Thia-Aza Pyridinophane Chelators for Copper Coordination and 64Cu Radiolabeling Studies

Abstract

A new macrocyclic ligand, 3-thia-7-aza-1,5(2,6)-dipyridinacyclooctaphane, has been synthesized and functionalized to produce a family of nitrogen/sulfur–based chelators with tunable donor environments. Alkyl and picolyl derivatives were obtained through selective N-alkylation of the secondary amine site with methyl, isopropyl, and picolyl substituents, and a tridentate macrocyclic NNS analogue was also prepared by N-deletion. The coordination chemistry of these ligands toward Cu(II) and Cu(I) was investigated, and the copper complexes were characterized using X-ray crystallography, UV–vis, cyclic voltammetry (CV), EPR or NMR, and elemental analysis (EA). Acid dissociation constants and metal complex stability constants were determined by UV–Vis spectrophotometric titrations, providing insight into the ligands’ coordination ability. Radiolabeling with 64Cu revealed that while the isopropyl-functionalized complex exhibited moderate radiolabeling efficiency, the picolyl analogue achieved quantitative 64Cu incorporation, underscoring its potential for PET imaging applications.