Labeled inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer

Abstract

The present invention generally relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of prostate cancer. Thus, the present invention concerns compounds that are represented by the general Formulae (Ia) or (Ib).

What is claimed is: 
     
         1 . A compound of Formula (Ia) or (Ib): 
       
         
           
           
               
               
           
         
         with: 
       
       
         
           
                 
                 
               
                     
                 
                   n: 
                   0,1 
                 
                   m: 
                   1,2,3,4 
                 
                   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 (=2,3-benzopyrrolyl), 
                 
                     
                   Benzothiazolyl 
                 
                   Y: 
                   Aryl, Alkylaryl, Cyclopentyl, Cyclohexyl, Cycloheptyl 
                 
                   Che- 
                   1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid 
                 
                   lator: 
                   (=DOTA), 
                 
                     
                   N,N″-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- 
                 
                     
                   N,N″-diacetic acid (=HBED-CC), 
                 
                     
                   1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 
                 
                     
                   2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid 
                 
                     
                   (NODAGA), 
                 
                     
                   2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- 
                 
                     
                   yl)pentanedioic acid 
                 
                     
                   (DOTAGA), 
                 
                     
                   1,4,7-triazacyclononane phosphinic acid (TRAP), 
                 
                     
                   1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic 
                 
                     
                   acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 
                 
                     
                   3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-1(15),11,13-triene-3,6,9- 
                 
                     
                   triacetic acid (=PCTA), 
                 
                     
                   N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5- 
                 
                     
                   aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N- 
                 
                     
                   hydroxysuccinamide (DFO), 
                 
                     
                   Diethylenetriaminepentaacetic acid (DTPA) 
                 
                     
                   Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA) 
                 
                     
                   1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A) 
                 
                     
                   p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA) 
                 
                     
                   1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M) 
                 
                     
                   2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B) 
                 
                     
                   1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA) 
                 
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . The compound of  claim 1  having the structure R′-Linker-R with R′=DOTA and R=.Glu-Urea-Lys: 
       
         
           
           
               
               
           
         
         wherein the linker is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A radiolabeled compound comprising the compound of  claim 1 . 
     
     
         5 . A metal complex comprising a radionuclide and a compound of  claim 1 . 
     
     
         6 . The metal complex of  claim 5 , wherein the radionuclide is  111 In,  90 Y,  68 Ga,  177 Lu,  99m Tc,  64 Cu,  153 Gd,  155 Gd,  157 Gd,  213 Bi,  225 Ac or Fe. 
     
     
         7 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier. 
     
     
         8 . The compound of  claim 1  for use in a method of imaging in a patient. 
     
     
         9 . The compound of  claim 1  for use in a method of diagnosing prostate cancer and/or metastasis thereof. 
     
     
         10 . The compound of  claim 1  for use in a method of treating prostate cancer and/or metastasis thereof. 
     
     
         11 . A pharmaceutical composition comprising the metal complex of  claim 5 , or a pharmaceutically acceptable salt, or ester thereof, and a pharmaceutically acceptable carrier. 
     
     
         12 . The metal complex of  claim 5  for use in a method of imaging in a patient. 
     
     
         13 . The metal complex of  claim 5  for use in a method of diagnosing prostate cancer and/or metastasis thereof. 
     
     
         14 . The metal complex of  claim 5  for use in a method of treating prostate cancer and/or metastasis thereof.