Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa.
Chelating Rare-Earth Metals (Ln3+) and 225Ac3+ with the Dual-Size-Selective Macrocyclic Ligand Py2-Macrodipa.
复制标题
使用双尺寸选择性大环配体 Py2-Macrodipa 螯合稀土金属 (Ln3) 和 225Ac3。
DOI：
10.1021/acs.inorgchem.2c01998
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发表时间：
2022
影响因子：
4.6
通讯作者：
Thiele,NikkiA
中科院分区：
文献类型：
--
作者：
Hu,Aohan;Simms,MeganE;Kertesz,Vilmos;Wilson,JustinJ;Thiele,NikkiA
金属元素的放射性同位素或放射性金属广泛应用于治疗和诊断核医学。对于此应用，需要有效结合感兴趣的放射性金属并与其形成稳定的金属配体络合物的螯合剂。为了开发用于核医学的新型螯合剂，我们最近报道了一类新型 18 元大环螯合剂，其特点是能够与大稀土金属和小稀土金属 (Ln3+) 形成稳定的络合物，这种特性被称为双尺寸选择性。此类中的一种特定螯合剂称为 py-macrodipa，其大环核心内含有一个吡啶基，被确定为 135La3+、213Bi3+ 和 44Sc3+ 螯合的有希望的候选者。基于先前的工作，我们在此报告了一种名为 py2-macrodipa 的新型螯合剂的合成和表征，该螯合剂具有两个融合到大环主链中的吡啶基单元。通过核磁共振波谱、X 射线晶体学、密度泛函理论 (DFT) 计算、分析滴定和转螯合分析研究了其与 Ln3+ 系列的配位化学。这些研究表明，与 py-macrodipa 相比，py2-macrodipa 保留了预期的双尺寸选择性，并且对所有 Ln3+ 具有增强的热力学亲和力。相比之下，Ln3+ 与 py2-macrodipa 配合物的动力学稳定性仅针对轻、大的 Ln3+ 离子而得到改善。基于这些观察，我们进一步评估了 py2-macrodipa 与 225Ac3+ 一起使用的适用性，225Ac3+ 是一种大型放射性金属，对于靶向 α 治疗具有有价值的特性。放射性标记和稳定性研究表明 py2-macrodipa 能够有效地掺入 225Ac3+ 并形成在人血清中惰性超过 3 周的复合物。虽然 py2-macrodipa 在 225Ac3+ 螯合方面没有超过最先进的螯合剂 Macropa，但它确实提供了另一种有效的 225Ac3+ 螯合剂。这些研究揭示了 Ln3+ 系列的基本配位化学，并可能激发未来螯合剂的设计工作。
Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal–ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln3+), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for135La3+,213Bi3+, and44Sc3+chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py2-macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln3+series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py2-macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln3+compared to py-macrodipa. By contrast, the kinetic stability of Ln3+complexes with py2-macrodipa is only improved for the light, large Ln3+ions. Based upon these observations, we further assessed the suitability of py2-macrodipa for use with225Ac3+, a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py2-macrodipa to efficiently incorporate225Ac3+and to form a complex that is inert in human serum over 3 weeks. Although py2-macrodipa does not surpass the state-of-the-art chelator macropa for225Ac3+chelation, it does provide another effective225Ac3+chelator. These studies shed light on the fundamental coordination chemistry of the Ln3+series and may inspire future chelator design efforts.