Chemotactic peptide antagonists for imaging sites of inflammation

Abstract

Radiopharmaceuticals comprising molecules that target to N-formyl-methionyl-leucyl-phenylalanine (fMLF) receptor on leukocytes in order to target sites of inflammation for diagnostic imaging are described. The targeting molecules are attached to capping groups that make the entire molecule either antagonists or weak agonists of fMLF receptor and therefore do not elicit a chemotactic response resulting in neutropenia. The preferred targeting molecule is ReO-Gly-lys(Dimethylgly-t-Butylgly-cys-gly)-glu-trp-phe-leu-nle-NHCOcyclopropyl. The invention also relates to the use of combinatorial chemistry to obtain preferred molecules that target sites of inflammation for diagnostic imaging.

1 - 20 . (canceled)  
     
     
         21 . A compound for binding to sites of inflammation having the following formula I:  
       
         
           
           
               
               
           
         
         wherein CG is a capping group selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         wherein Cl represents the point of attachment of the capping group;  
         X, X 2 , X 3  and X 4  are amino acids selected from natural and unnatural amino acids; Z is a chelator capable of complexing a radionuclide metal or a chelator complexed to a radionuclide metal, X 3  being a site of attachment for said chelator.  
       
     
     
         22 . A compound according to  claim 21  having the following formula II:  
       
         
           
           
               
               
           
         
         wherein R, and R 2  is a linear or branched, saturated or unsaturated C 1-6  alkyl chain that is optionally interrupted by one or two heteroatoms selected from N, O, and S; and is optionally substituted by at least one group selected from hydroxyl, amino, carboxyl, C 1-6  alkyl, aryl and C(O)R; R 3  is selected from H; alkyl; an alkyl substituted by a group selected from amino, aminoacyl, carboxyl, guaniginyl, hydroxyl, thiol, phenyl, phenolyl, indolyl, and imidazolyl.  
       
     
     
         23 . A compound according to  claim 21  wherein the compound binds to N-formyl-methionyl-leucyl-phenylalanine (fMLF) receptor.  
     
     
         24 . A compound according to  claim 21  wherein X 3  is Lys and X 4  is Gly.  
     
     
         25 . A compound according to  claim 24  having the following formula III:  
       
         
           
           
               
               
           
         
       
     
     
         26 . A method for imaging sites of inflammation in a patient comprising administering a compound of  claim 21  and imaging.  
     
     
         27 . The method of  claim 26  wherein the compound has the following formula II:  
       
         
           
           
               
               
           
         
         wherein R, and R 2  is a linear or branched, saturated or unsaturated C 1-6  aklyl chain that is optionally interrupted by one or two heteroatoms selected from N, O, and S; and is optionally substituted by t least one group selected from hydroxyl, amino, carboxyl, C 1-6  alkyl, aryl and C(O)R; R 3  is selected from H; alkyl; an alkyl substituted by a group selected from amino, aminoacyl, carboxyl, guaniginyl, hydroxyl, thiol, phenyl, phenolyl, indolyl, and imidazolyl.  
       
     
     
         28 . The method of  claim 27 , wherein the compound has the following formula IV:  
       
         
           
           
               
               
           
         
         wherein M is  99m Tc or Re.