Picolinamide-functionalized macrocyclic chelators for 203/212Pb theranostic radiotracers

Abstract

Picolinamide-functionalized macrocyclic ligands represent a promising class of chelators for ^203/212Pb-based theranostic applications, offering a dual role in both diagnostic imaging and targeted radiotherapy. In this study, two 18-membered diazacrown ligands, K22_PicAm and the novel NPK_PicAm, were synthesized and complexed with both non-radioactive Pb²⁺ and radiotherapeutic ²¹²Pb²⁺. Structural characterization via NMR spectroscopy and X-ray diffraction confirmed the formation of a single, highly rigid, symmetric [Pb(K22_PicAm)]²⁺ species. Density Functional Theory (DFT) and Natural Bond Orbital (NBO) analysis indicated stereochemically inactive 6s² lone pairs in the Pb²⁺ complexes, leading to holodirected geometries. Potentiometric titrations revealed that both ligand systems form Pb²⁺ complexes with superior thermodynamic stability compared to benchmark chelators DOTAM and macropa. Radiolabelling studies with ²¹²Pb demonstrated near-quantitative radiochemical conversion within 15 minutes. These results establish picolinamide-bearing macrocycles as promising candidates for the development of next-generation, targeted ^203/212Pb theranostic agents and support their further exploration in radiopharmaceutical research.