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

Inorg Chem. 2021 Dec 6;60(23):18082-18093. doi: 10.1021/acs.inorgchem.1c02709. Epub 2021 Nov 17.

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 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 C2v 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 KML = 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.

MeSH terms

  • 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*

Substances

  • Chelating Agents
  • Coordination Complexes
  • Pyrazoles
  • Radiopharmaceuticals
  • Zirconium