H2pyhox - Octadentate Bis(pyridyloxine)

A new versatile chelating ligand for intermediate size and softness radiometals [64Cu]Cu2+ and [111In]In3+, H2pyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu2+, La3+ and In3+ demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu2+, In3+ and La3+. Preliminary concentration dependent radiolabeling studies with [111In]In3+ and [64Cu]Cu2+ show the robustness of H2pyhox to successfully coordinate both radiometals under mild conditions (< 15 min, room temperature, pH 6). H2pyhox is the first oxinate ligand to successfully radiolabel [225Ac]Ac3+, albeit only at high concentrations (0.1 – 1 mM) with gentle heating to 37℃. Whole serum, protein and ligand challenge assays further demonstrate the kinetic inertness of the radiometal-ligand complexes, confirming H2pyhox to be a promising versatile radiopharmaceutical chelator.