Convenient synthesis and evaluation of a heptadentate bifunctional ligand for radioimmunotherapy applications

摘要

An efficient synthetic route to a bifunctional chelating agent C-NE3TA-NCS for antibody-targeted radioimmunotherapy (RIT) applications was developed. Various synthetic methods centered on key reaction steps, including bimolecular cyclization, ring-opening reactions of aziridine and aziridinium cations, and reductive amination, were explored to optimize the preparation of a tetraaza-based chelate TANPA and C-NE3TA analogues. Heptadentate C-NE3TA-NCS was conjugated to a tumor-targeting antibody and compared with hexadentate C-NOTA-NCS for radiolabeling reaction kinetics with lanthanides for RIT. The C-NE3TA-antibody conjugate displayed significantly enhanced complexation kinetics with ~(90)Y compared with the C-NOTA-antibody conjugate. The synthetic methods for TANPA and C-NE3TA-NCS reported herein have broad applications for the preparation of bifunctional and macrocyclic chelating agents.