CEMCA, Université Brest, UMR 6521, CNRS, 6 avenue Victor le Gorgeu, 29238 Brest, France.
Department of Chemistry, Stony Brook University, 100 Nicolls Road, Stony Brook, New York 11794, United States.
Inorg Chem. 2023 Dec 18;62(50):20634-20645. doi: 10.1021/acs.inorgchem.3c01417. Epub 2023 Aug 8.
We synthesized, thanks to the regiospecific -functionalization using an orthoamide intermediate, two 1,4,7-triazacyclononane derivatives containing an acetate arm and either a methylpyridine or a picolinic acid group, respectively, H and H, as new Ga chelators for potential use in nuclear medicine. The corresponding Ga complexes were synthesized and structurally characterized in solution by H and C NMR. The [Ga()] complex appears to exist in solution as two diasteroisomeric pairs of enantiomers, as confirmed by density functional theory (DFT) calculations, while for [Ga()], a single species is present in solution. Solid-state investigations were possible for the [Ga()] complex, which crystallized from water as a pair of enantiomers. The average length of the N-Ga bonds of 2.090 Å is identical with that found for the [Ga()] complex, showing that the presence of the picolinate arm does not hinder the coordination of the ligand to the metal ion. Protonation constants of and were determined by potentiometric titrations, providing an overall basicity ∑log ( = 1-4) that increases in the order < < with increases in the negative charge of the ligand. Stability constants determined by pH-potentiometric titrations supplemented with Ga NMR data show that the stabilities of [Ga()] and [Ga()] are lower compared to that of [Ga()] but higher than those of other standards such as [Ga()]. Ga radiolabeling studies were performed in order to demonstrate the potential of these chelators for Ga-based radiopharmaceuticals. The labelings of H and H were nearly identical, outperforming H. Stability studies were conducted in phosphate-buffered saline and in the presence of human serum transferrin, revealing no significant decomplexation of [Ga][Ga()] and [Ga][Ga()] compared to [Ga][Ga()]. Finally, all complexes were found to be highly hydrophilic, with calculated log values of -3.42 ± 0.05, -3.34 ± 0.04, and -3.00 ± 0.23 for H, H, and H, respectively, correlating with the charge of each complex and the electrostatic potentials obtained with DFT.
我们通过使用邻酰胺中间体的区域特异性功能化，合成了两种含有乙酸酯臂的 1,4,7-三氮杂环壬烷衍生物，分别为 H 和 H，作为新的 Ga 螯合剂，用于潜在的核医学应用。相应的 Ga 配合物通过 H 和 C NMR 在溶液中合成并结构表征。[Ga()]配合物似乎以两种非对映异构体对的形式存在于溶液中，正如密度泛函理论（DFT）计算所证实的那样，而对于[Ga()]，则存在一种单一的物种。[Ga()]配合物可以进行固态研究，其从水中结晶为一对对映异构体。N-Ga 键的平均长度为 2.090 Å，与[Ga()]配合物相同，表明吡啶甲酸酯臂的存在不会阻碍配体与金属离子的配位。通过电位滴定法测定了 和 的质子化常数，提供了一个整体碱性∑log （= 1-4），随着配体负电荷的增加，该值按 < < 的顺序增加。pH 电位滴定结合 Ga NMR 数据确定的稳定常数表明，[Ga()]和[Ga()]的稳定性与[Ga()]相比较低，但与其他标准如[Ga()]相比较高。进行了 Ga 放射性标记研究，以证明这些螯合剂用于 Ga 基放射性药物的潜力。H 和 H 的标记几乎相同，优于 H。在磷酸盐缓冲盐水和人血清转铁蛋白存在下进行了稳定性研究，与[Ga][Ga()]和[Ga][Ga()]相比，[Ga][Ga()]没有明显的去络合。最后，所有配合物都被发现具有高度亲水性，计算的 log 值分别为-3.42 ± 0.05、-3.34 ± 0.04 和-3.00 ± 0.23，分别对应于每个配合物的电荷和通过 DFT 获得的静电势。
