Synthesis and Preclinical Evaluation of Bifunctional Ligands for Improved Chelation Chemistry of 90Y and 177Lu for Targeted Radioimmunotherapy

摘要

We report a practical and high yield synthesis of a bimodal bifunctional ligand 3p-C-NETA-NCS containing the isothiocyanate group for conjugation to a tumor targeting antibody. 3p-C-NETA-NCS was conjugated to a tumor-targeting antibody, trastuzumab, and the corresponding 3p-C-NETA-trastuzumab conjugate was evaluated and compared to trastuzumab conjugates of the known bifunctional ligands C-DOTA, C-DTPA, C-NOTA, and 3p-C-DEPA for radiolabeling kinetics with ⁹⁰Y and ¹⁷⁷Lu. 3p-C-NETA-trastuzumab conjugate exhibited extremely rapid complexation kinetics with ⁹⁰Y and ¹⁷⁷Lu. ⁹⁰Y-3p-C-NETA-trastuzumab and ¹⁷⁷Lu-3p-C-NETA-trastuzumab conjugates were stable in human serum for 2 weeks. A pilot biodistribution study was conducted to evaluate in vivo stability and tumor targeting of ¹⁷⁷Lu-radiolabeled trastuzumab conjugate using nude mice bearing ZR-75-1 human breast cancer. ¹⁷⁷Lu-3p-C-NETA-trastuzumab conjugate displayed low radioactivity level at blood (1.6%), low organ uptake (<2.2%), and high tumor-to-blood ratio (6.4) at 120 h. 3p-C-NETA possesses favorable in vitro and in vivo profiles and is an excellent bifunctional chelator that can be used for targeted RIT applications using ⁹⁰Y and ¹⁷⁷Lu and has potential to replace DOTA and DTPA analogues in current clinical use.