Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa

Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal-ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln³⁺), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for ¹³⁵La³⁺, ²¹³Bi³⁺, and ⁴⁴Sc³⁺ chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py₂-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln³⁺ series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py₂-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln³⁺ compared to py-macrodipa. By contrast, the kinetic stability of Ln³⁺ complexes with py₂-macrodipa is only improved for the light, large Ln³⁺ ions. Based upon these observations, we further assessed the suitability of py₂-macrodipa for use with ²²⁵Ac³⁺, a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py₂-macrodipa to efficiently incorporate ²²⁵Ac³⁺ and to form a complex that is inert in human serum over 3 weeks. Although py₂-macrodipa does not surpass the state-of-the-art chelator macropa for ²²⁵Ac³⁺ chelation, it does provide another effective ²²⁵Ac³⁺ chelator. These studies shed light on the fundamental coordination chemistry of the Ln³⁺ series and may inspire future chelator design efforts.