Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Inorg Chem. 2020 May 18;59(10):7238-7251. doi: 10.1021/acs.inorgchem.0c00671. Epub 2020 Apr 27.
A phosphinate-bearing picolinic acid-based chelating ligand (Hdappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In, Lu, Y, Sc, La, Bi). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes. The thermodynamic stability of Hdappa with four metal ions (In, Lu, Y, Sc) was deeply investigated via potentiometric and spectrophotometric (UV-vis) titrations, employing a combination of acidic in-batch, joint potentiometric/spectrophotometric, and ligand-ligand competition titrations; high stability constants and pM values were calculated for all four metal complexes. Radiolabeling conditions for three clinically relevant radiometal ions were optimized ([In]In, [Lu]Lu, [Y]Y), and the serum stability of [In][In(dappa)] was studied. Through concentration-, time-, temperature-, and pH-dependent labeling experiments, it was determined that Hdappa radiolabels most effectively at near-physiological pH for all radiometal ions. Furthermore, very rapid radiolabeling at ambient temperature was observed, as maximal radiolabeling was achieved in less than 1 min. Molar activities of 29.8 GBq/μmol and 28.2 GBq/μmol were achieved for [In]In and [Lu]Lu, respectively. For Hdappa, high thermodynamic stability did not correlate with kinetic inertness-lability was observed in serum stability studies, suggesting that its metal complexes might not be suitable as a BFC in radiopharmaceuticals.
合成了一种含膦酸的吡啶酸基螯合配体（Hdappa），并对其进行了表征，以评估其作为无机放射性药物双功能螯合剂（BFC）的潜力。采用核磁共振（NMR）光谱研究了配体与各种非放射性三价金属离子（In、Lu、Y、Sc、La、Bi）的配位化学。密度泛函理论（DFT）计算研究了上述金属配合物的配位环境。通过电位法和分光光度法（UV-vis）滴定，结合酸批内、联合电位/分光光度法和配体-配体竞争滴定，深入研究了 Hdappa 与四种金属离子（In、Lu、Y、Sc）的热力学稳定性；计算了所有四种金属络合物的高稳定性常数和 pM 值。优化了三种临床相关放射性金属离子的标记条件（[In]In、[Lu]Lu、[Y]Y），并研究了[In][In（dappa）]的血清稳定性。通过浓度、时间、温度和 pH 值依赖性标记实验，确定 Hdappa 在接近生理 pH 值的条件下对所有放射性金属离子的标记效果最佳。此外，在环境温度下观察到非常快速的标记，因为在不到 1 分钟的时间内达到了最大标记。[In]In 和[Lu]Lu 的摩尔活度分别达到 29.8GBq/μmol 和 28.2GBq/μmol。对于 Hdappa，高热力学稳定性与动力学惰性之间没有相关性-在血清稳定性研究中观察到不稳定性，表明其金属配合物可能不适合作为放射性药物中的 BFC。
