Radiolabeled ligands for targeted pet/spect imaging and methods of their use

Abstract

The present disclosure provides compounds, complexes, compositions, and methods for the detection of cancer. Specifically, the compounds, complexes, compositions of the present technology include pH (low) insertion peptides. Also disclosed herein are methods of using the complexes and compositions of the present technology in diagnostic imaging to detect cancer in a subject.

1 . A compound or pharmaceutically acceptable salt thereof comprising
 a pH (low) insertion peptide (“pHLIP”) configured to localize to an extracellular environment having a pH that is lower than 7.4, wherein the pHLIP comprises a C-terminus and an N-terminus; and   X 1  covalently attached to a heteroatom of a side chain of an amino acid residue of the pHLIP, where the amino acid residue is from 0, 1, 2, 3, 4, 5, or 6 residues from the C-terminus or the N-terminus;   wherein
 X 1  is of Formula I 
   
       
         
           
           
               
               
           
         
         
           where Z 1  and Z 2  are each independently a lone pair of electrons (i.e., providing an oxygen anion) or H; and 
           Z 3  is 
         
       
       
         
           
           
               
               
           
         
         
            where n is 1, 2, 3, 4, 5, 6, 7, or 8, —NH-alkylene-, —NH—CH 2 CH 2 -((poly(alkylene glycol))-, or a bond. 
         
       
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein Z 3  is 
       
         
           
           
               
               
           
         
       
       —NH—(CH 2 ) m —, —NH—CH 2 CH 2 —(O—CH 2 CH 2 ) p —, or a bond, where
 n is 1, 2, 3, 4, 5, 6, 7, or 8; 
 m is 1, 2, 3, 4, 5, 6, 7, or 8; and 
 p is 1, 2, 3, 4, 5, 6, 7, or 8. 
 
     
     
         5 . The compound of  claim 1 , wherein the pHLIP is 
       
         
           
                 
               
                   (SEQ ID NO: 1) 
                 
                   ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT, 
                 
                     
                 
                   (SEQ ID NO: 2) 
                 
                   ACDDQNPWRAYLDLLFPTDTLLLDLLW, 
                 
                     
                 
                   (SEQ ID NO: 3) 
                 
                   ADDQNPWRAYLDLLFPTDTLLLDLLWCG, 
                 
                   or 
                 
                     
                 
                   (SEQ ID NO: 4) 
                 
                   ACEEQNPWARYLEWLFPTETLLLEL. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the amino acid residue is a cysteine or lysine. 
     
     
         7 . The compound of  claim 1 , wherein X 1  is covalently attached to a sulfur atom of a cysteine residue of the pHLIP or is covalently attached to a ε-nitrogen atom of a lysine residue the pHLIP. 
     
     
         8 . The compound of  claim 1 , wherein the compound is AC(X 1 )EQNPIYWARYADWLFTTPLLLLDLALLVDADEGT (SEQ ID NO:5), AC(X 1 )DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO:6), ADDQNPWRAYLDLLFPTDTLLLDLLWC(X 1 )G (SEQ ID NO:7), or AC(X 1 )EEQNPWARYLEWLFPTETLLLEL (SEQ ID NO:8), or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 1 , wherein X 1  is of Formula Ia 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein the compound is AC(X 1 )DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO:6), ADDQNPWRAYLDLLFPTDTLLLDLLWC(X 1 )G (SEQ ID NO:7), or a pharmaceutically acceptable salt thereof; wherein X 1  is of Formula Ia. 
     
     
         11 . A complex comprising the compound of  claim 1  and a radionuclide. 
     
     
         12 . The complex of  claim 11 , wherein X 1  is of Formula II 
       
         
           
           
               
               
           
         
       
       wherein M 1  is  60 Cu 2+ ,  61 Cu 2+ ,  62 Cu 2+ ,  64 Cu 2+ ,  67 Cu 2+ , [ 18 F]—AlF 2+ ,  67 Ga 3+ ,  68 Ga 3+ ,  69 Ga 3+ , or  71 Ga 3+ . 
     
     
         13 . The complex of  claim 11 , wherein X 1  is of Formula IIa 
       
         
           
           
               
               
           
         
       
     
     
         14 . The complex of  claim 11 , wherein the complex is AC(X 1 )DDQNPWRAYLDLLFPTDTLLLDLLW (SEQ ID NO:6), ADDQNPWRAYLDLLFPTDTLLLDLLWC(X 1 )G (SEQ ID NO:7), or a pharmaceutically acceptable salt thereof; wherein X 1  is of Formula IIa. 
     
     
         15 . A composition comprising a complex of  claim 11  and a pharmaceutically acceptable carrier. 
     
     
         16 . A pharmaceutical composition for detecting a tissue comprising an extracellular environment having a pH that is lower than 7.4, the pharmaceutical composition comprising an effective amount of the complex of  claim 11  and a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the tissue comprises one or more of the group consisting of an atherosclerotic plaque, ischemic myocardium, a tissue impacted by stroke, and a cancer tissue. 
     
     
         18 . (canceled) 
     
     
         19 . A method for detecting solid tumors in a subject in need thereof comprising
 (a) administering an effective amount of a complex of  claim 11  to the subject; and   (b) detecting the presence of a tissue comprising an extracellular environment having a pH that is lower than 7.4 in the subject by detecting radioactive levels emitted by the complex that are higher than a reference value.   
     
     
         20 . The method of  claim 19 , wherein the radioactive levels emitted by the complex are detected using positron emission tomography or single photon emission computed tomography. 
     
     
         21 . The method of  claim 19 , wherein the subject is diagnosed with, or is suspected of having an atherosclerotic plaque, ischemic myocardium, a tissue impacted by stroke, or cancer. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 19 , wherein the radioactive levels emitted by the complex are detected between 4 to 24 hours after the complex is administered. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . A kit comprising a compound of  claim 1 , at least a radionuclide, and instructions for use. 
     
     
         29 . (canceled)