Chelated PSMA Inhibitors

Abstract

Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided are compositions including a compound of Formula (I) together with a pharmaceutically acceptable carrier, and methods for imaging prostate cancer cells.

1 . A compound of Formula (I*) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 L 1  and L 2  are independently a divalent linking group; 
 R is a chelating agent optionally chelating a therapeutic radioisotope or a PET-active, SPECT-active, or MRI-active radioisotope; 
 each R 1  and R 2  are independently hydrogen, C 1 -C 6  alkyl or a protecting group; 
 R 3  represents hydrogen; and 
 X is an albumin bind moiety. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein the compound is of the formula (Ie): 
       
         
           
           
               
               
           
         
         wherein
 x is 0, 1, 2, 3, 4, 5 or 6; and 
 y is 2, 3, 4, 5 or 6. 
 
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The compound of  claim 1  that is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         15 . A method for imaging one or more prostate cancer cells in a patient comprising administering to the patient a compound of  claim 1 . 
     
     
         16 . A method for preparing a compound of  claim 1  or pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         the method comprising
 reacting an azide- or alkyne-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope with a azide- or alkyne-modified PMSA inhibitor of formula (IV) 
 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         
           
             comprises an azide or alkyne; 
             each R 1  and R 2  are independently hydrogen, C 1 -C 6  alkyl or a protecting group; and 
             X is an albumin bind moiety, 
           
         
         provided that when A C1  comprises an azide functional group it is reacted with an alkyne-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope, and when A C1  comprises an alkyne functional group it is reacted with an azide-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope. 
       
     
     
         17 . The method of  claim 16 , wherein the azide- or alkyne-modified PMSA inhibitor has the structure of Formula (IVa): 
       
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 16 , wherein the alkyne-modified PMSA inhibitor has the structure of Formula (IVh): 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 16 , wherein the alkyne-modified PMSA inhibitor has the structure of Formula (IVi): 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of any of  claim 16 , wherein the azide- or alkyne-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope of embodiment IV 1  has the structure of Formula (V):
   R-L 1B -A C2    (V)
   wherein
 R is a chelating agent optionally associated with a PET-active or therapeutic radioisotope; 
 L 1B  is a divalent linker; and 
 A C2  is an azide or alkyne. 
   
     
     
         21 . The method of any of  claim 16 , wherein the azide- or alkyne-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope of embodiment IV 1  has the structure of Formula (Va): 
       
         
           
           
               
               
           
         
         wherein
 R is a chelating agent optionally associated with a PET-active or therapeutic radioisotope, 
 A C2  is an azide or alkyne, and 
 x is 0, 1, 2, 3, 4, 5 or 6. 
 
       
     
     
         22 . The method of  claim 21 , wherein R comprises DOTA, NOTA, PCTA, DO3A, HBED, NODAG, CB-TE2A, CB-TE1K1P or desferrioxamine optionally associated with  89 Zr,  64 Cu,  68 Ga,  186/188 Re,  90 Y,  177 Lu,  153 Sm,  213 Bi,  225 Ac, or  223 Ra. 
     
     
         23 . The method of any  claim 16 , wherein the azide- or alkyne-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope has the structure of Formula (Vb): 
       
         
           
           
               
               
           
         
       
     
     
         24 . The method of any of  claim 16 , wherein the azide-containing chelating agent optionally associated with a PET-active or therapeutic radioisotope has the structure of Formula (Vd): 
       
         
           
           
               
               
           
         
         and the alkyne-modified PMSA inhibitor is of Formula (IVi): 
       
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 23 , wherein the azide- or alkyne-containing chelating agent is associated with  89 Zr,  64 Cu,  68 Ga,  186/188 Re,  90 Y,  177 Lu,  153 Sm,  213 Bi,  225 Ac, or  223 Ra. 
     
     
         26 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein
 L 1  and L 2  independently represent a divalent linking group; 
 each R 1  and R 2  is independently hydrogen, C 1 -C 6  alkyl or a protecting group; 
 R 3  represents hydrogen; and 
 w is 1, 2, 3, 4, 5 or 6. 
 
       
     
     
         27 . A compound according to  claim 26 , which is 
       
         
           
           
               
               
           
         
       
     
     
         28 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein
 R 1  is hydrogen, C 1 -C 6  alkyl or a protecting group; and 
 R 10  represents hydroxy or a group of the formula 
 
       
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound according to  claim 28 , which is 
       
         
           
           
               
               
           
         
       
     
     
         30 . A compound according to  claim 28 , which is