiocyanate.
4. The complex of claim 3, wherein the at least one of Ar' or Are
is further substituted with at least one hydrophilic group, and the
aromatic or heteroaromatic compound is represented by the formula
W--Ar--Z, wherein W is --COOH, --NH.sub.2, --OH, --SO.sub.3H, or
--PO.sub.3H.sub.2.
5. The complex of claim 3, wherein Ar' is selected from pyrazine,
quinoline, quinoxaline, and coumarin groups.
6. The complex of claim 3, wherein Ar.sup.1--Z.sup.1-- is selected
from 7-amino-4-methylcoumarin, 4-aminosalicylic acid,
1-aminonaphthalene, aminopyrazines, diaminopyrazines, pyrazine
carboxylic acid, pyrazine carboxamide,
2,5-diamino-3,6-dicyanopyrazine,
3,6-diamino-2,5-pyrazinedicarboyxlic acid,
3,6-diamino-2,5-pyrazinedicarboyxlic esters, and
3,6-diamino-2,5-pyrazinedicarboxamides.
7. The complex of claim 1, wherein at least one absorption band of
the Ar.sup.1--Z.sup.1-- substantially matches with at least one
excitation band of M.
8. The complex of claim 1, wherein M is a metal ion selected from
Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, and In.
9. The complex of claim 8, wherein X.sup.1 is Ar.sup.1--Z.sup.1--;
X.sup.2 and X.sup.3 are independently selected from --O.sup.-,
--NH(CH.sub.2).sub.aOH, --NH(CH.sub.2).sub.aCO.sub.2H,
--NH(CH.sub.2).sub.aSO.sub.3.sup.-, and
--O(CH.sub.2).sub.aSO.sub.3.sup.-, R.sup.1 to R.sup.5 are
independently selected from hydrogen, C1-C10 hydroxyalkyl,
carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.---(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, and
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-.
10. The complex of claim 8, wherein R.sup.1 is an
Ar.sup.2--Z.sup.2--; X.sup.1 to X.sup.3 are independently selected
from --O.sup.-, --NH(CH.sub.2).sub.aOH,
--NH(CH.sub.2).sub.aCO.sub.2H, --NH(CH.sub.2).sub.aSO.sub.3.sup.-,
and --O(CH.sub.2).sub.aSO.sub.3.sup.-; and R.sup.2 to R.sup.5 are
independently selected from hydrogen, C1-C10 hydroxyalkyl,
carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.---(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, and
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-.
11. The complex of claim 8, wherein R.sup.2 is Ar.sup.2--Z.sup.2--;
X.sup.1 to X.sup.3 are independently selected from --O.sup.-,
--NH(CH.sub.2).sub.aOH, --NH(CH.sub.2).sub.aCO.sub.2H,
--NH(CH.sub.2).sub.aSO.sub.3.sup.-, and
--O(CH.sub.2).sub.aSO.sub.3.sup.-; and R.sup.1, R.sup.3, R.sup.4,
and R.sup.5 are independently selected from hydrogen, C1-C10
hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.---(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, and
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-.
12. The complex of claim 8, wherein R.sup.3 is Ar.sup.2--Z.sup.2--;
X.sup.1 to X.sup.3 are independently selected from --O.sup.-,
--NH(CH.sub.2).sub.aOH, --(CH.sub.2).sub.aCO.sub.2H,
--NH(CH.sub.2).sub.aSO.sub.3.sup.-, and
--O(CH.sub.2).sub.aSO.sub.3.sup.-; and R.sup.1, R.sup.2, R.sup.4,
and R.sup.5 are independently selected from hydrogen, C1-C10
hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, and
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-.
13. The complex of claim 9, wherein X.sup.2 and X.sup.3 are
--O.sup.-; Y.sup.1 and r are independently selected from
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mOCNH--,
--(CH.sub.2).sub.mOCO.sub.2--, --(CH.sub.2).sub.mNHCO--,
--(CH.sub.2).sub.mNHCONH--, --(CH.sub.2).sub.mOSO.sub.2--, and
--(CH.sub.2).sub.mNHSO.sub.2--; and R.sup.1 to R.sup.5 are
hydrogens.
14. The complex of claim 10, wherein X.sup.1 to X.sup.3 are
--O.sup.-; R.sup.2 to R.sup.5 are hydrogens; and Y.sup.1 and
Y.sup.2 are independently selected from --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(C.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mOSO.sub.2--, and
--(CH.sub.2).sub.mNHSO.sub.2--.
15. The complex of claim 11, wherein X.sup.1 to X.sup.3 are
--O.sup.-; R.sup.1, R.sup.3, R.sup.4, and R.sup.5 are hydrogens;
and Y.sup.1 and Y.sup.2 are independently selected from
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mOCNH--,
--(CH.sub.2).sub.mOCO.sub.2--, --(C.sub.2).sub.mNHCO,
--(CH.sub.2).sub.mNHCONH--, --(CH.sub.2).sub.mOSO.sub.2--, and
--(CH.sub.2).sub.mNHSO.sub.2--.
16. The complex of claim 12, wherein X.sup.1 to X.sup.3 are
--O.sup.-; R.sup.1, R.sup.2, R.sup.4, and R.sup.5 are hydrogens;
and Y.sup.1 and Y.sup.2 are independently selected from
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mOCNH--,
--(CH.sub.2).sub.mOCO.sub.2--, --(CH.sub.2).sub.mNHCO,
--(CH.sub.2).sub.mNHCONH--, --(CH.sub.2).sub.mOSO.sub.2--, and
--(CH.sub.2).sub.mNHSO.sub.2--.
17. The complex of claim 1, wherein X.sup.1 is Ar.sup.1--Z.sup.1--
and X.sup.2 is --O.sup.-.
18. The complex of claim 1, wherein each of X.sup.1 and X.sup.2 is
Ar.sup.1--Z.sup.1--.
19. The complex of claim 1 wherein Ar.sup.1 is quinoxaline,
quinoxaline carboxylate, or cyanoquinoxaline.
20. The complex of claim 1 wherein Z.sup.1-- is --NH-- or
--NH(CH.sub.2).sub.m--.
21. The complex of claim 1, wherein each of Y.sup.1 and Y.sup.2 is
a single bond, X.sup.3 is --O.sup.-, and each of R.sup.1-R.sup.5 is
hydrogen.
22. The complex of claim 1, wherein Ar.sup.1 is quinoxaline,
quinoxaline carboxylate, or cyanoquinoxaline; and Z.sup.1-- is
--NH-- or --NH(CH.sub.2).sub.m--.
23. The complex of claim 1, wherein Ar.sup.1 is quinoxaline,
quinoxaline carboxylate or cyanoquinoxaline; each of Y.sup.1 and
Y.sup.2 is a single bond; X.sup.3 is --O.sup.-; and each of
R.sup.1-R.sup.5 is hydrogen.
24. The complex of claim 1, wherein Z.sup.1-- is --NH-- or
--NH(CH.sub.2).sub.m--; each of Y.sup.1 and Y.sup.2 is a single
bond; X.sup.3 is --O.sup.-; and each of R.sup.1-R.sup.5 is
hydrogen.
25. The complex of claim 1, wherein Ar.sup.1 is quinoxaline,
quinoxaline carboxylate, or cyanoquinoxaline; Z.sup.1-- is --NH--
or --NH(CH.sub.2).sub.m--; each of Y.sup.1 and Y.sup.2 is a single
bond; X.sup.3 is --O.sup.-; and each of R.sup.1-R.sup.5 is
hydrogen.
