Investigation of novel bis- and tris-tetraazamacrocycles for use in the copper-64 (Cu-64) radiolabeling of antibodies with potential to increase the therapeutic index for drug targeting.

The 64Cu complexes of a series of mono-, bis-, and tris-tetraazamacrocycles have been prepared, and their stability in human sera has been assessed. The ligands forming the most stable Cu2+ complexes were then conjugated to the B72.3 antibody (mAb). Conditions for conjugation of the ligands to the mAb were optimized for the concentration of protein, ligand, pH, temperature, and time. The optimum moles of Cu2+ attached to the mAb were as high as 3.5 for L2 and 5.5 or 2.7 for L5, and the immunoreactivity was ≥80%. Biodistribution of the radioimmunoconjugates showed good tumor localization and target-to-background ratios that were significantly enhanced compared to those achieved with monotetraazamacrocyclic derivatives. © 2009, American Chemical Societ