H2pyhox - Octadentate Bis(pyridyloxine)

Abstract

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 °C. Whole serum, protein, and ligand challenge assays further demonstrate the kinetic inertness of the [¹¹¹In]In³⁺ and [⁶⁴Cu]Cu²⁺ radiometal-ligand complexes, confirming H₂pyhox to be a promising versatile radiopharmaceutical chelator.