18f - tagged inhibitors of prostate specific membrane antigen (psma) and their use as imaging agents for prostate cancer

Abstract

The present invention generally relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers and imaging agents for various disease states of prostate cancer.

1 . A precursor or a solvate of the compound of Formula I: 
       
         
           
           
               
               
           
         
         with: 
       
       
         
           
                 
                 
               
                     
                 
                   i, j 
                   0, 1 
                 
                   m 
                   1-5 
                 
                   n 
                   0-3 
                 
                   R 
                   H, CH 3   
                 
                   AS 
                   Natural or non-natural amino acid, 
                 
                   Z: 
                   —CO 2 H, —SO 2 H, —SO 3 H, —SO 4 H, —PO 2 H,  
                 
                     
                   —PO 3 H, —PO 4 H 2   
                 
                   X: 
                   Naphthyl, Phenyl, Biphenyl, Indolyl, Benzothiazolyl, 
                 
                     
                   Quinoyl 
                 
                   Y: 
                   Aryl, Alkylaryl, Cyclopentyl, Cyclohexyl, Cycloheptyl,  
                 
                     
                   N-Piperidyl and N-methylated Piperidyl salt 
                 
                     
                 
                     18 F-Tag: 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   With: 
                 
                     
                   x = 1-5 
                 
                     
                   Carbohydrate: 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl or aryl group 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl or aryl group 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl or aryl group 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl or aryl group 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl or aryl group 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl or aryl group 
                 
                     
                 
                     
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                     
                   R 1 : Any alkyl, aryl or arylalkyl linker 
                 
                     
                   R 2 : Any alkyl, or aryl group. 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . The precursor or the solvate of  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         wherein the linker A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein R 1 =(Glu)-(Urea)-(Lys) and R 2 =(Linker B) m - 18 F Tag, m=1-5, 
         and linker B is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The precursor or the solvate of  claim 1 , wherein the compound is selected from the following 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The precursor or the solvate of  claim 1 , wherein the non-natural amino acid has the formula 
       
         
           
           
               
               
           
         
         and R′=H, CO 2 H, CH 2 CO 2 H, C 2 H 4 CO 2 H, CH(CO 2 H) 2 , CH(CH 2 CO 2 H) 2 , CH(CO 2 H)(CH 2 CO 2 H), CH 2 CH(CO 2 H) 2 , SO 3 H; 
         o=1-3; R=H, CH 3 . 
       
     
     
         5 . The precursor or the solvate of  claim 1 , wherein R 1  is selected from the group consisting of: methyl, 2-ethyl, 3-propyl, 2-,3-,4-phenyl, 2-,3-,4-phenylmethyl, and 2,3-,4-phenylpropyl. 
     
     
         6 . The precursor or the solvate of  claim 1 , wherein R 2  is selected from the group consisting of methyl, isopropyl, tert-butyl, phenyl, and 1-naphtyl. 
     
     
         7 . A pharmaceutical composition comprising the precursor or the solvate of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         8 . A method of imaging a prostate region in a patient comprising the steps of:
 (i) administering to a patient a diagnostically effective amount of the precursor or the solvate of  claim 1 ,   (ii) exposing the prostate region of the patient to a scanning device to detect the 18F-tag; and   (iii) obtaining an image of the prostate region of the patient by the scanning device.