Bifunctional chelators for targeted alpha therapy

Coordination chemistry plays an essential role in the development of metal-based radioactive agents. Targeted delivery of radiation can be achieved by incorporating the radionuclides into chelating agents that generate stable complexes and are tethered to peptides or monoclonal antibodies. Over the past decade, stable, targeted, and easily manufactured radioactive beta emitting complexes have made a substantial impact on nuclear medicine. Alpha particle emitting radiometals have recently received renewed interest for use as complementary therapeutics. Unlike beta electrons, alpha particles deposit large amounts of energy per distance travelled, while travelling only a few cell diameters potentially reducing off-target effects to adjacent healthy cells. As such, alpha-emitting radiometals are a key component in emerging radioactive agents, but their stable encapsulation for effective targeted delivery is challenging because of the high energy of the alpha particles, the decay to alpha-emitting progeny, and the large charge diffuse ionic radii of suitable radionuclides resulting in weak metal-ligand interactions. This project addresses the coordination chemistry and radiochemistry challenges presented by the alpha emitters Ac-225, Pb-212, Bi-212/213 and Ra-223/224 to develop novel chelators with superior radiolabelling properties and stability.