Modified PSMA ligands and uses related thereto

Abstract

The instant invention provides reagents and methods for diagnosis, detection and treatment of cancers (for example, prostate cancers). In particular, the invention provides methods to generate various functionalized PSMA ligands, and their uses in diagnosis, detection, imaging, and treatment of prostate cancers, especially those overexpressing PSMA.

1 . A compound represented in the general formula (Ia):
 wherein:   
       
         
           
           
               
               
           
         
         X represents O or S; 
         Y represents: 
       
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R1 and R3, independently for each occurrence, represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         D 1  represents O or S; 
         D 2  represents N 3 , SH 2 , NH 2 , or NO 2 ; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         2 . A compound represented in the general formula (Ib): 
       
         
           
           
               
               
           
         
         wherein: 
         X represents O or S; 
         Y represents: 
       
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R1 and R3, independently for each occurrence, represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         D 1  represents O or S; 
         D 2  represents N 3 , SH 2 , NH 2 , or NO 2 ; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         3 . A compound represented in the general formula (Id):
 wherein:   
       
         
           
           
               
               
           
         
         X represents O or S; 
         Y represents: 
       
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R1 and R3, independently for each occurrence, represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         D 1  represents O or S; 
         D 2  represents N 3 , SH 2 , NH 2 , or NO 2 ; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         4 . A compound represented in the general formula (Ie):
 wherein:   
       
         
           
           
               
               
           
         
         X represents O or S; 
         Y represents: 
       
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R1 and R3, independently for each occurrence, represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         D 1  represents O or S; 
         D 2  represents N 3 , SH 2 , NH 2 , or NO 2 ; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         5 . A compound represented in the general formula (If):
 wherein:   
       
         
           
           
               
               
           
         
         X represents O or S; 
         Y represents: 
       
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R1 and R3, independently for each occurrence, represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         D 1  represents O or S; 
         D 2  represents N 3 , SH 2 , NH 2 , or NO 2 ; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         6 - 10 . (canceled) 
     
     
         11 . A compound represented in the general formula (Ic): 
       wherein: 
       
         
           
           
               
               
           
         
         X represents O or S; 
         Y represents: 
       
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R1 and R3, independently for each occurrence, represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         D 1  represents O or S; 
         D 2  represents N 3 , SH 2 , NH 2 , or NO 2 ; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         12 - 16 . (canceled) 
     
     
         17 . A compound represented in the general formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R3 represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         m is 1, 2, 3 or 4; and, 
         n is 0, 1, 2 or 3. 
       
     
     
         18 . A compound represented in the general formula (III):
 wherein:   
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R3 represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         R5 represents H or a lower alkyl; 
         m is 1, 2, 3 or 4; and 
         n is 0, 1, 2 or 3. 
       
     
     
         19 . A compound represented in the general formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R3 represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, —(CH 2 ) m -aryl, -alkyl-CO 2 R4, -alkenyl-CO 2 R4, -cycloalkyl-CO 2 R4, -cycloalkenyl-CO 2 R4 or -aryl-CO 2 R4; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         R5 represents H or a lower alkyl; 
         m is 1, 2, 3 or 4; and 
         n is 0, 1, 2 or 3. 
       
     
     
         20 . A compound represented in the general formula (V):
 wherein   
       
         
           
           
               
               
           
         
         R represents a chelate ligand, a fluorescence tag, or a cytotoxic moiety; 
         R2 and R4, independently for each occurrence, represent hydrogen, a lower alkyl, or a pharmaceutically acceptable salt; 
         R6 represents an alkyl, an alkenyl, a cycloalkyl, a cycloalkenyl, an aryl, or —(CH 2 ) m -aryl; 
         and, 
         m is 1, 2, 3 or 4. 
       
     
     
         21 - 42 . (canceled) 
     
     
         43 . A pharmaceutical composition comprising the compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         44 . A method for detecting or imaging PSMA (prostate-specific membrane antigen)-expressing cells in a patient, comprising:
 (a) contacting the patient with a modified PSMA ligand of  claim 1 ;   (b) detecting the modified PSMA ligand, thereby detecting PSMA-expressing cells in the patient.   
     
     
         45 - 51 . (canceled) 
     
     
         52 . A method for determining the abundance of PSMA in a sample, comprising:
 (a) contacting the sample with the modified PSMA ligand of  claim 1 ;   (c) determining the abundance of the modified PSMA ligands bound to PSMA, or the abundance of the modifying group of said bound ligands, thereby determining the abundance of PSMA in said sample.   
     
     
         53 . (canceled) 
     
     
         54 . A method to diagnose, in a test sample, the presence of a prostate disease condition associated with PSMA-overexpression, comprising:
 (a) using the method of  claim 52 , determining the abundance of PSMA in the test sample and a normal control sample;   (b) comparing the level of abundance of PSMA in the test sample and the control sample;   wherein statistically significant higher levels of abundance of PSMA in the test sample indicates the presence of a prostate disease condition associated with PSMA-overexpression.   
     
     
         55 . A method to treat a patient suffering from a disease condition associated with PSMA-overexpression, comprising administering to the patient an effective amount of modified PSMA ligand of  claim 1 . 
     
     
         56 - 61 . (canceled) 
     
     
         62 . A kit for diagnosing or detecting the presence of a PSMA, comprising:
 (a) at least one of the modified PSMA ligand of  claim 1 ;   (b) an instruction.   
     
     
         63 - 65 . (canceled) 
     
     
         66 . A method to treat a patient suffering from a disease condition associated with PSMA-overexpression, comprising administering to the patient an effective amount of IRDye78.