68Ga-LABELED NOTA-CHELATED PSMA-TARGETED IMAGING AND THERAPEUTIC AGENTS

Abstract

PSMA-targeted PET/SPECT agents for imaging PSMA-positive cancer and or tumor neovasculature and PSMA-targeted radiotherapeutic agent for the treatment of PSMA-positive cancer or tumor neovasculature are disclosed. Methods of imaging PSMA expressing tumors, or cells and kits also are disclosed.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is tetrazole or CO 2 Q; 
 Q is H or a protecting group; 
 X and Y are each independently O or S; 
 a is an integer selected from the group consisting of 1, 2, 3 and 4; 
 b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 W is selected from the group consisting of —C(═O)—NR 4 —, —NR 4 —C(═O)—, —NR 4 —C(═O)—NR 4 —, —NR 4 —C(═S)—NR 4 —, —NR 4 —C(═O)—O—, —O—C(═O)—NR 4 —, —O—C(═O)—, and —C(═O)—O; 
 each R 1  is independently H or C 1 -C 4  alkyl; 
 each R 2  is independently H or —COOR 3 , wherein each R 3  is independently H or a C 1 -C 6  alkyl; 
 each R 4  is independently H or C 1 -C 4  alkyl; 
 each R is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkyaryl, arylakyl, and alkylheteroaryl; 
 n is an integer selected from the group consisting of 0, 1, 2, 3 and 4; and 
 M is a metal; and 
 pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein the metal (M) is selected from the group consisting of Tc-94m, Tc-99m, In-111, Ga-67, Ga-68, Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, Gd-152, or Dy-166. 
     
     
         3 . The compound of  claim 2 , wherein the metal (M) is Ga-68. 
     
     
         4 . The compound of  claim 1 , wherein the compound of Formula (I) is  68 Ga-2. 
     
     
         5 . A method for imaging one or more prostate-specific membrane antigen (PSMA) tumors, or cells the method comprising contacting the one or more tumors, or cells, with an effective amount of a compound of Formula (I) and making an image, the compound of Formula (I) comprising: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z is tetrazole or CO 2 Q; 
 Q is H or a protecting group; 
 X and Y are each independently O or S; 
 a is an integer selected from the group consisting of 1, 2, 3 and 4; 
 b and c are each independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 W is selected from the group consisting of —C(═O)—NR 4 —, —NR 4 —C(═O)—, —NR 4 —C(═O)—NR 4 —, —NR 4 —C(═S)—NR 4 —, —NR 4 —C(═O)—O—, —O—C(═O)—NR 4 —, —O—C(═O)—, and —C(═O)—O—; 
 each R 1  is independently H or C 1 -C 4  alkyl; 
 each R 2  is independently H or —COOR 3 , wherein each R 3  is independently H or a C 1 -C 6  alkyl; 
 each R 4  is independently H or C 1 -C 4  alkyl; 
 each R is independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkyaryl, arylakyl, and alkylheteroaryl; 
 n is an integer selected from the group consisting of 0, 1, 2, 3 and 4; and 
 M is a radioactive metal suitable for imaging; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
         6 . The method of  claim 5 , wherein the radioactive metal suitable for imaging (M) is selected from the group consisting of Tc-94m, Tc-99m, In-111, Ga-67, Ga-68, Y-86, Y-90, Lu-177, Re-186, Re-188, Cu-64, Cu-67, Co-55, Co-57, Sc-47, Ac-225, Bi-213, Bi-212, Pb-212, Sm-153, Ho-166, Gd-152, or Dy-166. 
     
     
         7 . The method of  claim 5 , wherein the radioactive metal suitable for imaging (M) is Ga-68. 
     
     
         8 . The method of  claim 5 , wherein the compound of Formula (I) is  68 Ga-2. 
     
     
         9 . The method of  claim 5 , wherein the imaging comprises positron emission tomography (PET). 
     
     
         10 . The method of  claim 5 , wherein the imaging comprises single-photon emission computed tomography (SPECT). 
     
     
         11 . The method of  claim 5 , wherein the one or more PSMA-expressing tumors or cells is selected from the group consisting of: a prostate tumor or cell, a metastasized prostate tumor or cell, a lung tumor or cell, a renal tumor or cell, a glioblastoma, a pancreatic tumor or cell, a bladder tumor or cell, a sarcoma, a melanoma, a breast tumor or cell, a colon tumor or cell, a germ cell, a pheochromocytoma, an esophageal tumor or cell, a stomach tumor or cell, and combinations thereof. 
     
     
         12 . The method of  claim 5 , wherein the one or more PSMA-expressing tumors or cells is a prostate tumor or cell. 
     
     
         13 . The method of  claim 5 , wherein the one or more PSMA-expressing tumors or cells is in vitro, in vivo or ex-vivo. 
     
     
         14 . The method of  claim 5 , wherein the one or more PSMA-expressing tumors or cells is present in a subject. 
     
     
         15 . The method of  claim 14 , wherein the compound of formula (I) comprising the radioactive metal suitable for imaging is cleared from the tumor or cell in the subject. 
     
     
         16 . The method of  claim 14 , wherein the compound of formula (I) comprising the radioactive metal suitable for imaging is cleared more rapidly from a subject's kidneys than from a tumor of the subject. 
     
     
         17 . The method of  claim 5 , wherein the compound of formula (I) comprising the radioactive metal suitable for imaging substantially localizes to the tumor or cell within about 60 minutes of administration. 
     
     
         18 . A kit comprising a compound according to  claim 1 .