Department of Chemistry, College of Arts and Science, University of Saskatchewan, Saskatoon, SK Canada S7N 5C9.
Molecular and Environmental Science Group, Department of Geological Sciences, College of Arts and Science, University of Saskatchewan, Saskatoon, Canada S7N 5E2.
Inorg Chem. 2020 Dec 7;59(23):17443-17452. doi: 10.1021/acs.inorgchem.0c02725. Epub 2020 Nov 12.
Positron emission tomography (PET) using radiolabeled, monoclonal antibodies has become an effective, noninvasive method for tumor detection and is a critical component of targeted radionuclide therapy. Metal ion chelator and bacterial siderophore desferrioxamine (DFO) is the gold standard compound for incorporation of zirconium-89 in radiotracers for PET imaging because it is thought to form a stable chelate with [Zr]Zr. However, DFO may not bind zirconium-89 tightly , with free zirconium-89 reportedly liberated into the bones of experimental mouse models. Although high bone uptake has not been observed to date in humans, this potential instability has been proposed to be related to the unsaturated coordination sphere of [Zr]Zr-DFO, which is thought to consist of the 3 hydroxamate groups of DFO and 1 or 2 water molecules. In this study, we have used a combination of X-ray absorption spectroscopy and density functional theory (DFT) geometry optimization calculations to further probe the coordination chemistry of this complex in solution. We find the extended X-ray absorption fine structure (EXAFS) curve fitting of an aqueous solution of Zr(IV)-DFO to be consistent with an 8-coordinate Zr with oxygen ligands. DFT calculations suggest that the most energetically favorable Zr(IV) coordination environment in DFO likely consists of the 3 hydroxamate ligands from DFO, each with bidentate coordination, and 2 hydroxide ligands. Further EXAFS curve fitting provides additional support for this model. Therefore, we propose that the coordination sphere of Zr(IV)-DFO is most likely completed by 2 hydroxide ligands rather than 2 water molecules, forming Zr(DFO)(OH).
正电子发射断层扫描（PET）使用放射性标记的单克隆抗体已成为肿瘤检测的有效、非侵入性方法，也是靶向放射性核素治疗的关键组成部分。金属离子螯合剂和细菌铁载体去铁胺（DFO）是将锆-89 掺入放射性示踪剂进行 PET 成像的金标准化合物，因为它被认为与 [Zr]Zr 形成稳定的螯合物。然而，DFO 可能不能紧密结合锆-89，据报道，游离的锆-89会释放到实验小鼠模型的骨骼中。尽管迄今为止在人类中尚未观察到高骨摄取，但这种潜在的不稳定性据推测与 [Zr]Zr-DFO 的不饱和配位球有关，据认为该配位球由 DFO 的 3 个羟肟酸基团和 1 或 2 个水分子组成。在这项研究中，我们使用 X 射线吸收光谱和密度泛函理论（DFT）几何优化计算的组合，进一步探究了该配合物在溶液中的配位化学。我们发现，Zr(IV)-DFO 水溶液的扩展 X 射线吸收精细结构（EXAFS）曲线拟合与具有氧配体的 8 配位 Zr 一致。DFT 计算表明，DFO 中最有利于 Zr(IV)配位的环境可能由 DFO 的 3 个羟肟酸配体组成，每个配体都具有双齿配位，以及 2 个氢氧化物配体。进一步的 EXAFS 曲线拟合为该模型提供了额外的支持。因此，我们提出 Zr(IV)-DFO 的配位球最有可能由 2 个氢氧化物配体而不是 2 个水分子完成，形成 Zr(DFO)(OH)。
