Fap-targeted radiopharmaceuticals and imaging agents, and uses related thereto

Abstract

The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer-associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of FAP, which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. The present invention provides small-molecule radiopharmaceutical and imaging agents based on a FAP-specific inhibitor.

1 . A compound represented by Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R represents a radioactive moiety, a chelating agent, a fluorescent moiety, a photoacoustic reporting molecule, a Raman-active reporting molecule, a contrast agent, detectable nanoparticle or an enzyme; 
         R 1  represents a (C 1 -C 6 )alkyl; 
         R 2  represents —B(—Y 1 )(—Y 2 ) or —CN; 
         Y 1  and Y 2  are independently —OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5- to 8-membered ring that is hydrolysable to a boronic acid; 
         R 3  represents H or a (C 1 -C 6 )alkyl; 
         R 4  is absent or represents one, two, or three substituents, each independently selected from the group consisting of (C 1 -C 6 )alkyl, —OH, —NH 2 , and halogen; 
         X represents O or S; and 
         L represents a bond or a linker. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  represents —CH 3  or —CH 2 CH 3 . 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 2 , wherein R 2  represents —B(—Y 1 )(—Y 2 ). 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein R 4  is absent. 
     
     
         8 . The compound of  claim 1 , wherein X represents O. 
     
     
         9 . The compound of  claim 1 , represented by Formulae II or III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R represents a radioactive moiety, a chelating agent, a fluorescent moiety, a photoacoustic reporting molecule, a Raman-active reporting molecule, a contrast agent, detectable nanoparticle or an enzyme; and 
         L represents a bond or a linker. 
       
     
     
         10 . A compound comprising: two or more FAP inhibitor moieties covalently linked to a radioactive isotope or chelating agent therefor, and which agent causes internalization of FAP and the radioisotope by cells expressing FAP. 
     
     
         11 . (canceled) 
     
     
         12 . An PK/BD modified FAP-targeted agent for FAP-specific delivery of a radioisotope or imaging agent having an FAP Inhibitory moiety linked: to (i) a radioactive moiety, chelating agent, fluorescent dye or a contrast agent; and (ii) a moiety that modifies the pharmacokinetics and or biodistribution of the molecule, such as the serum half-life of the molecule and/or the tumor distribution of the PK/BD modified FAP-targeted agent. 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein the compound comprises one or more radioactive isotopes. 
     
     
         15 . The compound of  claim 1 , wherein R is a radioactive moiety. 
     
     
         16 . The compound of  claim 1 , wherein R is a chelating agent. 
     
     
         17 - 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein the compound is complexed with a radioactive isotope or a metal ion. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . The compound of  claim 1 , wherein the radionuclide is  43 Sc,  44 Sc,  51 Mn,  52 Mn, 64Cu,  67 Ga,  68 Ga,  86 Y,  89 Zr,  94m Tc,  99m Tc,  111 In,  149 Tb,  152 Tb,  155 Tb,  201 Tl,  203 Pb,  18 F,  76 Br,  77 Br,  123 I,  124 I, or  125 I. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The compound of  claim 1 , wherein the radionuclide is  47 Sc,  67 Cu,  89 Sr,  90 Y,  153 Sm,  149 Tb,  161 Tb,  177 Lu,  186 Re,  188 Re,  212 Pb,  213 Bi,  223 Ra,  225 Ac,  226 Th,  227 Th,  131 I or  211 At. 
     
     
         28 - 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising a compound of  claim 1 ; and a pharmaceutically acceptable excipient. 
     
     
         35 - 40 . (canceled) 
     
     
         41 . A kit comprising a compound of  claim 1 , and instructions for the diagnosis or treatment of a disease. 
     
     
         42 . A method for diagnosing, imaging, or reducing tissue overexpressing FAP in an animal, comprising administering to the animal a compound of  claim 1 . 
     
     
         43 . A method of treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of  claim 1  to the subject. 
     
     
         44 - 50 . (canceled) 
     
     
         51 . A method for conducting image-guided surgery comprising (i) administering to a subject in need thereof a compound of  claim 1  in an amount sufficient to become preferentially localized in tissue that is the target of the surgery, and (ii) detecting the presence or absence of the compound during the surgery. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled)