Impact of Bipyridine and Phenanthroline Incorporation into the Macropa Scaffold on Ba(II)/Ra(II) Chelation

Two new decadentate macrocyclic chelators, bpycropa and phencropa, were synthesized by incorporating 2,2'-bipyridine and 1,10-phenanthroline units, respectively, into the picolinate-functionalized aza-crown ether scaffold of macropa, with the aim of enhancing cavity preorganization for heavy alkaline earth metal complexation. Both ligands and their barium complexes, employed as nonradioactive surrogates for radium-223, were characterized by NMR spectroscopy, mass spectrometry, potentiometric titrations, X-ray crystallography, and DFT calculations. Solid-state structures revealed asymmetric coordination geometries markedly different from the more symmetric arrangement in [Ba(macropa)], reflecting conformational constraints imposed by the aromatic fragments. Under physiologically relevant conditions, phencropa exhibited thermodynamic stability toward Ba(II) comparable to macropa (pBa = 11.7 vs 11.6), while bpycropa showed lower affinity (pBa = 10.0). Kinetic studies demonstrated enhanced inertness for both systems relative to macropa, with dissociation half-lives of 71.3 min for [Ba(bpycropa)] and 160.5 min for [Ba(phencropa)] compared to 21 min for [Ba(macropa)] (20 °C, pH 7.4, 10 mM, I = 0.15 M NaCl). Despite these promising results, radiolabeling studies with radium-223 revealed that neither chelator achieved the serum stability of [223Ra]Ra-macropa, highlighting the delicate interplay between preorganization, donor atom composition, and kinetic inertness required for effective radium coordination and offering design principles for next-generation chelators.