Heterodimers of glutamic acid

Abstract

R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 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 for treating a PSMA-associated disease in a subject comprising administering a compound comprising glutamate-urea-lysine conjugated to a metal chelating moiety and a radionuclide. 
     
     
         69 . The method of  claim 68 , wherein the PSMA-associated disease is a prostate cancer or colorectal cancer. 
     
     
         70 . The method of  claim 68 , wherein the cancer is prostate cancer. 
     
     
         71 . The method of  claim 70 , wherein the compound is of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R is a C 6 -C 12  substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C 1 -C 6  substituted or unsubstituted alkyl or —NR′R′; 
         Q is C(O), O, S, S(O) 2 , C(O) 2  (CH 2 ) p ; 
         Y is C(O), O, S, S(O) 2 , C(O) 2  (CH 2 ) p ; 
         Z is H or C 1 -C 4  alkyl; 
         m is 0, 1, 2, 3, 4 or 5; 
         n is 0, 1, 2, 3, 4, 5 or 6; 
         n′ is 0, 1, 2, 3, 4, 5 or 6; 
         p is 0, 1, 2, 3, 4, 5 or 6; 
         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; 
         further wherein at least one of R or R′ is a substituted or unsubstituted C 6 -C 12  heteroaryl. 
       
     
     
         72 . The method of  claim 68 , wherein the compound provides an analgesic effect. 
     
     
         73 . The method of  claim 68 , wherein the compound is prepared from a glutamate-urea-lysine moiety of structure: 
       
         
           
           
               
               
           
         
       
     
     
         74 . The process of  claim 73  wherein the PSMA-binding compound comprises a metal chelating moiety and a radionuclide. 
     
     
         75 . A kit comprising: (i) a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a metal chelating moiety, and (ii) a radionuclide. 
     
     
         76 . The kit of  claim 75 , wherein the radionuclide is appropriate for the detection or treatment of prostate cancer. 
     
     
         77 . The kit of  claim 76 , wherein the radionuclide is selected from technetium-99m, rhenium-186, rhenium-188, or combinations thereof. 
     
     
         78 . A method of using the kit of  claim 75  for the production of a PSMA-binding compound, wherein the PSMA-binding compound comprises a glutamate-urea-lysine PSMA-binding moiety conjugated to a radionuclide chelate complex. 
     
     
         79 . A process for producing a PSMA-binding compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a radionuclide chelate complex, the process comprising chelating a radionuclide with a compound comprising a glutamate-urea-lysine PSMA-binding moiety conjugated to a metal chelating moiety. 
     
     
         80 . A prostate-specific membrane antigen (PSMA)-binding moiety comprising a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         characterized in that the PSMA-binding moiety binds to a PSMA positive human prostate tumor in a mouse xenograft assay or in vitro cell binding assay at an IC 50  of about 10 nM or less; and 
         wherein each Z is, independently, H or C 1 -C 4  alkyl. 
       
     
     
         81 . The PSMA-binding moiety of  claim 80 , wherein the PSMA-binding moiety binds to a PSMA positive human prostate tumor in a mouse xenograft assay or in vitro cell binding assay at an IC 50  of about 4 nM or less. 
     
     
         82 . The PSMA-binding moiety of  claim 81 , wherein the PSMA-binding moiety binds to a PSMA positive human prostate tumor in a mouse xenograft assay or in vitro cell binding assay at an IC 50  of about 2 nM or less.