Effect of Pendant Groups in Double-Armed Crown Ethers on Lead Radionuclide Chelation

A series of pyridine-containing diaza-18-crown-6 ethers with acetate, phosphonate, acetamide, and picolinate arms were synthesized and fully characterized for Pb²⁺ binding to identify their potential for applications in [^203/212Pb]Pb-based radiopharmaceuticals. Their coordination chemistry with the Pb²⁺ ion was investigated by potentiometry, UV-vis spectrophotometry, mass spectrometry, NMR spectroscopy, X-ray diffraction, radionuclide labeling, as well as in vitro and in vivo experiments. It was shown how the nature of the pendant arms and the presence of a rigid pyridyl unit in the macrocyclic structure affect the basicity of the ligands, the efficiency of radiolabeling, the thermodynamic stability of their complexes in aqueous solutions, and their kinetic inertness in biological environments. Consequently, the picolinate macrocycle PADPA was determined to be the most efficient chelating agent for Pb²⁺, making it a potential candidate for use in radiopharmaceuticals.