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

Ac-225 (t(1/2) = 10 days) is an alternative alpha-emitter that has been proposed for radioimmunotherapy (RIT) due to its many favorable properties, such 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. Herein is described the first reported bifunctional chelate for (225)AC that has been evaluated for stability for in vivo applications. The detailed synthesis 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.