Description
[0001] This application is a Division of pending U.S. patent
application Ser. No. 11/572,920, filed Jan. 30, 2007, which was the
National Stage Entry of International Application No.
PCT/US05/27486, filed Aug. 3, 2005, which claims priority to U.S.
Ser. No. 60/604,573, filed Aug. 26, 2004, each of which is
expressly incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to fluorescent
diethylenetriaminepentaacetate (DTPA) metal complexes,
corresponding DTPA ligands, and methods of monitoring renal
function using such metal complexes.
BACKGROUND
[0003] It is to be noted that throughout this application, various
publications are referenced by Arabic numerals in brackets. Full
citation corresponding to each reference number is listed at the
end of the specification. The disclosures of these publications are
herein incorporated by reference in their entirety in order to
describe fully and clearly the state of the art to which this
invention pertains.
[0004] Acute renal failure (ARF) is a common ailment in patients
admitted to the general medical-surgical hospitals. Furthermore,
approximately half of the patients who develop ARF die, and
survivors face marked increases in morbidity and prolonged
hospitalization [1]. Early diagnosis is critical because renal
failure is often asymptomatic, and it requires careful tracking of
renal function markers in the blood. Dynamic monitoring of renal
functions of patients at the bedside is highly desirable in order
to minimize the risk of acute renal failure brought about by
various clinical, physiological, and pathological conditions [2-6].
It is particularly important in the case of critically ill or
injured patients because a large percentage of these patients face
the risk of multiple organ failure (MOF) resulting in death [7, 8].
MOF is a sequential failure of lung, liver, and kidneys and is
incited by one or more severe causes such as acute lung injury
(ALI), adult respiratory distress syndrome (ARDS), hypermetabolism,
hypotension, persistent inflammatory focus, or sepsis syndrome. The
common histological features of hypotension and shock leading to
MOF include tissue necrosis, vascular congestion, interstitial and
cellular edema, hemorrhage, and microthrombi. These changes affect
the lung, liver, kidneys, intestine, adrenal glands, brain, and
pancreas in descending order of frequency [9]. The transition from
early stages of trauma to clinical MOF is marked by the extent of
liver and renal failure and a change in mortality risk from about
30% to about 50% [10].
[0005] Currently, the renal function is determined commonly by
crude measurements such as urine output and plasma creatinine
levels [11-13]. These values are frequently misleading because the
values are affected by age, state of hydration, renal perfusion,
muscle mass, dietary intake, and many other clinical and
anthropometric variables. In addition, a single value obtained
several hours after sampling is difficult to correlate with other
important physiologic events such as blood pressure, cardiac
output, state of hydration and other specific clinical events
(e.g., hemorrhage, bacteremia, ventilator settings and others). An
approximation of glomerular filtration rate (GFR) can be made via a
24 hour urine collection, but this process requires 24 hours to
collect, several more hours to analyze, and a meticulous bedside
collection technique. Unfortunately, detecting a patient's GFR by
this time may be too late to treat the patient and have any hope of
saving the kidney. New or repeat data are equally cumbersome to
obtain. Occasionally, changes in serum creatinine must be further
adjusted based on the values for urinary electrolytes, osmolality,
and derived calculations such as the "renal failure index" or the
"fractional excretion of sodium." These require additional samples
of serum collected contemporaneously with urine samples and, after
a delay, precise calculations. Frequently, dosing of medication is
adjusted for renal function and thus can be equally as inaccurate,
equally delayed, and as difficult to reassess as the values upon
which they are based. Finally, clinical decisions in the critically
ill population are often equally as important in their timing as
they are in their accuracy. Thus, there is a need to develop
improved devices and methods for measuring GFR using non-ionizing
radiation. The availability of a real-time, accurate, repeatable
measure of renal excretion rate using exogenous markers under
specific yet changing circumstances would represent a substantial
improvement over any currently available or widely practiced
method. Moreover, since such a method would depend solely on the
renal elimination of the exogenous chemical entity, the measurement
would be absolute and requires no subjective interpretation based
on age, muscle mass, blood pressure, etc. In fact, if such a method
were developed, it would represent the nature of renal function in
the particular patient, under particular circumstances, at a
precise moment in time.
[0006] Hydrophilic, anionic substances are generally recognized to
be excreted by the kidneys [14]. Renal clearance occurs via two
pathways, glomerular filtration and tubular secretion; the latter
requires an active transport process, and hence, the substances
clearing via this pathway are expected to possess very specific
properties with respect to size, charge, and lipophilicity. It is
widely accepted that the level of GFR represents the best overall
measure of kidney function in the state of health or illness [15].
Fortunately, however, most of the substances that pass through the
kidneys are filtered through the glomerulus. The structures of
typical exogenous renal agents are shown in FIGS. 1 and 2.
Substances clearing by glomerular filtration (hereinafter referred
to as `GFR agents`) comprise inulin (1), creatinine (2),
iothalamate (3) [16-18], .sup.99mTc-DTPA (4), and .sup.51Cr-EDTA
(5), those undergoing clearance by tubular secretion include
.sup.99mTc-MAG3 (6) and o-iodohippuran (7) [16, 19, 20]. Among
inulin is regarded as the "gold standard" for GFR measurement. All
the compounds shown in FIGS. 1 and 2, except creatinine, require
radioisotopes for detection.
[0007] As would be evident to one skilled in the art, cursory
inspection of structures 1-7 provides no insight to ascertain the
subtle factors responsible for directing the molecule to clear via
a particular renal pathway. Clearly, gross physicochemical features
such as charge, molecular weight, or lipophilicity are inadequate
in even explaining the mode of clearance. Inulin (1, MW.about.5000)
and creatinine (2, MW 113) are both filtered through the
glomerulus. On the other hand, the anionic chromium complex 5 (MW
362) and technetium complex 6 (MW 364) are cleared by different
pathways. Structure-activity relationship (SAR) data on this very
limited set of compounds is insufficient to ascertain the subtle
differences between the two clearance pathways. Therefore, at the
time of instant invention, prior art publications could not be
relied upon to provide sufficient teaching or motivation for
rational design of novel GFR agents. Thus, each new compound must
be tested and compared against a known GFR agent, such as
.sup.99mTc-DTPA (4) or inulin (1), to confirm the clearance
pathway.
[0008] As mentioned before, most of the currently known exogenous
renal agents are radioactive. Currently, no reliable, continuous,
repeatable bedside method for the assessment of specific renal
function using non-radioactive exogenous GFR agent is commercially
available. Among the non-radioactive methods, fluorescence
measurement offers the greatest sensitivity. In principle, there
are two general approaches for designing fluorescent GFR agents.
The first approach involves enhancing the fluorescence of known
renal agents (e.g. lanthanide or transition metal complexes) that
are intrinsically poor emitters; and the second one involves
transforming highly fluorescent conventional dyes, which are
intrinsically lipophilic, into hydrophilic, anionic species to
force them to clear via the kidneys. The present invention focuses
on the former approach. Metal complexes of DTPA, DTPA-monoamides,
DTPA-bisamides, and DTPA substituted at the ethylene portion of the
ligand, have been used extensively in biomedical applications, and
have been shown to clear through the kidneys. Work described in
[21, 22, and 23] have independently suggested the use of
luminescent metal complexes derived from polyaminocarboxylate
ligands for measuring renal clearance.
