Abstract
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 (Ln(3+)), 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 (135)La(3+), (213)Bi(3+), and (44)Sc(3+) chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py(2)-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln(3+) series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py(2)-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln(3+) compared to py-macrodipa. By contrast, the kinetic stability of Ln(3+) complexes with py(2)-macrodipa is only improved for the light, large Ln(3+) ions. Based upon these observations, we further assessed the suitability of py(2)-macrodipa for use with (225)Ac(3+), a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py(2)-macrodipa to efficiently incorporate (225)Ac(3+) and to form a complex that is inert in human serum over 3 weeks. Although py(2)-macrodipa does not surpass the state-of-the-art chelator macropa for (225)Ac(3+) chelation, it does provide another effective (225)Ac(3+) chelator. These studies shed light on the fundamental coordination chemistry of the Ln(3+) series and may inspire future chelator design efforts.