HETERODIMERS OF GLUTAMIC ACID
Compounds of Formula (Ia) wherein R is a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl or —NR′R′, Q is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Y is C(O), O, NR′, S, S(O) 2 , C(O) 2 (CH2)p Z is H or C 1 -C 4 alkyl, R′ is H, C(O), S(O) 2 , C(O) 2 , a C 6 -C 12 substituted or unsubstituted aryl, a C 6 -C 12 substituted or unsubstituted heteroaryl or a C 1 -C 6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C 6 -C 12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.
1 - 67 . (canceled)
68 . A method of tumor detection in a patient suffering from a disease, disorder, or condition, comprising administering a compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein R is a C 3 -C 12 heteroaryl substituted with a halogen;
each Z is independently hydrogen or C 1 -C 4 alkyl;
Q is NH;
Y is C(O), S(O) 2 , C(O) 2 , or (CH 2 ) p ;
m is 4;
n is 0; and
p is 0, 1, 2, 3, 4, 5 or 6; and
wherein the compound of Formula (I) is prepared via an intermediate having the formula:
69 . The method of claim 68 , wherein the disease, disorder, or condition is painful and sensory diabetic neuropathy, neuronal damage, prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral sclerosis, or diabetic neuropathy.
70 . The method of claim 69 , wherein the disease, disorder, or condition is colorectal cancer or prostate cancer.
71 . The method of claim 70 , wherein the disease, disorder, or condition is prostate cancer.
72 . The method of claim 68 , wherein Y is C(O).
73 . The method of claim 72 , wherein R is pyridinyl substituted with halogen.
74 . The method of claim 73 , wherein the halogen is a radiohalogen.
75 . The method of claim 74 , wherein the radiohalogen is selected from the group consisting of: I-123, I-124, I-125, I-131, Br-75, Br-77, and F-18.
76 . The method of claim 75 , wherein each Z is hydrogen.
77 . The method of claim 75 , wherein each Z is C 1 -C 4 alkyl.
78 . The method of claim 77 , wherein each Z is independently selected from t-butyl and methyl.
79 . The method of claim 75 , wherein the radiohalogen is F-18.
80 . The method of claim 79 , wherein the radiohalogen is at a position para to variable Y.
81 . The method of claim 68 , wherein the method comprises obtaining an image of one or more organs or tissues or both in the patient.
82 . The method of claim 81 , further comprising determining from the image an amount of PSMA which is present in the one or more organs or tissues or both in the patient.
83 . The method of claim 82 , wherein the one or more organs or tissues or both includes prostate tissue, kidney tissue, brain tissue, vascular tissue, or tumor tissue.
84 . A method of inhibiting prostate-specific membrane antigen (PSMA) in a subject suffering from a disease, disorder, or condition, comprising administering a compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein R is a C 3 -C 12 heteroaryl substituted with a halogen;
each Z is independently hydrogen or C 1 -C 4 alkyl;
Q is NH;
Y is C(O), S(O) 2 , C(O) 2 , or (CH 2 ) p ;
m is 4;
n is 0; and
p is 0, 1, 2, 3, 4, 5 or 6; and
wherein the compound of Formula (I) is prepared via an intermediate having the formula:
85 . The method of claim 84 , wherein the disease, disorder, or condition is painful and sensory diabetic neuropathy, neuronal damage, prostate cancer, schizophrenia, colorectal cancer, inflammation, amyotrophic lateral sclerosis, or diabetic neuropathy.
86 . The method of claim 85 , wherein the disease, disorder, or condition is colorectal cancer or prostate cancer.
87 . The method of claim 86 , wherein the disease, disorder, or condition is prostate cancer.
88 . The method of claim 84 , wherein Y is C(O).
89 . The method of claim 88 , wherein R is pyridinyl substituted with halogen.
90 . The method of claim 89 , wherein the halogen is a radiohalogen.
91 . The method of claim 90 , wherein the radiohalogen is selected from the group consisting of: I-123, I-124, I-125, I-131, Br-75, Br-77, and F-18.
92 . The method of claim 84 , wherein each Z is hydrogen.
93 . The method of claim 84 , wherein each Z is C 1 -C 4 alkyl.
94 . The method of claim 93 , wherein each Z is independently selected from t-butyl and methyl.
95 . The method of claim 91 , wherein the radiohalogen is F-18.
96 . The method of claim 95 , wherein the radiohalogen is at a position para to variable Y.