Development of a Highly Effective Bifunctional Ligand 2E-C-NETA for Targeted Lu-177 Therapy: Synthesis, Radiolabeling, In Vitro Stability, and In Vivo Biodistribution.

Lutetium-177 is a β-particle-emitting radionuclide widely used in targeted radionuclide therapy (TRT). The recent FDA approvals of 177Lu-based radiopharmaceuticals including Lutathera and Pluvicto have accelerated research efforts to develop more effective TRT agents. A critical component for the generation of effective 177Lu radiopharmaceuticals is a bifunctional chelator that can rapidly and stably sequester 177Lu under mild labeling conditions. Herein, we introduce a novel bifunctional chelator (2E-C-NETA) for applications in 177Lu-based TRT. The chelator 2E-C-NETA was synthesized and evaluated for radiolabeling efficiency with 177Lu. 2E-C-NETA rapidly bound 177Lu at room temperature, and the resulting complex exhibited excellent serum stability for over 2 weeks. To demonstrate its utility in antibody-targeted radionuclide therapy, the chelator was further structurally modified for conjugation to Herceptin, an FDA-approved monoclonal antibody for metastatic breast cancer. The 2E-C-NETA-Herceptin conjugate was also rapidly labeled with 177Lu at room temperature. The 177Lu-labeled 2E-C-NETA-Herceptin conjugate displayed high stability in human serum for 2 weeks. In mice bearing human colorectal carcinoma (LS-174T) tumors, 177Lu-2E-C-NETA-Herceptin demonstrated favorable biodistribution, showing fast blood clearance, minimal uptake in normal tissues, and significant and prolonged tumor accumulation. In summary, these results support 2E-C-NETA as a promising bifunctional chelator for the development of 177Lu-based radiopharmaceuticals.