Psma binding ligand-linker conjugates and methods for using

Abstract

Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical composition containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.

1 . (canceled) 
     
     
         2 . A compound of the formula:
   B-L-IA   or a salt thereof, wherein:   B is a ligand of prostate specific membrane antigen (PSMA) that is a urea of two amino acids, wherein the two amino acids are independently selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine and combinations thereof;   L is a divalent linker of 14 to 100 atoms in length, the divalent linker comprising a divalent amino alkylene carbonyl group and a chelating portion; and   IA is an imaging agent.   
     
     
         3 . The compound of  claim 2 , or a salt thereof, wherein Lisa divalent linker of 14 to 24 atoms. 
     
     
         4 . The compound of  claim 2 , or a salt thereof, wherein L is a divalent linker of 14 to 31 atoms. 
     
     
         5 . The compound of  claim 2 , or a salt thereof, wherein the chelating portion comprises a group of the formula: 
       
         
           
           
               
               
           
         
         wherein each R is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl and at least one R comprises a nitrogen atom, an oxygen atom, or a sulfur atom. 
       
     
     
         6 . The compound of  claim 2 , or a salt thereof, wherein the chelating portion comprises a group of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         each R is independently selected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; 
         at least one R comprises a nitrogen atom, an oxygen atom, or a sulfur atom; 
         X is oxygen, nitrogen or sulfur and X is attached to linker L; and 
         n is an integer from 1 to 5. 
       
     
     
         7 . The compound of  claim 2 , or a salt thereof, wherein the chelating portion comprises a radioactive metal isotope chelated thereto, wherein the radioactive metal isotope is selected from the group consisting of technetium, rhenium, gallium, gadolinium, indium, and copper. 
     
     
         8 . The compound of  claim 2 , or a salt thereof, wherein the IA is an optical imaging agent. 
     
     
         9 . The compound of  claim 8 , or a salt thereof, wherein the optical imaging agent is selected from the group consisting of fluorescein, BODIPY F1, BODIPY 505, tetramethylrhodamine, AlexaFluor 488, AlexaFluor 647, DyLight 680, DyLight 800, IR800CW, ICG, Oregon Green 488, Oregon Green 514, Texas Red, and phycoerythrin. 
     
     
         10 . The compound of  claim 9 , or a salt thereof, wherein the optical imaging agent is Alexa 647 or Oregon Green 488. 
     
     
         11 . The compound of  claim 2 , or a salt thereof, wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         or a salt thereof; 
       
       
         
           
           
               
               
           
         
         or a salt thereof; or