Heterodimers of glutamic acid

Abstract

Compounds of Formula (Ia)wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′,Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)pY is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)pZ is H or C1-C4 alkyl,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 compound comprising a prostate-specific membrane antigen (PSMA)-binding moiety having the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein the PSMA-binding moiety is conjugated to a metal chelating moiety; and 
       wherein each Z is, independently, H or C 1 -C 4  alkyl. 
     
     
         69 . The compound of  claim 68 , wherein the compound inhibits PSMA in an vitro cell binding assay at an IC 50  of about 10 nM or less. 
     
     
         69 . The compound of  claim 68 , wherein the compound inhibits PSMA in an vitro cell binding assay at an IC 50  of about 4 nM or less. 
     
     
         70 . The compound of  claim 68 , wherein the compound inhibits PSMA in an vitro cell binding assay at an IC 50  of about 2 nM or less. 
     
     
         71 . The compound of  claim 68 , wherein the compound inhibits PSMA positive human prostate tumor in a mouse xenograft assay. 
     
     
         72 . The compound of  claim 68 , wherein each Z is H. 
     
     
         73 . The compound of  claim 68 , wherein the compound further comprises a radionuclide. 
     
     
         74 . The compound of  claim 73 , wherein the PSMA-binding moiety is conjugated to the metal chelating moiety by a tether. 
     
     
         75 . The compound of  claim 73 , wherein the radionuclide is a therapeutic radionuclide. 
     
     
         76 . The compound of  claim 73 , wherein the radionuclide is an imaging radionuclide. 
     
     
         77 . The compound of  claim 76 , wherein the radionuclide is selected from technetium-99m, rhenium-186, rhenium-188, radio copper, or combinations thereof. 
     
     
         78 . The compound of  claim 68 , characterized in that uptake in a tumor of a mouse bearing a PSMA positive LNCaP xenograft is about 17±6% ID/g after 1 hour. 
     
     
         79 . The compound of  claim 68 , wherein the compound is prepared from a glutamate-urea-lysine moiety of structure: 
       
         
           
           
               
               
           
         
       
     
     
         80 . A method for treating a PSMA-associated disease in a subject comprising administering a compound comprising a glutamate-urea-lysine moiety conjugated to a metal chelating moiety and a radionuclide. 
     
     
         81 . The method of  claim 80 , wherein the glutamate-urea-lysine moiety is of the structure: 
       
         
           
           
               
               
           
         
       
       wherein each Z, independently, is H or C 1 -C 4  alkyl. 
     
     
         82 . The method of  claim 81 , wherein each Z is H. 
     
     
         83 . The method of  claim 82 , wherein the radionuclide is selected from technetium-99m, rhenium-186, rhenium-188, radio copper, or combinations thereof. 
     
     
         84 . A process for producing a PSMA-binding compound comprising a glutamate-urea-lysine 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. 
     
     
         85 . The process of  claim 84 , wherein the glutamate-urea-lysine PSMA-binding moiety is of the structure: 
       
         
           
           
               
               
           
         
       
       wherein each Z, independently, is H or C 1 -C 4  alkyl. 
     
     
         86 . A method of treating a patient with prostate cancer, the method comprising a step of: 
       administering a therapeutically effective amount of a glutamate-urea-lysine prostate specific membrane antigen (PSMA)-binding moiety, wherein the glutamate-urea-lysine PSMA-binding moiety comprises a structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein each Z, independently, is H or C 1 -C 4  alkyl.