Ternary ligand complexes useful as radiopharmaceuticals

Details Ternary ligand complexes useful as radiopharmaceuticals Ternary ligand complexes useful as radiopharmaceuticals

1997-05-28

2002-06-11

Dees, Jose′ G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001770, C534S010000, C534S014000

Reexamination Certificate

active

06403054

ABSTRACT:

FIELD OF INVENTION
The present invention provides novel radiopharmaceuticals useful for imaging the heart, brain, lungs, liver or kidneys, kits useful for preparing the radiopharmaceuticals, and methods of imaging the heart, brain, lungs, liver or kidneys in a patient in need of such imaging.
BACKGROUND OF THE INVENTION
Radiopharmaceuticals form the chemical basis for the medical specialty of nuclear medicine, a group of techniques used for diagnosis and therapy of a variety of diseases. In vivo diagnostic information is obtained by intravenous injection of the radiopharmaceutical and determining its biological distribution using a gamma camera. The distribution usually takes a form that is organ or lesion specific. From the distribution of the radiopharmaceutical and its behavior over time, it is possible to obtain information about the presence, progression and state of a disease.
Radiopharmaceuticals useful for imaging the heart based on homoleptic Tc-99m-isonitrile complexes have been described by Jones et. al. in U.S. Pat. No. 4,452,774 and Bergstein et. al. in U.S. Pat. No. 4,988,827. Radiopharmaceuticals based on technetium-99m complexes of binary ligand systems have been described by Bergstein et. al. in U.S. Pat. No. 5,279,811 for imaging the brain, Kelly et. al. in U.S. Pat. No. 5,045,302 for imaging the heart, Nosco in U.S. Pat. No. 5,330,738 for imaging the kidneys, as well as others. A recent review of radiopharmaceuticals based on metal radionuclide complexes is provided by Jurisson et. al., Chem. Rev. 1993, 93, 1137.
The biological properties of metal radionuclide complexes are determined by their chemical and physical properties, such as lipophilicity and charge, as opposed to conjugates of a metal radionuclide complex and a biologically active molecule in which the biological properties of the conjugate are determined by the biologically active molecule. The chemical and physical properties of the complexes are determined by the ligand system used and the choice of the substituents on the ligand or ligands. Therefore, for any particular ligand system, the choice of substituents will control the biological properties of the complex and the ultimate utility as a radiopharmaceutical. An example of this effect is the fact that the Tc-99m complex of N,N′-1,2-ethylenediyl-bis-L-cysteine diethyl ester (ECD) is a brain imaging agent while the Tc-99m complex of N,N′-1,2-ethylenediyl-bis-L-cysteine (EC), in which the two ester groups are replaced by carboxylic acid groups, is a renal imaging agent.
For metal radionuclide complexes with a homoleptic ligand system, such as the Tc-99m-isonitriles, Tc(CNR)
6
+
, a change in the substituent, R, is replicated six times, making it difficult to precisely control the chemical and physical properties of the complexes. For complexes comprised of a binary ligand system the substituents can be independently changed on the two types of ligands, giving somewhat better control. Superior control of the properties should be achievable for complexes comprised of a ternary ligand system in which the substituents on the three types of ligands can be independently varied. However, as the order of the ligand system increases the probability of forming complexes of one single stoichiometry is expected to decrease.
Archer et. al., European Patent Application 90914225.9 describes a series of technetium-99m complexes having a ternary ligand system comprised of a hydrazido or diazenido ligand, a phosphine ligand and a halide, in which the substituents on the hydrazido or diazenido ligand and those on the phosphine ligand can be independently varied; the halide ligand has no substituents. This disclosure does not teach or suggest how to achieve the superior control of biological properties that would result from a ternary ligand system in which the substituents on the three types of ligands can be independently varied.
