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

• Published in: Inorganic chemistry 2021-12, Vol.60 (23), p.18082-18093
• Main Authors: Southcott, Lily, Li, Lily, Patrick, Brian O, Stephan, Holger, Jaraquemada-Peláez, María de Guadalupe, Orvig, Chris
• Format: Article
• Language: English
• Subjects: Chelating Agents - chemistry; Coordination Complexes - blood; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Crystallography, X-Ray; Humans; Kinetics; Models, Molecular; Molecular Conformation; Pyrazoles - blood; Pyrazoles - chemistry; Radiopharmaceuticals - blood; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Thermodynamics; Zirconium - blood; Zirconium - chemistry
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.1c02709

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 nonradioactive 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 C 2v symmetry of the complex. The geometry of [Zr­(pypa)] was further detailed via X-ray crystallography and compared with 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 K ML = 38.92, pZr = 39.4). Radiochemical studies demonstrated quantitative radiolabeling achieved at 10 μM chelator concentration within 2 h at 40 °C and pH = 7, antibody-compatible conditions. Of the 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 toward human serum.