[0009] The method of enhancing the fluorescence through
intramolecular energy transfer process is well established [24],
and has been applied to boost the fluorescence of metal ion through
ligand-metal energy transfer [25-28]. The method essentially
involves designing metal complexes containing an "antenna". As used
herein, an antenna is a moiety that has high photon capture cross
section placed at an optimal distance (referred to as `Foster`
distance) from the metal ion wherein the moiety has a large surface
area and a polarizable electron cloud. The distance between the
antenna and the metal ion ranges from about 2-20 .ANG., preferably,
from about 3-10 .ANG..
[0010] Novel fluorescent DTPA complexes for use in improved methods
for providing data related to organ functioning are described
below. These complexes may be said by some to be capable of
real-time, accurate, repeatable measure of renal excretion
rate.
SUMMARY
[0011] A first aspect of the invention is directed to DTPA
complexes of Formula I below. With regard to this first aspect, M
is generally a metal ion whose absorption and emission occur in the
visible and/or NIR region, and n is at least 1. At least one of the
substituents, X.sup.1 to X.sup.3 and R.sup.1 to R.sup.5, in Formula
I is generally an antenna. The other remaining R and/or X groups
may optionally be introduced to optimize biological and/or
physicochemical properties of the metal complex. Each of Y.sup.1
and Y.sup.2 is independently a single bond or a spacer group that
connects the antenna or other substituent group to the DTPA.
[0012] In a second aspect of the invention, DTPA ligands
corresponding to complexes of Formula I are provided. The DTPA
ligands of this second aspect are believed to be useful for, among
others things, preparing metal complexes, such as metal complexes
of Formula I.
##STR00002##
[0013] Yet a third aspect of the invention is directed to methods
of determining renal function using at least one metal complex,
such as one or more metal complexes of Formula I. With regard to
this third aspect, an effective amount of a metal complex(es)
(e.g., a metal complex of Formula I) capable of absorbing and
emitting electromagnetic radiation at different wavelengths is
administered into the body of a patient (e.g., a mammal such as a
human subject or other animal subject). A signal emanating from a
body portion in the patient's body is detected (e.g., at one or
more times or continuously in real-time). This signal results from
the metal complex(es) not yet removed from the body during the
detection. Renal function is determined based on the detection of
the signal.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1: Structures of molecules clearing via glomerular
filtration.
[0015] FIG. 2: Structures of molecules clearing via tubular
secretion.
[0016] FIG. 3: Attachment of the antenna at the carboxyl position
in DTPA.
[0017] FIG. 4: Attachment of the antenna at the R-position in the
ethylene unit of DTPA.
[0018] FIG. 5: Attachment of the antenna at the a-carbon to the
central acetate of DTPA.
[0019] FIG. 6: Attachment of the antenna at the a-position in the
ethylene unit of DTPA.
[0020] FIG. 7: Bar graph of normal rat biodistribution of
Tc-DTPA.
[0021] FIG. 8: Bar graph of normal rat biodistribution of
.sup.111In-DTPA-mono(coumarin amide) complex.
[0022] FIG. 9: Bar graph of normal rat biodistribution of
.sup.111In-DTPA-mono(salicylamide) complex.
[0023] FIG. 10: Bar graph of normal rat biodistribution of
.sup.111In-DTPA-mono(1-naphthylamide) complex.
[0024] FIG. 11: Bar graph of normal rat biodistribution of
.sup.111In-HMDTPA-1-naphthylurethane complex.
[0025] FIG. 12: Bar graph of normal rat biodistribution of
.sup.111In-DTPA-bis(salicylamide) complex.
[0026] FIG. 13: Bar graph of normal rat biodistribution of
.sup.111In-DTPA-mono(pyrazinylamino)ethylamide complex.
[0027] FIG. 14: Bar graph of normal rat biodistribution of
.sup.111In-DTPA-mono(quinoxanylamino)ethylamide complex.
DETAILED DESCRIPTION
[0028] Exemplary embodiments of the present invention include renal
function monitoring compositions of Formula I. With regard to these
embodiments, M is a metal ion whose absorption and emission occur
in the visible and/or NIR region, and n varies from 1 to 5.
Suitable metal ions, M, include, but are not limited to, the
lanthanide series of elements such as Eu, Tb, Dy and Sm, and the
transition metals such as Rh, Re, Ru, and Cr, and Group IIIb metals
such as Ga and In, and the like. For instance, in some embodiments,
M is chosen from Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr and In.
##STR00003##
[0029] As a further description of the exemplary embodiments, each
of X.sup.1, X.sup.2 and X.sup.3 is independently an antenna,
--O.sup.-, --NH(CH.sub.2).sub.aOH, --NH(CH.sub.2).sub.aCO.sub.2H,
--NH(CH.sub.2).sub.aSO.sub.3.sup.-,
--NH(CH.sub.2).sub.aOSO.sub.3.sup.-,
--NH(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--O(CH.sub.2).sub.aSO.sub.3.sup.-,
--O(CH.sub.2).sub.aOSO.sub.3.sup.-,
--O(CH.sub.2).sub.aNHSO.sub.3.sup.-,
--NH(CH.sub.2).sub.aPO.sub.3H.sup.-, ,
--NH(CH.sub.2).sub.aPO.sub.3.sup.=,
--NH(CH.sub.2).sub.aOPO.sub.3H.sup.-,
--NH(CH.sub.2).sub.aOPO.sub.3.sup.=,
--NH(CH.sub.2).sub.aNHPO.sub.3H.sup.-,
--NH(CH.sub.2).sub.aNHPO.sub.3.sup.=,
--O(CH.sub.2).sub.aPO.sub.3H.sup.-,
--O(CH.sub.2).sub.aPO.sub.3.sup.=,
--O(CH.sub.2).sub.aOPO.sub.3H.sup.-,
--O(CH.sub.2.sub.aOPO.sub.3.sup.=,
--O(CH.sub.2).sub.aNHPO.sub.3H.sup.-, and
--O(CH.sub.2).sub.aNHPO.sub.3.sup.=; a ranges from 1 to 6. Each of
R.sup.1 to R.sup.5 is independently an antenna, hydrogen, C1-C10
alkyl, C1-C10 hydroxyalkyl, C1-C10 polyhydroxyalkyl, carboxyl,
C1-C10 carboxyalkyl, C1-C10 alkoxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bOSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bCO.sub.2(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.3).sub.bNHCO(CH.sub.3).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHCONH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHCSNH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCONH(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bPO.sub.3H.sup.-,
--(CH.sub.2).sub.bPO.sub.3.sup.=,
--(CH.sub.2).sub.bOPO.sub.3H.sup.-,
--(CH.sub.2).sub.bOPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHPO.sub.3.sup.=,
--(CH.sub.2).sub.bCO.sub.2(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bCO.sub.2(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHCONH(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHCONH(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bNHCSNH(CH.sub.2).sub.cPO.sub.3H.sup.-,
--(CH.sub.2).sub.bNHCSNH(CH.sub.2).sub.cPO.sub.3.sup.=,
--(CH.sub.2).sub.bOCONH(CH.sub.2).sub.cPO.sub.3H.sup.-, and
--(CH.sub.2).sub.bOCONH(CH.sub.2).sub.cPO.sub.3.sup.=. The
constituents, b and c, range from 1 to 6, and at least one of
X.sup.1, X.sup.2, X.sup.3 and R.sup.1 to R.sup.5 is an antenna.
[0030] Each of Y.sup.1 and Y.sup.2 is independently a single bond
or a spacer group, such as --(CH2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(CH.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, and --(CH.sub.2).sub.mSO.sub.2NH--.
In some embodiments, m varies from 1 to 10, while in other
embodiments, m varies from 1 to 6.
