Department of Chemistry, College of Arts and Science, University of Saskatchewan, Saskatoon, SKS7N 5C9, Canada.
Molecular and Environmental Science Group, Department of Geological Sciences, College of Arts and Science, University of Saskatchewan, Saskatoon, SKS7N 5E2, Canada.
Inorg Chem. 2023 Feb 13;62(6):2637-2651. doi: 10.1021/acs.inorgchem.2c03573. Epub 2023 Jan 30.
Desferrioxamine (DFO) has long been considered the gold standard chelator for incorporating [Zr]Zr in radiopharmaceuticals for positron emission tomography (PET) imaging. To improve the stability of DFO with zirconium-89 and to expand its coordination sphere to enable binding of large therapeutic radiometals, we have synthesized the highest denticity DFO derivatives to date: dodecadentate DFO2 and DFO2p. In this study, we describe the synthesis and characterization of a novel DFO-based chelator, DFO2p, which is comprised of two DFO strands connected by an -NO-phenyl linker and therefore contains double the chelating moieties of DFO (potential coordination number up to 12 vs 6). The chelator DFO2p offers an optimized synthesis comprised of only a single reaction step and improves water solubility relative to DFO2, but the shorter linker reduces molecular flexibility. Both DFO2 and DFO2p, each with 6 potential hydroxamate ligands, are able to reach a more energetically favorable 8-coordinate environment for Zr(IV) than DFO. The zirconium(IV) coordination environment of these complexes were evaluated by a combination of density functional theory (DFT) calculations and synchrotron spectroscopy (extended X-ray absorption fine structure), which suggest the inner-coordination sphere of zirconium(IV) to be comprised of the outermost four hydroxamate ligands. These results also confirm a single Zr(IV) in each chelator, and the hydroxide ligands which complete the coordination sphere of Zr(IV)-DFO are absent from Zr(IV)-DFO2 and Zr(IV)-DFO2p. Radiochemical stability studies with zirconium-89 revealed the order of real-world stability to be DFO2 > DFO2p ≫ DFO. The zirconium-89 complexes of these new high-denticity chelators were found to be far more stable than DFO, and the decreased molecular flexibility of DFO2p, relative to DFO2, could explain its decreased stability, relative to DFO2.
去铁胺（DFO）长期以来一直被认为是将[Zr]Zr 掺入正电子发射断层扫描（PET）成像放射性药物的金标准螯合剂。为了提高 DFO 与锶-89 的稳定性，并扩展其配位场以允许结合大的治疗放射性金属，我们合成了迄今为止最高齿密度的 DFO 衍生物：十二齿 DFO2 和 DFO2p。在这项研究中，我们描述了一种新型 DFO 基螯合剂 DFO2p 的合成和表征，它由两个通过-NO-苯基连接体连接的 DFO 链组成，因此含有两倍的螯合部分（潜在配位数高达 12 比 6）。配体 DFO2p 提供了一个仅由单个反应步骤组成的优化合成，并提高了相对于 DFO2 的水溶性，但较短的连接体降低了分子的灵活性。DFO2 和 DFO2p 都有 6 个潜在的羟肟酸配体，都能够为 Zr(IV) 达到更具能量优势的 8 配位环境，而不是 DFO。通过密度泛函理论（DFT）计算和同步辐射光谱（扩展 X 射线吸收精细结构）相结合，评估了这些配合物的锆（IV）配位环境，这表明锆（IV）的内配位球由最外层的四个羟肟酸配体组成。这些结果还证实了每个螯合剂中只有一个 Zr(IV)，并且在 Zr(IV)-DFO 中不存在完成 Zr(IV)配位球的氢氧化物配体。锶-89 的放射化学稳定性研究表明，实际稳定性的顺序为 DFO2 > DFO2p ≫ DFO。这些新的高齿密度螯合剂的锶-89 配合物被发现比 DFO 稳定得多，而 DFO2p 相对于 DFO2 的分子灵活性降低可能解释了其相对 DFO2 的稳定性降低。
