Compositions And Methods For In Vivo Imaging

Abstract

This document relates to compounds useful for targeting PARP1. Also provided herein are methods for using such compounds to detect and image cancer cells.

1 . A compound of Formula (I):
   P-L n -T m -D   
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 P is a PARP1 inhibitor; 
 L is a linker; 
 T is: 
 
       
         
           
           
               
               
           
         
         D is a detectable agent; 
         m is 0 or 1; and 
         n is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein P is selected from the group consisting of: benzamide, quinolone, dihydroisoquinolinone, isoquinolinone, isoquinolone, benzopyrone, cyclic benzamide, benzimidazole, indole, isoindolinone, nicotinamide, 3-AB, phthalazinone, and quinazolinone. 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein P is selected from the group consisting of AZD2281, AG014699, ABT888, BSI201, BSI101, DR2313, FR 247304, GPI15427, GPI16539, MK4827, NU1025, NU1064, NU1085, PD128763, PARP Inhibitor II, PARP Inhibitor III, PARP Inhibitor VIII, PARP Inhibitor IX, and TIQ-A. 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein P is AZD2281. 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt form thereof, 
       wherein:
 L is a linker; 
 T is: 
 
       
         
           
           
               
               
           
         
         D is a detectable agent; 
         m is 0 or 1; and 
         n is 0 or 1. 
       
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein D comprises one or more of organic small molecules, inorganic compounds, nanoparticles, enzymes or enzyme substrates, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, and contrast agents. 
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt thereof, wherein D comprises a radioactive material, a fluorescent material, or a mixture thereof. 
     
     
         8 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R is Texas Red, a cyanine dye, Alexafluor-680, a BODIPY dye, a xanthene derivatives, a naphthalene dye, a courmarin derivative, an oxadiazole derivative, a pyrene derivative, an oxazine derivative, an acridine derivative, an arylmethine derivative, and a tetrapyrrole derivative. 
       
     
     
         9 . The compound of  claim 8 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A pharmaceutical composition comprising a compound of  claim 1 , 
       or a pharmaceutically acceptable salt thereof, and 
       a pharmaceutically acceptable carrier or diluent. 
     
     
         12 . A method for detecting a cancer in a subject, the method comprising:
 (a) administering to a subject an effective amount of a compound of  claim 1 ,   
       or a pharmaceutically acceptable salt form thereof, 
       and
 (b) detecting the detectable agent in the subject. 
 
     
     
         13 . The method of  claim 12 , wherein detecting the detectable agent comprises using histochemistry, fluorescence detection, chemiluminescence detection, bioluminescence detection, magnetic resonance imaging, nuclear magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, X-ray imaging, X-ray computed tomography, ultrasound imaging, or photoacoustic imaging. 
     
     
         14 . The method of  claim 12 , wherein the cancer is selected from the group consisting of pancreatic cancer, ovarian cancer, and breast cancer. 
     
     
         15 . The method of  claim 12 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered before and after surgical removal of the cancer. 
     
     
         16 . A method for imaging a cancer cell, the method comprising:
 (a) contacting a cancer cell with an effective amount of a compound of  claim 1 ,   
       or a pharmaceutically acceptable salt form thereof, 
       and
 (b) imaging the cell. 
 
     
     
         17 . A method for monitoring the cancer treatment of a patient, the method comprising:
 (a) administering to the patient, prior to a treatment, an effective amount of a compound of  claim 1 ,   
       or a pharmaceutically acceptable salt form thereof, 
       and 
       imaging the patient;
 (b) administering to the patient, at a point following treatment, an effective amount the compound, or a pharmaceutically acceptable salt thereof, and imaging the patient; and 
 (c) comparing the image collected in step (a) with the image collected in step (b) to monitor the treatment. 
 
     
     
         18 . The method of  claim 17 , wherein the treatment further comprises administration of an anti-cancer agent. 
     
     
         19 . The method of  claim 17 , wherein the method further comprises: administering to the patient an effective amount of the compound, or a pharmaceutically acceptable salt thereof, during treatment and imaging the patient.