##STR00004##
[0031] Some embodiments of the invention include ligands
corresponding to the metal complexes of formula I. Such embodiments
are represented by formula II above. X.sup.1 to X.sup.3, Y.sup.1
and Y.sup.2, and R.sup.1 to R.sup.5 in formula II correspond to
those same substituents as defined in formula I. For substituents
X.sup.1 to X.sup.3 and R.sup.1 to R.sup.5 that are shown in their
anion form, it is noted that those substituents can optionally be
in the corresponding neutral form (e.g., --O.sup.- can be either
--O.sup.- or --OH).
[0032] Regarding the exemplary embodiments of the compositions
formula I above, if R.sup.1 to R.sup.5 are hydrogens, and if
M.sup.n+ is a lanthanide ion, then X.sup.1 to X.sup.3 are not
derived from aniline, benzylamine, 2-aminomethyl-pyridine,
1-amino-naphthalene, 2-aminonaphthalene, 7-amino-4-methylcoumarin,
4-aminosalicylic acid, 2-(2-aminoethyl)aminopyrazine,
2-(2-aminoethyl)-aminopyrazine,
2-(2-aminoethyl)aminoquinoxaline-2-carboxylic acid, or
2-(2-aminoethyl)-aminoquinoxaline-2-carboxamide. In addition, if
X.sup.1 to X.sup.3 are --O.sup.-, and if M.sup.n+ is a lanthanide
ion, then R.sup.1 to R.sup.5 are not phenyl or benzyl.
[0033] Regarding the ligands of formula II above, if R.sup.1 to
R.sup.5 are hydrogens, then X.sup.1 to X.sup.3 are not derived from
aniline, benzylamine, 2-aminomethyl-pyridine, 1-aminonaphthalene,
2-amino-naphthalene, 7-amino-4-methyl coumarin, 4-aminosalicylic
acid, 2-(2-aminoethyl)aminopyrazine, 2-(2-aminoethyl)-
aminopyrazine, 2-(2-aminoethyl)aminoquinoxaline-2-carboxylic acid,
or 2-(2-aminoethyl)-aminoquinoxaline-2-carboxamide. In addition, if
X.sup.1 to X.sup.3 are --O.sup.-, then R.sup.1 to R.sup.5 are not
phenyl or benzyl.
[0034] An "antenna" refers to a group whose absorption and emission
preferably occur in the visible and/or NIR region. Suitable
antennae are typically aromatic or heteroaromatic chromophores that
are derived from unsubstituted or substituted aromatic or
heteroaromatic compounds. The aromatic or heteroaromatic compound
can be represented by the formula Ar--Z, where Z is a linker group,
and the antenna can be represented by the formula Ar--Z'--. The
base aromatic or heteroaromatic ring structure preferably is
monocyclic or bicyclic and contains 5 to 10 carbon atoms. The
aromatic or heteroaromatic ring structure can optionally contain
substituent groups other than Z (e.g., alkyl groups such as
methyl). An example of such a substituted Ar--Z compound is
7-amino-4-methylcoumarin. The aromatic or heteroaromatic ring
structure can also optionally be substituted with one or more
hydrophilic groups, W. Suitable W groups include, but are not
limited to, --COOH, --NH.sub.2, --OH, --SO.sub.3H,
--PO.sub.3H.sub.2, and the like. For the development of renal
agents of some embodiments, the aromatic or heteroaromatic ring
structure is substituted with at least one W group.
[0035] Suitable antennae include, but are not limited to, Ar--Z'--
groups derived from substituted or unsubstituted benzene, pyridine,
pyrazine, pyrimidine, pyridazine, naphthalene, quinoline,
quinoxaline (also known as 2,3-benzopyrazine or quinazine),
coumarin, benzofuran, isobenzofuran, indole, isoindole,
benzimidazole, benzothiophene, isobenzothiophene, benzoxazole,
benzothiazole, pyrrolopyridazine, pyrrolopyrazine, and the like.
Although the antenna could be any aromatic or heteroaromatic
moiety, it is preferable to select one in which at least one of
electronic absorption band of the antenna substantially match with
at least one of the excitation or absorption band of the metal ion
in order to maximize the efficiency of energy transfer from the
ligand to the metal. Suitable Z groups include, but are not limited
to, amino, hydroxyl, carboxyl (--COOH), carboxylate (salts of
--COOH), acid halide, alkyl halides or sulfonates, sulfonyl halide,
phosphoryl chloride, N-succinimido ester, chloroformate,
isocyanate, acyl azide, isothiocyanate, and the like, wherein the
preferred halide is chloride. Positioning of a spacer, Z', in the
antenna is not critical. It would be readily apparent to the one
skilled in the art that any suitable position that will accommodate
a spacer/linker should be adequate as long as the distance between
the antenna and metal ion and the absorption/emission wavelength is
effective for energy transfer. The distance between the antenna and
the metal ion is between about 2 .ANG. and about 20 .ANG. in some
embodiments and between about 3 .ANG. and about 10 .ANG. in other
embodiments.
[0036] Examples of Ar--Z compounds include, but are not limited to,
7-amino-4-methylcoumarin, 4-aminosalicylic acid,
1-aminonaphthalene, aminopyrazines, diaminopyrazines, pyrazine
carboxylic acid, pyrazine carboxamide,
2,5-diamino-3,6-dicyanopyrazine,
3,6-diamino-2,5-pyrazinedicarboyxlic acid,
3,6-diamino-2,5-pyrazinedicarboyxlic esters, and
3,6-diamino-2,5-pyrazinedicarboxamides.
[0037] The compositions and ligands of the invention preferably
contain at least one antenna. For instance, some embodiments
include 1 to 3 antennae, while other embodiments include 1 to 2
antennae. Yet other embodiments may include other appropriate
quantities and ranges of antennae.
[0038] In one group of compounds represented by Formula I, M is
selected from Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, and In; n varies from
1 to 5; X.sup.1 is an antenna; each of X.sup.2 and X.sup.3 is
independently --O.sup.-, --NH(CH.sub.2).sub.aOH,
--NH(CH.sub.2).sub.aCO.sub.2H, --NH(CH.sub.2).sub.aSO.sub.3.sup.-,
or --O(CH.sub.2).sub.aSO.sub.3.sup.-, a ranges from 1 to 6; each of
Y.sup.1 and Y.sup.2 is independently a single bond,
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(CH.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, or --(CH.sub.2).sub.mSO.sub.2NH--;
m varies from 1 to 10; each of R.sup.1 to R.sup.5 is independently
hydrogen, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, or
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-; and b and c
independently range from 1 to 6.
[0039] As another group of compounds represented by Formula I, M is
Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr or In; n varies from 1 to 5; X.sup.1
is an antenna; each of X.sup.2 and X.sup.3 is --O.sup.-; at least
one of Y.sup.1 and Y.sup.2 is --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mOSO.sub.2--, or --(CH.sub.2).sub.mNHSO.sub.2--;
the other (if and) of Y.sup.1 and Y.sup.2 is a single bond
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(CH.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(C.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, or --(CH.sub.2).sub.mSO.sub.2NH--;
m varies from 1 to 10; and each of R.sup.1 to R.sup.5 is
hydrogen.
