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. A method of making a human prostate specific membrane (PSMA)-binding compound, or a pharmaceutically acceptable salt thereof, comprising the use of an intermediate having the formula:
wherein each Z is independently hydrogen or C 1 -C 4 alkyl, and
wherein the human PSMA-binding compound comprises at least one of (i) a chelator, (ii) a radionuclide, or (iii) a radiohalogen.
2. The method of claim 1 , wherein the PSMA-binding compound comprises a radionuclide.
3. The method of claim 2 , wherein the radionuclide is selected from the group consisting of technetium-99m, rhenium-186, and rhenium-188.
4. The method of claim 1 , wherein the PSMA-binding compound comprises a radiohalogen.
5. The method of claim 4 , wherein the radiohalogen is selected from the group consisting of: I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
6. The method of claim 1 , wherein each Z is independently hydrogen.
7. The method of claim 1 , wherein each Z is independently C 1 -C 4 alkyl.
8. A method of making a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, comprising the use of an intermediate having the formula:
wherein:
R is a C 6 -C 12 substituted or unsubstituted aryl, a C 3 -C 12 substituted or unsubstituted heteroaryl, a C 1 -C 6 substituted or unsubstituted alkyl, or NR′R′;
each R′ is independently hydrogen, a C 6 -C 12 substituted or unsubstituted aryl, a C 3 -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 3 -C 12 heteroaryl, or COOZ;
each Z is independently hydrogen or C 1 -C 4 alkyl;
Q is NR′;
Y is C(O), O, NR′, S(O) 2 , C(O) 2 , or (CH 2 ) p ;
m is 4;
n is 0;
p is 0, 1, 2, 3, 4, 5 or 6; and
further wherein:
(i) at least one of R or R′ is a C 6 -C 12 aryl or C 3 -C 12 heteroaryl substituted with a halogen, or
(ii) at least one of R or R′ is a C 3 -C 12 heteroaryl.
9. The method of claim 8 , wherein:
R is a C 6 -C 12 substituted or unsubstituted aryl;
Y is C(O) or CH 2 .
10. The method of claim 8 , wherein R is a phenyl moiety substituted with a halogen.
11. The method of claim 10 , wherein the halogen is a radiohalogen.
12. The method of claim 10 , wherein the radiohalogen is selected from the group consisting of: I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
13. The method of claim 8 , wherein the compound is:
wherein X is selected from the group consisting of halogen, radiohalogen, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18.
14. The method of claim 8 , wherein the compound is of the following structure:
wherein X is selected from halogen and hydrogen.
15. The method of claim 14 , wherein the halogen is a radiohalogen.
16. The method of claim 14 , wherein X is selected from the group consisting of: I, Br, Cl, F, I-123, I-125, I-131, I-124, Br-75, Br-77, F-18, and hydrogen.
17. The method of claim 14 , wherein X is I-123, I-125, I-131, or I-124.
18. The method of claim 8 , wherein the compound is of the following structure:
wherein X is selected from halogen and hydrogen.
19. The method of claim 18 , wherein the halogen is a radiohalogen.
20. The method of claim 18 , wherein X is selected from the group consisting of: I, Br, Cl, F, I-123, I-125, I-131, I-124, Br-75, Br-77, F-18, and hydrogen.
21. The method of claim 18 , wherein X is I-123, I-125, I-131, or I-124.
22. The method of claim 8 , wherein each Z is independently hydrogen.
23. The method of claim 8 , wherein each Z is independently C 1 -C 4 alkyl.
24. A method of making a compound of the following structure:
or a pharmaceutically acceptable salt thereof, comprising the use of an intermediate having the formula:
wherein:
X is selected from hydrogen and halogen; and
each Z is independently hydrogen or C 1 -C 4 alkyl.
25. The method of claim 24 , wherein the halogen is a radiohalogen.
26. The method of claim 24 , wherein X is selected from the group consisting of: I, Br, Cl, F, I-123, I-125, I-131, I-124, Br-75, Br-77, and F-18, and hydrogen.
27. The method of claim 24 , wherein X is I-123, I-125, I-131, or I-124.
28. The method of claim 24 , wherein the compound has the formula:
29. The method of claim 24 , wherein each Z is independently hydrogen.
30. The method of claim 24 , wherein each Z is independently C 1 -C 4 alkyl.