Another important consideration for any radiopharmaceutical is specific activity, the amount of the radiopharmaceutical present in a dosage to the amount of unlabeled excess ligand or ligands used to synthesize the radiopharmaceutical. High specific activity is required when one or more of the ligands are either potentially toxic, very expensive to manufacture, or may compete with the radiopharmaceutical for a binding site in vivo, to minimize the amount of excess ligand in the dosage administered. The radiopharmaceuticals described by Archer et. al. are formed in low specific activity. Therefore, there remains a need for new radiopharmaceuticals comprised of a ternary ligand system for which the substituents on all three ligands can be independently varied and that can be formed in high specific activity.
SUMMARY OF THE INVENTION
The present invention provides novel radiopharmaceuticals useful for imaging the heart, brain, lungs, liver or kidneys, kits useful for preparing the radiopharmaceuticals, and methods of imaging the heart, brain, lungs, liver or kidneys in a patient in need of such imaging. The radiopharmaceuticals are comprised of technetium or rhenium radionuclide complexes of a ternary ligand system: one hydrazido or diazenido ligand, one aminoalcohol ligand, and one pi-acid ligand selected from phosphines, arsines, and imine nitrogen-containing heterocycles. The radiopharmaceuticals can be formed in high specific activity, are stable in vitro, and their biological properties can be tailored by the selection of substituents on the three ligands.
DETAILED DESCRIPTION OF THE INVENTION
[1] In a first embodiment, the present invention provides a novel radiopharmaceutical of the formula:
 ML
1
L
2
L
3
or a pharmaceutically acceptable salt thereof, wherein,
M is
99m
Tc,
186
Re or
188
Re;
L
1
is a ligand having the formula ═N—NR
1
R
2
or ═N
+
═NR
1
;
R
1
is selected from the group: aryl substituted with 0-3 R
3
, 5-10 membered heterocycle containing from 1-4 heteroatoms selected from N, O, and S and substituted with 0-3 R
3
, C
1
-C
10
alkyl substituted with 0-3 R
3
, and C
3-13
cycloalkyl substituted with 0-3 R
3
;
R
2
is selected from the group: hydrogen, aryl substituted with 0-3 R
3
, 5-10 membered heterocycle containing from 1-4 heteroatoms selected from N, O, and S and substituted with 0-3 R
3
, C
1
-C
10
alkyl substituted with 0-3 R
3
, and C
3-13
cycloalkyl substituted with 0-3 R
3
;
R
3
is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF
3
, —CN, —CO
2
R
4
, —C(═O)R
4
, —C(═O)N(R
4
)
2
, —CH
2
OR
4
, —OC(═O)R
4
, —OC(═O)OR
4
, —OR
4
, —OC(═O)N(R
4
)
2
, —NR
4
C(═O)R
4
, —NR
4
C(═O)OR
4
, —NR
4
C(═O)N(R
4
)
2
, —NR
4
SO
2
N(R
4
)
2
, —NR
4
SO
2
R
4
, —SO
3
H, —SO
2
R
4
, —S(═O)R
4
, —SO
2
N(R
4
)
2
, —N(R
4
)
2
, —N(R
4
)
3
+
, —NHC(═NH)NHR
4
, —C(═NH)NHR
4
, ═NOR
4
, —NO
2
, —C(═O)NHOR
4
, —C(═O)NHN(R
4
)
2
, —OCH
2
CO
2
H, 2-(1-morpholino)ethoxy, C
1
-C
10
alkyl substituted with 0-3 R
5
, C
2
-C
10
alkenyl substituted with 0-3 R
5
, C
3
-C
6
cycloalkyl substituted with 0-3 R
5
, aryl substituted with 0-3 R
5
, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from N, O, and S and substituted with 0-3 R
5
;
R
4
is independently selected at each occurrence from the group: H, C
1
-C
10
alkyl substituted with 0-3 R
5
, C
2
-C
10
alkenyl substituted with 0-3 R
5
, C
3
-C
6
cycloalkyl substituted with 0-3 R
5
, aryl substituted with 0-3 R
5
, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from N, O, and S and substituted with 0-3 R
5
;
R
5
is independently selected at each occurrence from the group: ═O, F, Cl, Br, I, —CF
3
, —CN, —CO
2
R
6
, —C(═O)R
6
, —C(═O)N(R
6
)
2
, —CH
2
OR
6
, —OC(═O)R
6
, —OC(═O)OR
6
, —OR
6
, —OC(═O)N(R
6
)
2
, —NR
6
C(═O)R
6
, —NR
6
C(═O)OR
6
, —NR
6
C(═O)N(R
6
)
2
, —NR
6
SO
2
N(R
6
)
2
, —NR
6
SO
2
R
6
, —SO
3
H, —SO
2
R
6
, —S(═O)R
6
, —SO
2
N(R
6
)
2
, —N(R
6
)
2
, —N(R
6
)
3
+
, —NHC(═NH)NHR
6
, —C(═NH)N

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