[0040] In yet another group of compounds represented by Formula I,
M is Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr or In; n varies from 1 to 5;
each of Y.sup.1 and Y.sup.2 is independently a single bond,
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(CH.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH', --(CH.sub.2).sub.mOCO.sub.2--,
--(C.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, or --(CH.sub.2).sub.mSO.sub.2NH--;
m varies from 1 to 10; R.sup.1 is an antenna; each of X.sup.1 to
X.sup.3 is independently --O.sup.-, --NH(CH.sub.2).sub.aOH,
--NH(CH.sub.2).sub.aCO.sub.2H, --NH(CH.sub.2).sub.aSO.sub.3.sup.-,
or --O(CH.sub.2).sub.aSO.sub.3.sup.-; a ranges from 1 to 6; each of
R.sup.2 to R.sup.5 is independently hydrogen, C1-C10 hydroxyalkyl,
carboxyl, C1-C10 carboxyalkyl, --(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, or
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-; and b and c
independently range from 1 to 6.
[0041] In still another group of compounds represented by Formula
I, M is Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr or In; n varies from 1 to 5;
R.sup.1 is an antenna; each of X.sup.1 to X.sup.3 is --O.sup.-; at
least one of Y.sup.1 and Y.sup.2 is --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mOSO.sub.2--, or --(CH.sub.2).sub.mNHSO.sub.2--;
the other (if any) of Y.sup.1 and Y.sup.2 is a single bond
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(CH.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.3--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, or --(CH.sub.2).sub.mSO.sub.2NH--;
m varies from 1 to 10; and each of R.sup.2 to R.sup.5 is
hydrogen.
[0042] In yet another group of compounds represented by Formula I,
M is Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, or In; n varies from 1 to 5;
each of Y.sup.1 and Y.sup.2 is independently a single bond,
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(CH.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, or --(CH.sub.2).sub.mSO.sub.2NH--;
m varies from 1 to 10; R.sup.2 is an antenna; each of X.sup.1 to
X.sup.3 is independently-O.sup.-, --NH(CH.sub.2).sub.aOH,
--H(CH.sub.2).sub.aCO.sub.2H, --NH(CH.sub.2).sub.aSO.sub.3.sup.-,
or --O(CH.sub.2).sub.aSO.sub.3.sup.-; a ranges from 1 to 6; each of
R.sup.1, R.sup.3, R.sup.4, and R.sup.5 is independently hydrogen,
C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, or
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-; and b and c
independently range from 1 to 6.
[0043] In yet another group of compounds represented by Formula I,
M is Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, or In; n varies from 1 to 5;
R.sup.2 is an antenna; each of X.sup.1 to X.sup.3 is --O.sup.-; at
least one of Y.sup.1 and Y.sup.2 is --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mOSO.sub.2--, and --(CH.sub.2).sub.mNHSO.sub.2--;
the other (if any) of Y.sup.1 and Y.sup.2 is a single bond
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.mO--,
--(CH.sub.2).sub.mOCO--, --(C.sub.2).sub.mCO.sub.2--,
--(CH.sub.2).sub.mOCNH--, --(CH.sub.2).sub.mOCO.sub.2--,
--(CH.sub.2).sub.mNHCO--, --(CH.sub.2).sub.mNHCONH--,
--(CH.sub.2).sub.mNHCSNH--, --(CH.sub.2).sub.mOSO.sub.2--,
--(CH.sub.2).sub.mOSO.sub.3--, --(CH.sub.2).sub.mSO.sub.2--,
--(CH.sub.2).sub.mNHSO.sub.2--, or --(CH.sub.2).sub.mSO.sub.2NH--;
m varies from 1 to 10; and each of R.sup.1, R.sup.3, R.sup.4, and
R.sup.5 is hydrogen.
[0044] In still yet another group of compounds represented by
Formula I, M is Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, or In; n varies
from 1 to 5; R.sup.3 is an antenna; each of X.sup.1 to X.sup.3 is
independently-O.sup.-, --NH(CH.sub.2).sub.aOH,
--NH(CH.sub.2).sub.aCO.sub.2H, --NH(CH.sub.2).sub.aSO.sub.3.sup.-,
or --O(CH.sub.2).sub.aSO.sub.3.sup.-; a ranges from 1 to 6; at
least one of Y.sup.1 and Y.sup.2 is independently a single bond or
a spacer group; m varies from 1 to 10; each of R.sup.1, R.sup.2,
R.sup.4, and R.sup.5 is independently hydrogen, C1-C10
hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl,
--(CH.sub.2).sub.bSO.sub.3.sup.-,
--(CH.sub.2).sub.bNHSO.sub.3.sup.-,
--(CH.sub.2).sub.bOCO(CH.sub.2).sub.cSO.sub.3.sup.-,
--(CH.sub.2).sub.bCONH(CH.sub.2).sub.cSO.sub.3.sup.-, or
--(CH.sub.2).sub.bNHCO(CH.sub.2).sub.cSO.sub.3.sup.-; and b and c
independently range from 1 to 6.
[0045] In still a further group of compounds represented by Formula
I, M is Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, or In; n varies from 1 to
5; R.sup.3 is an antenna; each of X.sup.1 to X.sup.3 is --O.sup.-;
at least one of Y.sup.1 and Y.sup.2 is independently
--(CH.sub.2).sub.mO--, --(CH.sub.2).sub.mOCNH--,
--(CH.sub.2).sub.mOCO.sub.2--, --(CH.sub.2).sub.mNHCO--,
--(CH.sub.2).sub.mNHCONH--, --(CH.sub.2).sub.mOSO.sub.2--, or
--(CH.sub.2).sub.mNHSO.sub.2--; the other (if any) of Y.sup.1 and
Y.sup.2 is a spacer; m varies from 1 to 10; and each of R.sup.1,
R.sup.2, R.sup.4, and R.sup.5 is hydrogen.
[0046] The antennae of the present invention can be attached to the
DTPA at the five carboxyl groups or at the nine methylene positions
in Formula I by conventional methods well known in the art [28,
29]. For example, the attachment at the carboxyl position can be
accomplished by first reacting DTPA dianhydride (8) with the
antenna bearing a hydroxyl or an amino group to give the
corresponding ester and amide ligands followed by metal
complexation to give the complexes 9 or 10 respectively (FIG.
3)[30-32]. The metal complexation of polyaminocarboxylate ligands
are typically accomplished using the desired metal oxide, metal
carbonate, metal halide or other metal salts, and weak complexes
such as acetylacetonate, and the like.
[0047] The attachment of an antenna to the carbon atom to the
ethylene unit on the carbon at the .beta. position to the central
nitrogen of DTPA can be accomplished by condensing the known
hydroxymethyl-DTPA derivative 11 [33] with Ar--Z, i.e. the antennae
containing reactive linking groups (also referred to as `handles`)
such as carboxyl, acid halide, alkyl halides or sulfonates,
sulfonyl halide, phosphoryl chloride, N-succinimido ester,
chloroformate, isocyanate, acyl azide, isothiocyanate, and the like
(FIG. 4). The metal complexation of the resulting ligand 12 can be
carried out in the same manner as described above to give complex
13.
[0048] The attachment of an antenna to the carbon atom at the a
position to the carboxyl group of the acetate residue attached to
the central nitrogen can be accomplished by introducing the
hydroxymethyl group at this position as described in FIG. 5.
Alkylation of serine t-butylester (14) [34] with
N-(2-bromo)ethyliminodiacetate (15)[35], followed by condensation
of the hydroxyl group with the antennae containing reactive linking
groups mentioned previously provides the ligand 16. The metal
complexation of ligand 16 can be carried out in the same manner as
described above to give 17.
