The radionuclide 213 Bi can be applied for targeted α therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi 3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi 3+ center arising from the stereochemically active 6s 2 lone pair. The kinetic properties of the Bi 3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms

A comparative investigation of two structurally related potentially nonadentate chelating ligands, H4neunpa-NH2 and H4noneunpa, has been undertaken to examine the influence of bifunctionalization on their coordination chemistry and metal ion selectivity. Significantly improved synthetic routes for each compound have been developed, employing straightforward high-yielding strategies. Radiolabeling studies with [44Sc]­Sc3+, [111In]­In3+, [177Lu]­Lu3+, and [225Ac]­Ac3+ revealed a sharp contrast between the affinity of each chelator for large radiometal ions. H4noneunpa demonstrated highly effective coordination of [177Lu]­Lu3+ and [225Ac]­Ac3+ achieving quantitative radiochemical yields (>98%) at ligand concentrations of 10–6 M (room temperature (RT), 10 min), with excellent stability when challenged in human serum, while H4neunpa-NH2 was unable to complex either metal ion effectively. Nuclear magnetic resonance (NMR) spectroscopy was employed to explore the coordination chemistry of each chelating ligand with nonradioactive metal ions, spanning a range of ionic radii and coordination numbers. A comprehensive conformational analysis of each metal complex was undertaken using density functional theory (DFT) calculations to explore the coordination geometries and explain the discrepancy in binding characteristics. Theoretical simulations revealed notable differences in the coordination geometry and apparent denticity of each ligand, which together account for the observed selectivity in metal binding and have important implications for the future design of complexes based upon this framework to target large radiometal ion coordination.

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.