Methods and Compositions for Improved F-18 Labeling of Proteins, Peptides and Other Molecules

Abstract

The present application discloses compositions and methods of synthesis and use of 18 F- or 19 F-labeled molecules of use in PET, SPECT and/or MR imaging. Preferably, the 18 F or 19 F is conjugated to a targeting molecule by formation of a complex with a group IIIA metal and binding of the complex to a bifunctional chelating agent, which may then be directly or indirectly attached to the targeting molecule. In other embodiments, the 18 F or 19 F labeled moiety may comprise a targetable construct used in combination with a bispecific antibody to target a disease-associated antigen. The disclosed methods and compositions allow the simple and reproducible labeling of molecules at very high efficiency and specific activity in 30 minutes or less. In preferred embodiments, the bifunctional chelating agent bound to 18 F- or 19 F-metal complex may be conjugated to the molecule to be labeled at a reduced temperature, e.g. room temperature.

What is claimed is: 
     
         1 . A chelating moiety of the structure: 
       
         
           
           
               
               
           
         
         wherein R is a folate or a folate analog that is covalently attached to the chelating moiety. 
       
     
     
         2 . The chelating moiety of  claim 1 , wherein the chelating moiety is attached to a metal. 
     
     
         3 . The chelating moiety of  claim 2 , wherein the metal is selected from the group consisting of Al, Ba, Bi, Ca, Cr, Co, Cu, Fe, Gd, Ga, In, Pb, La, Mg, Mn, Hg, Ni, Os, Pt, Ra, Ag, Sr, Sn, Sc, Tc, Th, Ti, V, Zn, Zr and Y. 
     
     
         4 . The chelating moiety of  claim 3 , wherein the metal is selected from the group consisting of  64 Cu,  66 Ga,  68 Ga,  94m Tc,  86 Y,  90 Y, and  227 Th. 
     
     
         5 . The chelating moiety of  claim 1 , wherein the chelating moiety is attached to a complex of aluminum and fluoride. 
     
     
         6 . The chelating moiety of  claim 5 , wherein the fluoride is  18 F or  19 F. 
     
     
         7 . A chelating moiety of the structure: 
       
         
           
           
               
               
           
         
         wherein R is a folate or a folate analog that is covalently attached to the chelating moiety. 
       
     
     
         8 . The chelating moiety of  claim 7 , wherein the chelating moiety is attached to a metal. 
     
     
         9 . The chelating moiety of  claim 8 , wherein the metal is selected from the group consisting of Al, Ba, Bi, Ca, Cr, Co, Cu, Fe, Gd, Ga, In, Pb, La, Mg, Mn, Hg, Ni, Os, Pt, Ra, Ag, Sr, Sn, Sc, Tc, Th, Ti, V, Zn, Zr and Y. 
     
     
         10 . The chelating moiety of  claim 9 , wherein the metal is selected from the group consisting of  64 Cu,  66 Ga,  68 Ga,  94m Tc,  86 Y,  90 Y, and  227 Th. 
     
     
         11 . The chelating moiety of  claim 8 , wherein the chelating moiety is attached to a complex of aluminum and fluoride. 
     
     
         12 . The chelating moiety of  claim 11 , wherein the fluoride is  18 F or  19 F. 
     
     
         13 . The chelating moiety of  claim 11 , wherein the chelating moiety is labeled with aluminum and fluoride without an organic co-solvent. 
     
     
         14 . The chelating moiety of  claim 1 , wherein the chelating moiety is labeled with aluminum and fluoride at a reduced temperature of less than 90° C. 
     
     
         15 . The chelating moiety of  claim 7 , wherein the chelating moiety is labeled with aluminum and fluoride at a reduced temperature of less than 90° C.