[0049] The attachment of antenna to the carbon atom of the ethylene
unit at the a position to the central nitrogen can be effected by
first preparing the hydroxymethyl intermediate 19 from
N-benzoylserinamide (18) and alkylating it with
N-(2-bromo)ethyliminodiacetate 15 followed by condensation of the
resulting hydroxymethyl derivative with the antennae (FIG. 6). The
metal complexation of ligand 20 can be carried out in the same
manner as described above to give 21. One of the advantages of at
least some embodiments of the present invention is that the
synthetic method may be carried out in a modular fashion so as to
allow for preparation of a wide variety of DTPA-antenna conjugates
in a simple and rapid manner. Hydroxymethyl-DTPA derivatives tend
to be versatile intermediates in that the hydroxyl group can be
transformed into various other functionalities such as amino,
formyl, or carboxyl, which can further serve as a handle to link
the antennae endowed with complementary functional groups.
[0050] In accordance with the present invention, one protocol for
measuring physiological functions of body cells includes selecting
a suitable DTPA complex from the compositions of Formula I
(hereinafter referred to as `tracers`) capable of absorbing and
emitting electromagnetic radiation at different wavelengths,
administering an effective amount of the tracer into a patient's
body, detecting signal emanating from the tracer by invasive or
non-invasive optical probes, determining the signal intensity over
time as necessitated by the clinical condition, and correlating an
intensity-time profile with a physiological or pathological
condition of the patient.
[0051] The antennae of the present invention may vary widely
depending on the metal ion of interest and on the detection
apparatus employed. The DTPA derivatives of the present invention
may optionally contain more than one light absorbing or emitting
units for increasing the sensitivity of detection. The dosage is
readily determined by one of ordinary skill in the art and may vary
according to the clinical procedure contemplated, generally ranging
from 1 nanomolar to 100 micromolar. The tracers may be administered
to the patient by any suitable method, including intravenous,
intraperitoneal, or subcutaneous injection or infusion, oral
administration, transdermal absorption through the skin, or by
inhalation. The detection of the tracers is achieved by optical
fluorescence, absorbance, or light scattering methods known in the
art using invasive or non-invasive probes such as endoscopes,
catheters, ear clips, hand bands, head bands, surface coils, finger
probes, and the like [37]. Physiological function may be correlated
with clearance profiles and rates of these agents from the body
fluids [38].
[0052] Organ function can be assessed by comparing differences in
the manner in which normal and impaired cells remove the tracer
from the bloodstream, by measuring the clearance or accumulation of
these tracers in the organs or tissues, and/or by obtaining
tomographic images of the organs or tissues. Blood pool clearance
may be measured non-invasively from convenient surface capillaries
such as those found in an ear lobe or a finger or can be measured
invasively using an endovascular catheter. Accumulation of the
tracer within the cells of interest can be assessed in a similar
fashion. The clearance of the tracer compounds can be determined by
selecting excitation wavelengths and filters for the emitted
photons. The concentration/time curves may be analyzed (preferably,
but not necessarily in real time) by a microprocessor or the
like.
[0053] In addition to noninvasive techniques, a modified pulmonary
artery catheter that can be used to make desired measurements has
been developed [39]. This is a distinct improvement over current
pulmonary artery catheters that measure only intravascular
pressures, cardiac output and other derived measures of blood flow.
Current critically ill patients are managed using these parameters
but rely on intermittent blood sampling and testing for assessment
of renal function. These laboratory parameters represent
discontinuous data and are frequently misleading in many patient
populations. Yet, importantly, they are relied upon heavily for
patient assessment, treatment decisions, and drug dosing.
[0054] The modified pulmonary artery catheter incorporates an
optical sensor into the tip of a standard pulmonary artery
catheter. This wavelength-specific optical sensor can monitor the
renal function specific elimination of a designed optically
detectable chemical entity. Thus, by a method substantially
analogous to a dye dilution curve, real-time renal function can be
monitored by the disappearance of the optically detected compound.
Appropriate modification of a standard pulmonary artery catheter
generally includes merely making the fiber optic sensor
wavelength-specific. Catheters that incorporate fiber optic
technology for measuring mixed venous oxygen saturation exist
currently.
[0055] The following examples illustrate specific embodiments of
the invention. As would be apparent to skilled artisans, various
changes and modifications are possible and are contemplated within
the scope of the invention described.
Example 1
Preparation and biodistribution of .sup.99mTc-DTPA
[0056] Commercially available DTPA kit (Draximage Co., Ontario,
Canada) was labeled with .sup.99mTc by the standard procedure
described in the package insert that was supplied with the kit, and
was administered to Sprague-Dawley rats (3 rats for each time point
of 15 minutes, 60 minutes, 120 minutes, and 24 hours). The
biodistribution data, shown in FIG. 7, serves as a positive control
for determining whether the novel compounds of the present
invention clear via glomerular filtration.
Example 2
Preparation and biodistribution of compound of Formula I, wherein
X.sup.2 is --O.sup.-; X.sup.3 and R.sup.1 to R.sup.5 are hydrogens;
M.sup.n+ is .sup.111In.sup.3+ and X.sup.1 is an antenna derived
from 7-amino-4-methylcoumarin; and Y.sup.1 and Y.sup.2 are single
bonds
[0057] A mixture of the stock solution of
DTPA-mono(7-amino-4-methylcoumarin)amide ligand (1 mg/mL in 0.5M
sodium acetate buffer, 100 .mu.L), obtained from Gunma University,
Japan (Ozaki, et. al. Reference 30), sodium acetate solution (0.5M,
100 .mu.L), and commercially available .sup.111InCl.sub.3 solution
(0.1 M HCl, 100-200 .mu.Ci/100 .mu.L) was adjusted to pH 4.5 and
incubated at ambient temperature for 30 minutes. The resulting
indium complex was purified by reverse phase HPLC and administered
to Sprague-Dawley rats. The biodistribution was carried out in the
same manner as that of .sup.99mTc-DTPA in Example 1 (FIG. 8). This
indium complex exhibited slightly more hepatobiliary clearance than
.sup.99mTc-DTPA, but cleared substantially through the kidneys.
Example 3
Preparation and biodistribution of compound of Formula I, wherein
X.sup.2, X.sup.3 and R.sup.1 to R.sup.5 are hydrogens; M.sup.n+ is
.sup.111In.sup.3+, and X.sup.1 is an antenna derived from
4-aminosalicvlic acid; and Y.sup.1 and Y.sup.2 are single bonds
[0058] The DTPA-mono(4-aminosalicyl)amide ligand was obtained from
Gunma University, Japan (Ozaki, et. al. Reference 30). The indium
labeling and biodistribution of this ligand is carried out in the
same manner as in Example 2. The biodistribution of this complex
(FIG. 9) is nearly identical to that of .sup.99mTc-DTPA.
Example 4
Preparation and biodistribution of compound of Formula I, wherein
X.sup.2 is --O.sup.-; X.sup.3 and R.sup.1 to R.sup.5 are hydrogens;
M.sup.n+ is .sup.111In.sup.3+; X.sup.1 is an antenna derived from
1-aminonaphthalene; and Y.sup.1 and Y.sup.2 are single bonds
[0059] The DTPA-mono(1-aminonaphthyl)amide ligand was obtained from
Gunma University, Japan (Ozaki, et. al. Reference 30). The indium
labeling and biodistribution of this ligand is carried out in the
same manner as in Example 2. The biodistribution of this complex
(FIG. 10) is nearly identical to that of .sup.99mTc-DTPA.
