99mTc IMAGING AGENTS AND METHODS OF USE

Abstract

An embodiment of the invention comprises a ligand of Formula I wherein R 1 and R 2 are independently an alkyl or cycloalkyl; R 3 is and alkyl; X is CO or SO 2 ; Y is (CH2) n , C 6 H 4 , (OCH 2 CH 2 ) n (NHCH 2 CH 2 ) n and (OCH 2 CH 2 CH 2 ) n , or a combination thereof; Z is linker group capable of conjugating to a vector; and n is an integer between 0 and 10. Also included are an imaging agent comprising a compound of Formula I complexed to 99m Tc and their method of use to image a subject having a target site using single photon emission computed tomography (SPECT).

1 . A ligand of Formula I 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently an alkyl or cycloalkyl; 
         R 3  is and alkyl; 
         X is CO or SO 2 , 
         Y is (CH 2 ) n , C 6 H 4 , (OCH 2 CH 2 ) n (NHCH 2 CH 2 ) n  and (OCH 2 CH 2 CH 2 ) n  or a combination thereof; 
         Z is linker group capable of conjugating to a vector; and 
         n is an integer between 0 and 10. 
       
     
     
         2 . The ligand of  claim 1  wherein R 1 , R 2 , and R 3  are independently lower alkyl groups. 
     
     
         3 . The ligand of  claim 1  wherein R 1 , R 2 , and R 3  are CH 3 , X is SO 2 , Y is CH 2 , and n is 1. 
     
     
         4 . The ligand of  claim 1  wherein Z comprises carboxylic acid, an activated ester, a phosphoramidite, isocyanate, isothiocyanate, aldehyde, acid chloride, sulfonyl chloride, alkyl halide, amine, phosphine, phosphate, alcohol, thiol, or a combination thereof. 
     
     
         5 . The ligand of  claim 4  wherein the activated ester comprises N-hydroxysuccinimide ester, pentafluorophenyl ester, or a combination thereof 
     
     
         6 . The ligand of  claim 1  wherein Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         7 . An imaging agent comprising a compound of Formula I complexed to  99m Tc wherein Formula I comprises: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently an alkyl or cycloalkyl; 
         R 3  is and alkyl; 
         X is CO or SO 2 , 
         Y is (CH 2 ) n , C 6 H 4 , (OCH 2 CH 2 ) n (NHCH 2 CH 2 ) n  and (OCH 2 CH 2 CH 2 ) n  or a combination thereof; 
         Z is linker group capable of conjugating to a vector; and 
         n is an integer between 0 and 10. 
       
     
     
         8 . The imaging agent of  claim 7  wherein R 1 , R 2 , and R 3  are independently lower alkyl groups. 
     
     
         9 . The imaging agent of  claim 8  wherein R 1 , R 2 , and R 3  are CH 3 , X is SO 2 , Y is CH 2 , and n is 1 
     
     
         10 . The imaging agent of  claim 7  wherein Z comprises carboxylic acid, an activated ester a phosphoramidite, isocyanate, isothiocyanate, aldehyde, acid chloride, sulfonyl chloride, e, alkyl halide, amine, phosphine, phosphate, alcohol, thiol, or a combination thereof. 
     
     
         11 . The imaging agent of  claim 10  wherein the activated ester comprises N-hydroxysuccinimide ester, pentafluorophenyl ester, or a combination thereof 
     
     
         12 . The imaging agent of  claim 7  wherein Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The imaging agent of  claim 7  further comprising a vector covalently bound to the ligand through a linker moiety. 
     
     
         14 . The imaging agent of  claim 13  wherein the vector comprises 3-100 mer peptides or peptide analogues, monoclonal anitbodies or fragments thereof; enzyme substrates, enzyme inhibitors; synthetic receptor-binding compounds; oligonucleotides, oligo-DNA fragments, oligo-RNA fragments, or a combination thereof. 
     
     
         15 . The imaging agent of  claim 14  wherein the vector comprises a 3-100 mer peptide, peptide analogues, or combinations thereof. 
     
     
         16 . A method of imaging a target site comprising:
 administering to a subject having a target site, an imaging agent comprising a ligand, complexed with  99m Tc, and chemically bound to a vector through a linker moiety, and wherein said ligand comprises a compound of Formula I   
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently an alkyl or cycloalkyl; 
         R 3  is and alkyl; 
         X is CO or SO 2 , 
         Y is (CH 2 ) n , C 6 H 4 , (OCH 2 CH 2 ) n (NHCH 2 CH 2 ) n  and (OCH 2 CH 2 CH 2 ) n  or a combination thereof; 
         Z is linker group capable of conjugating to a vector; and 
         n is an integer between 0 and 10; 
         allowing the imaging agent to localize to the target site;and 
         detecting the imaging agent at the target using single photon emission computed tomography (SPECT). 
       
     
     
         17 . The method of  claim 16  wherein R 1 , R 2 , and R 3  are independently lower alkyl groups. 
     
     
         18 . The method of  claim 17  wherein R 1 , R 2 , and R 3  are CH 3 , X is SO 2 , Y is CH 2 , and n is 1. 
     
     
         19 . The method of  claim 17  wherein Z comprises carboxylic acid, an activated ester a phosphoramidite, isocyanate, isothiocyanate, aldehyde, acid chloride, sulfonyl chloride, alkyl halide, amine, phosphine, phosphate, alcohol, thiol, or a combination thereof. 
     
     
         20 . The method of  claim 19  wherein the activated ester comprises N-hydroxysuccinimide ester, pentafluorophenyl ester, or a combination thereof 
     
     
         21 . The method of  claim 17  wherein Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         22 . The method of  claim 16  wherein the vector comprises 3-100 mer peptides or peptide analogues, monoclonal antibodies or fragments thereof; enzyme substrates, enzyme inhibitors; synthetic receptor-binding compounds, oligonucleotides, oligo-DNA fragments, oligo-RNA fragments, or a combination thereof. 
     
     
         23 . The method of  claim 22  wherein the vector comprises a 3-100 mer peptide, peptide analogues, or combinations thereof.