Synthesis, Conjugation, and Radiolabeling of a Novel Bifunctional Chelating Agent for 225Ac Radioimmunotherapy Applications

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Abstract
225Ac (t1/2 = 10 days) is an alternative α-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 225Ac in RIT is the lack of an acceptably stable chelate for in vivo applications. Herein is described the first reported bifunctional chelate for 225Ac 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 225Ac, and serum stability study of the [225Ac]BL-3-HEHA conjugate was performed.

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