Example 5
Preparation and biodistribution of compound of Formula I, wherein
X.sup.1 to X.sup.3 and R.sup.2 to R.sup.5 are hydrogens; M.sup.n+
is In.sup.3+; R.sup.1 is an antenna derived from
1-aminonaphthalene; Y.sup.1 is --CH.sub.2O--; and Y.sup.2 is a
single bond
[0060] Step 1. A mixture of the hydroxymethyl-DTPA (11) 100 mg (0.1
mmol) and 1-naphthylisocyanate (101 mg, 1.0 mmol) in toluene (20
mL) was heated under reflux for 16 hours. The solvent was
evaporated in vacuo and the residue was purified by flash
chromatography (Argonaut Flashmaster Solo) using
hexanes/ethylacetate as eluent (linear gradient: 0% to 75%
ethylacetate in 40 minutes) to give the DTPA-1-naphthylurethane
derivative as the penta-t-butylester.
[0061] Step 2. The pentaester from Step 1 (1.2 g) was dissolved in
96% formic acid (10 mL) and heated until boiling and thereafter
kept at ambient temperature for 16 hours. The solution was poured
onto ether (500 mL). The gummy residue was separated from the bulk
solvent by decantation and was purified by reverse phase flash
chromatograpy (Argonaut Flashmaster Solo) to give the desired
ligand.
[0062] Step 3. The indium labeling and biodistribution of this
ligand is carried out in the same manner as in Example 2. The
biodistribution of this complex (FIG. 11) is similar to that of
.sup.111In-DTPA-coumarin derivative in Example 2, with much higher
hepatobiliary clearance.
Example 6
Preparation and biodistribution of compound of Formula I, wherein
X.sup.3 and R.sup.1 to R.sup.5 are hydrogens; M.sup.n+ is
.sup.111In.sup.3+; X.sup.1 and X.sup.2 are antennae derived from
4-aminosalicvlic acid; and Y.sup.1 and Y.sup.2 are single bonds
[0063] The DTPA-bis(4-aminosalicyl)amide ligand was obtained from
Gunma University, Japan (Ozaki, et. al. Reference 30). The indium
labeling and biodistribution of this ligand is carried out in the
same manner as in Example 2. The biodistribution of this complex
(FIG. 12) is nearly identical to that of .sup.99mTc-DTPA.
Example 7
Preparation and biodistribution of compound of Formula I, wherein
X.sup.3 and R.sup.1 to R.sup.5 are hydrogens; M.sup.n+ is
.sup.111In.sup.3+; X.sup.1 and X.sup.2 are antennae derived from
2-(N-2-aminoethyl)-aminopvrazine; and Y.sup.1 and Y.sup.2 are
single bonds
[0064] A mixture of DTPA-bisanhydride 0.45 g. (1.3 mmol) and
N,N'-dimethyl-N-pyrazin-2-ylethane-1,2-diamine 0.42 g. (2.5 mmol)
in anhydrous DMSO (8 mL) was heated at 50-55.degree. C. for 1 hour
and stirred at room temperature for another 16 hours. The crude
product was precipitated in acetone (100 mL) and the residue
purified by reversed phase flash chromatography (Argonaut
Flashmaster Solo) using deionized water as eluant followed by
evaporation of water to give the desired bisamide ligand.
[0065] The indium labeling and biodistribution of this ligand was
carried out in the same manner as in Example 2. The biodistribution
of this complex (FIG. 13) is nearly identical to that of
.sup.99mTc-DTPA.
Example 8
Preparation and biodistribution of compound of Formula I, wherein
X.sup.2 is --O.sup.-; X.sup.3 and R.sup.1 to R.sup.5 are hydrogens;
M.sup.n+ is .sup.111In.sup.3+; X.sup.1 is an antenna derived from
2-carboxy-3-(2-aminoethyl)aminoguinoxaline; and Y.sup.1 and Y.sup.2
are single bonds
[0066] A mixture of DTPA-bisanhydride 0.20 g. (0.6 mmol) and
3-[(2-aminoethyl)amino]-guinoxaline-2-carboxylic acid hydrochloride
0.30 g. (1.1 mmol) in triethylamine (1.5 mL) and anhydrous DMSO (5
mL) was heated at 50-55.degree. C. for 4 hours and stirred at room
temperature for another 16 hours. The crude product was
precipitated in acetone (100 mL) and the residue solution was
acidified to pH 3 with dilute hydrochloric acid, then purified by
reversed phase flash chromatography (Argonaut Flashmaster Solo)
using deionized water/acetonitrile eluent gradient (0% to 20%
acetonitrile over 30 minutes), followed by evaporation of solvents
to give the desired monoamide ligand.
[0067] The indium labeling and biodistribution of this ligand was
carried out in the same manner as in Example 2. The biodistribution
of this complex (FIG. 14) is nearly identical to that of the
DTPA-coumarin derivative in Example 2.
[0068] These examples demonstrate that GFR agents based on
polyaminocarboxylate metal complexes with the appropriate selection
of antenna group(s) would be effective as renal function agents and
would provide clearance properties similar to those of Tc-DTPA. In
particular, previous data on Eu-DTPA-coumarin complex based on the
ligand used in Example 2 showed that the coumarin antenna enhances
europium fluorescence by about 1000-fold [30]. The data of the
present invention showed that this complex has clearance properties
similar to that of Tc-DTPA, but with more hepatobiliary clearance.
Thus, introduction of appropriate hydrophilic functionalities in
the coumarin ring would make the complex clear in the same manner
as Tc-DTPA. Furthermore, hydrophilic antenna similar in size to the
coumarin moiety and that matches the excitation wavelengths of
europium metal can be readily attached to the DTPA portion to
achieve optimal fluorescence and clearance properties.
[0069] The examples further demonstrate that at least some
compounds of the invention have antennae that are cleared through
the kidneys by the GFR mechanism with hepatobiliary clearance
comparable to that with .sup.99mTc-DTPA, i.e. hepatobiliary
clearance essentially no greater than that with .sup.99mTc-DTPA. In
addition, compounds that are cleared through the kidneys by the GFR
mechanism but that have hepatobiliary clearance that is greater
than that with .sup.99mTc-DTPA have been found to be capable of
clearing essentially like .sup.99mTc-DTPA by adding a W substituent
group to the antenna.
REFERENCES
[0070] 1. Nally, J. V. Acute renal failure in hospitalized
patients. Cleveland Clinic Journal of Medicine 2002, 69(7),
569-574. [0071] 2. C. A. Rabito, L. S. T. Fang, and A. C. Waltman.
Renal function in patients at risk with contrast material-induced
acute renal failure: Noninvasive real-time monitoring. Radiology
1993, 186, 851-854. [0072] 3. N. L. Tilney, and J. M. Lazarus.
Acute renal failure in surgical patients: Causes, clinical
patterns, and care. Surgical Clinics of North America 1983, 63,
357-377. [0073] 4. B. E. VanZee, W. E. Hoy, and J. R. Jaenike.
Renal injury associated with intravenous pyelography in
non-diabetic and diabetic patients. Annals of Internal Medicine
1978, 89, 51-54. [0074] 5. S. Lundqvist, G. Edbom, S. Groth, U.
Stendahl, and S.-O. Hietala. Iohexol clearance for renal function
measurement in gynecologic cancer patients. Acta Radiologica 1996,
37, 582-586. [0075] 6. P. Guesry, L. Kaufman, S. Orloff, J. A.
Nelson, S. Swann, and M. Holliday. Measurement of glomerular
filtration rate by fluorescent excitation of non-radioactive
meglumine iothalamate. Clinical Nephrology 1975, 3, 134-138).
