Size-Adaptive Macrocyclic Coordination of ²⁰³ Pb, ²⁰⁷ Bi, and ¹³³ Ba by py-Macrodipa and py ₂ -Macrodipa

The coordination chemistry of large metal ions presents fundamental challenges arising from differences in ionic radius, charge, and electronic structure, particularly for heavy p-block and alkaline-earth metals. Herein, we report an experimental and computational investigation of the size-adaptive macrocyclic chelators py-macrodipa and py₂-macrodipa with Pb²⁺, Bi³⁺, and Ba²⁺, with Ba²⁺ employed as a nonradioactive surrogate for Ra²⁺. Potentiometric and spectrophotometric measurements reveal strong aqueous complexation across all three metals, with stability constants of log K = 14.01(1) and 14.37(4) for Pb²⁺, 16.74(2) and 17.36(3) for Bi³⁺, and 7.85(3) and 8.01(5) for Ba²⁺ with py-macrodipa and py₂-macrodipa, respectively. Single-crystal X-ray diffraction, NMR spectroscopy, and density functional theory calculations demonstrate the pronounced conformational flexibility of py-macrodipa and py₂-macrodipa. Radiochemical studies show quantitative labeling of ²⁰³Pb and ²⁰⁷Bi within 5 min at room temperature at micromolar ligand concentrations, comparable to macropa, while ¹³³Ba is quantitatively labeled with a 10⁻⁴ M ligand concentration within 1 h. All complexes remain stable in human serum at 37 °C for up to 5 days. These results demonstrate the potential of py-macrodipa and py₂-macrodipa as chelators for ²⁰³Pb, ²⁰⁷Bi, and ¹³³Ba, suggesting their potential as alternative diagnostic and therapeutic radionuclides.