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 177 Lu‐based radiopharmaceuticals including Lutathera and Pluvicto have accelerated research efforts to develop more effective TRT agents. A critical component for the generation of effective 177 Lu radiopharmaceuticals is a bifunctional chelator that can rapidly and stably sequester 177 Lu under mild labeling conditions. Herein, we introduce a novel bifunctional chelator (2E‐ C ‐NETA) for applications in 177 Lu‐based TRT. The chelator 2E‐ C ‐NETA was synthesized and evaluated for radiolabeling efficiency with 177 Lu. 2E‐ C ‐NETA rapidly bound 177 Lu 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 177 Lu at room temperature. The 177 Lu‐labeled 2E‐ C ‐NETA‐Herceptin conjugate displayed high stability in human serum for 2 weeks. In mice bearing human colorectal carcinoma (LS‐174T) tumors, 177 Lu‐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 177 Lu‐based radiopharmaceuticals.