Synthesis, conjugation, and radiolabeling of a novel bifunctional chelating agent for Ac-225 radioimmunotherapy applications

Ac-225 (t(1/2) = 10 days) is an alternative alpha-emitter that has been pro posed for radioimmunotherapy (RIT) due to its many favorable properties, su ch as half-life and mode of decay. The factor limiting use of Ac-225 in RIT is the lack of an acceptably stable chelate for in vivo applications. Here in is described the first reported bifunctional chelate for (225)AC that ha s been evaluated for stability for in vivo applications. The detailed synth esis of a bifunctional chelating agent 2-(4-isothiocyanatobenzyl)-1,4,7,10, 13,16- hexaazacyclohexadecane-1,4,7,10,13,16-hexaacetic acid (HEHA-NCS) is reported. This ligand was conjugated to three monoclonal antibodies, CC49, T101, and BL-3 with chelate-to-protein ratios between 1.4 and 2. The three conjugates were radiolabeled with Ac-225, and serum stability study of the [(225)AC]-BL-3-HEHA conjugate was performed.