Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Inorg Chem. 2021 Mar 15;60(6):4076-4092. doi: 10.1021/acs.inorgchem.1c00152. Epub 2021 Feb 26.
A comparative investigation of two structurally related potentially nonadentate chelating ligands, Hneunpa-NH and Hnoneunpa, has been undertaken to examine the influence of bifunctionalization on their coordination chemistry and metal ion selectivity. Significantly improved synthetic routes for each compound have been developed, employing straightforward high-yielding strategies. Radiolabeling studies with [Sc]Sc, [In]In, [Lu]Lu, and [Ac]Ac revealed a sharp contrast between the affinity of each chelator for large radiometal ions. Hnoneunpa demonstrated highly effective coordination of [Lu]Lu and [Ac]Ac achieving quantitative radiochemical yields (>98%) at ligand concentrations of 10 M (room temperature (RT), 10 min), with excellent stability when challenged in human serum, while Hneunpa-NH was unable to complex either metal ion effectively. Nuclear magnetic resonance (NMR) spectroscopy was employed to explore the coordination chemistry of each chelating ligand with nonradioactive metal ions, spanning a range of ionic radii and coordination numbers. A comprehensive conformational analysis of each metal complex was undertaken using density functional theory (DFT) calculations to explore the coordination geometries and explain the discrepancy in binding characteristics. Theoretical simulations revealed notable differences in the coordination geometry and apparent denticity of each ligand, which together account for the observed selectivity in metal binding and have important implications for the future design of complexes based upon this framework to target large radiometal ion coordination.
已经对两种结构相关的潜在非齿状螯合配体 Hneunpa-NH 和 Hnoneunpa 进行了比较研究，以考察双官能化对其配位化学和金属离子选择性的影响。为每个化合物开发了显著改进的合成途径，采用简单的高产策略。用 [Sc]Sc、[In]In、[Lu]Lu 和 [Ac]Ac 进行的放射性标记研究表明，每个螯合剂对大放射性金属离子的亲和力之间存在明显的对比。Hnoneunpa 表现出对 [Lu]Lu 和 [Ac]Ac 的高度有效配位，在 10 M（室温（RT），10 分钟）的配体浓度下实现了定量放射性化学产率（>98%），在人血清中受到挑战时具有极好的稳定性，而 Hneunpa-NH 则无法有效络合任何金属离子。核磁共振（NMR）光谱用于研究每个螯合配体与非放射性金属离子的配位化学，涵盖了一系列离子半径和配位数。使用密度泛函理论（DFT）计算对每个金属配合物进行了全面的构象分析，以探索配位几何形状并解释结合特征的差异。理论模拟揭示了每个配体的配位几何形状和表观齿合度的显著差异，这共同解释了金属结合的选择性，并对基于该框架设计靶向大放射性金属离子配位的配合物具有重要意义。
