[nat/89Zr][Zr(pypa)]: Thermodynamically Stable and Kinetically Inert Binary Nonadentate Complex for Radiopharmaceutical Applications

Abstract
H4pypa is a nonadentate nonmacrocyclic chelator which previously demonstrated high affinity for scandium-44, lutetium-177 and indium-111. Herein, we report the highly stable binary [Zr(pypa)] complex; the non-radioactive complex was synthesized and characterized in detail using high resolution
electrospray-ionization mass spectroscopy (HR-ESI-MS) and various nuclear magnetic resonance spectroscopies (NMR), which revealed a C2v-symmetry of the complex. The geometry of [Zr(pypa)] was further detailed via X-ray crystallography and compared to the structure of [Fe(Hpypa)]. Despite a slow complexation rate with an association half-life of 31.4 h at pH 2 and room temperature, the [Zr(pypa)] complex is thermodynamically stable (log KML = 38.92, pZr =39.4). Radiochemical studies demonstrated quantitative radiolabeling achieved at 10 µM chelatorconcentration within 2 h at 40°C and pH = 7, antibody-compatible conditions. Of utmost importance, [89Zr][Zr(pypa)] is highly kinetically inert upon challenge with excess EDTA and DFO ligands, superior to [89Zr][Zr(DFO)], and maintains inertness towards human serum.