Picolinate- and Phosphonated Pyridyl-TACN Ligands for Highly Stable and Inert Cu(II) Complexes for Radiochemical Applications

Abstract In this study, three novel chelators based on the 1,4,7-triazacyclononane (TACN) ligand platform were introduced. The ligands contain picolinate and phosphonated pyridine chelating arms to provide an optimal five-coordinate geometry for Cu(II). The solution chemistry of these complexes was systematically investigated using spectrophotometric titrations, UV-vis spectroscopy, electron paramagnetic resonance (EPR), and cyclic voltammetry (CV). Then, these ligands were employed in 64Cu radiolabeling studies and subsequent in vivo positron emission tomography (PET) imaging studies to reveal that the 64Cu complexes of the two phosphonated pyridine-TACN ligands were excreted via the renal pathway, while the picolinate-TACN analogue exhibited a shift in the excretion pathway due to its lipophilic nature, resulting in partial liver excretion. To our knowledge, the use of phosphonated pyridines as chelators in 64Cu PET imaging is uncommon, which underscores the significance of this study.