[0076] 7. C. C. Baker et al. Epidemiology of Trauma Deaths.
American Journal of Surgery 1980, 144-150. [0077] 8. R. G.
Lobenhoffer et al. Treatment Results of Patients with Multiple
Trauma: An Analysis of 3406 Cases Treated Between 1972 and 1991 at
a German Level I Trauma Center. Journal of Trauma 1995, 38, 70-77.
[0078] 9. J. Coalson, Pathology of Sepsis, Septic Shock, and
Multiple Organ Failure. In New Horizons: Multiple Organ Failure, D.
J. Bihari and F. B. Cerra, (Eds). Society of Critical Care
Medicine, Fullerton, Calif., 1986, pp. 27-59. [0079] 10. F. B.
Cerra, Multiple Organ Failure Syndrome. In New Horizons: Multiple
Organ Failure, D. J. Bihari and F. B. Cerra, (Eds). Society of
Critical Care Medicine, Fullerton, Calif., 1989, pp. 1-24. [0080]
11. R. Muller-Suur, and C. Muller-Suur. Glomerular filtration and
tubular secretion of MAG.sub.3 in rat kidney. Journal of Nuclear
Medicine 1989, 30, 1986-1991). [0081] 12. P. D. Dollan, E. L.
Alpen, and G. B. Theil. A clinical appraisal of the plasma
concentration and endogenous clearance of creatinine. American
Journal of Medicine 1962, 32, 65-79. [0082] 13. J. B. Henry (Ed).
Clinical Diagnosis and Management by Laboratory Methods, 17th
Edition, W. B. Saunders, Philadelphia, Pa., 1984. [0083] 14. F.
Roch-Ramel, K. Besseghir, and H. Murer. Renal excretion and tubular
transport of organic anions and cations. In Handbook of Physiology,
Section 8, Neurological Physiology, Vol. II, E. E. Windhager,
Editor, pp. 2189-2262. Oxford University Press: New York, 1992
[0084] 15. G. Ekanoyan and N. W. Levin. In Clinical Practice
Guidelines for Chronic Kidney Disease: Evaluation, Classification,
and Stratification (K/DOQI). National Kidney Foundation:
Washington, D.C. 2002, pp. 1-22. [0085] 16. D. L. Nosco and J. A.
Beaty-Nosco. Chemistry of technetium radiopharmaceuticals 1:
Chemistry behind the development of technetium-99m compounds to
determine kidney function. Coordination Chemistry Reviews 1999,
184, 91-123. [0086] 17. P. L. Choyke, H. A. Austin, and J. A.
Frank. Hydrated clearance of gadolinium-DTPA as a measurement of
glomerular filtration rate. Kidney International 1992, 41,
1595-1598. [0087] 18. N. Lewis, R. Kerr, and C. Van Buren.
Comparative evaluation of urographic contrast media, inulin, and
.sup.99mTc-DTPA clearance methods for determination of glomerular
filtration rate in clinical transplantation. Transplantation 1989,
48, 790-796). [0088] 19. W. N. Tauxe. Tubular Function. In Nuclear
Medicine in Clinical Urology and Nephrology, W. N. Tauxe and E. V.
Dubovsky, Editors, pp. 77-105, Appleton Century Crofts: East
Norwalk, 1985. [0089] 20. A. R. Fritzberg et al.
Mercaptoacetylglycylglycyglycine. Journal of Nuclear Medicine 1986,
27, 111-120. [0090] 21. Rajagopalan, R. et al. Quinoline ligands
and metal complexes for diagnosis and therapy. U.S. Pat. No. 2001;
6,277,841. [0091] 22. Rabito, C. Fluorescent agents for real-time
measurement of organ function. U.S. Pat. No. 2002; 6,440,389.
[0092] 23. M. F. Tweedle, X. Zhang, M. Fernandez, P. Wedeking, A.
D. Nunn, A. D. and H. W. Strauss. A noninvasive method for
monitoring renal status as bedside. Investigative Radiology 1997,
32, 802-805. [0093] 24. J. R. Lacowicz. Energy transfer. In
Principles of Fluorescence Spectroscopy, pp. 303-339. Plenum: New
York, N.Y., 1983. [0094] 25. A. Abusaleh and Meares, C. F.
Excitation and deexcitation process in lanthanide chelates bearing
aromatic side chains. Photochemistry and Photobiology 1984, 39(6),
763-769. [0095] 26. Gunnlaugsson, T., Parker, D. Luminescent
europium tetraazamacrocyclic complexes with wide range pH
sensitivity. Chemical Communications 1998, 511-512. [0096] 27.
Chen, J., Selvin, P. R. Thiol-reactive luminescent chelates of
terbium and europium. Bioconjugate Chemistry 1999, 10(2), 311-315.
[0097] 28. Wenzel, T. G. et al. "Bifunctional" chelating agents for
binding metal ions to proteins. Radioimmunoimaging and
Radioimmunotherapy 1983, 185-196. [0098] 29. Chang, C. H et al.
Bifunctional chelating agents: linking radiometals to biological
membranes. Applied Nuclear and Radiochemistry 1982, 103-114. [0099]
30. Ozaki, H. et al. Sensitization of europium(III) luminescence by
DTPA derivatives. Chemistry Letters 2000, 312-313. [0100] 31.
Geraldes, C. F. G. C. et al. Preparation, physicochemical
characterization, and relaxometry studies of various
gadolinium(III)-DTPA-bis(amide) derivatives as potential magnetic
resonance contrast agents. Magnetic Resonance Imaging 1995, 13(3),
401-420. [0101] 32. Konings, M. S. et al. Gadolinium complexation
by a new diethylenetriaminepentaacetic acid ligand. Amide oxygen
coordination. Inorganic Chemistry 1990, 29(8), 1488-1491. [0102]
33. Amedio, J. C. et al. A practical manufacturing synthesis of
1-(R)-hydroxymethyl-DTPA: an important intermediate in the
synthesis of MRI contrast agents. Synthetic Communications 1999,
29(14), 2377-2391. [0103] 34. Pickersgill, I. F. and Rapoport, H.
Preparation of functionalized, conformationally constrained DTPA
anlogues from L- or D-serine and trans-4-hydroxyproline.
Hydroxymethyl substituents on the central acetic acid and on the
backbone. Journal of Organic Chemistry 2000, 65, 4048-4057. [0104]
35. Achilefu, S., and Srinivasan, A. Methods for incorporating
metal chelators at carboxyl-terminal site of peptides. PCT
International Application 2001, WO 01/52898. [0105] 36. Achilefu,
S. et al. A new method for the synthesis of tri-tert-butyl
diethylenetriamine-pentaacetic acid and its derivatives. Journal of
Organic Chemistry 2000, 65(5), 1562-1565. [0106] 37. Muller et al.
Eds, Medical Optical Tomography, SPIE Volume IS11, 1993. [0107] 38.
R. B. Dorshow et al. Non-Invasive Fluorescence Detection of Hepatic
and Renal Function, Bull. Am. Phys. Soc. 1997, 42, 681. [0108] 39.
R. B. Dorshow et al. Monitoring Physiological Function by Detection
of Exogenous Fluorescent Contrast Agents. In Optical Diagnostics of
Biological Fluids IV, A. Priezzhev and T. Asakura, Editors,
Proceedings of SPIE 1999, 3599, 2-8). [0109] 40. C. E. Speicher.
The right test: A physician's guide to laboratory medicine, W. B.
Saunders, Philadelphia, Pa., 1989).
* * * * *