Coordination Chemistry of a Hybrid N/S Macrocyclic Framework: PyN2S Chelators toward Stabilization of 64Cu(II/I) in PET Imaging Applications

Abstract In recent efforts to develop optimal 64Cu chelators with ideal thermodynamic stability and high kinetic inertness, focus has shifted to the common problem of reduction-induced demetalation of 64Cu(I). The most common approach to remedy this issue is to make the reduction of 64Cu(II) to 64Cu(I) inaccessible, with anionic ligands comprising hard Lewis bases like carboxylates. However, an alternative approach has been to focus on the stability of the 64Cu(I) species, most commonly achieved by incorporating soft sulfur donors, such as thiols or thioethers, into the chelator framework. Herein, we present a novel copper chelator, PyN2S, comprising both N and S donors, allowing for an N3S binding mode. Five new ligands are introduced, and their coordination chemistry with copper is explored. Thermodynamic stability constants with Cu2+ and Zn2+ are presented, as well as solution and solid-state characterization of the Cu(II) complexes. Finally, the radiochemistry of the PyN2S ligands with 64Cu was explored, including both in vitro characterization and in vivo biodistribution in mice. Overall, the PyN2S framework has demonstrated promising stability for both Cu(II) and Cu(I), and quantitative radiolabeling with 64Cu was achieved, while in vivo biodistribution revealed the highest uptake in renal clearance pathway organs.