Chelating the Alpha Therapy Radionuclides ²²⁵Ac³⁺ and ²¹³Bi³⁺ with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa

Abstract

The radionuclides ²²⁵Ac³⁺ and ²¹³Bi³⁺ possess favorable physical properties for targeted alpha therapy (TAT), a therapeutic approach that leverages α radiation to treat cancers. A chelator that effectively binds and retains these radionuclides is required for this application. The development of ligands for this purpose, however, is challenging because the large ionic radii and charge-diffuse nature of these metal ions give rise to weaker metal-ligand interactions. In this study, we evaluated two 18-membered macrocyclic chelators, macrodipa and py-macrodipa, for their ability to complex ²²⁵Ac³⁺ and ²¹³Bi³⁺. Their coordination chemistry with Ac³⁺ was probed computationally and with Bi³⁺ experimentally via NMR spectroscopy and X-ray crystallography. Furthermore, radiolabeling studies were conducted, revealing the efficient incorporation of both ²²⁵Ac³⁺ and ²¹³Bi³⁺ by py-macrodipa that matches or surpasses the well-known chelators macropa and DOTA. Incubation in human serum at 37 °C showed that ∼90% of the ²²⁵Ac³⁺-py-macrodipa complex dissociates after 1 d. The Bi³⁺-py-macrodipa complex possesses remarkable kinetic inertness reflected by an EDTA transchelation challenge study, surpassing that of Bi³⁺-macropa. This work establishes py-macrodipa as a valuable candidate for ²¹³Bi³⁺ TAT, providing further motivation for its implementation within new radiopharmaceutical agents.