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Mn2+ Bispidine Complex Combining Exceptional Stability, Inertness, and MRI Efficiency
Journal of the American Chemical Society ( IF 15.0 ) Pub Date : 2022-11-29 , DOI: 10.1021/jacs.2c10108
Daouda Ndiaye 1 , Patrick Cieslik 2 , Hubert Wadepohl 2 , Agnès Pallier 1 , Sandra Même 1 , Peter Comba 2, 3 , Éva Tóth 1
Affiliation  

As an essential metal ion and an efficient relaxation agent, Mn2+ holds a great promise to replace Gd3+ in magnetic resonance imaging (MRI) contrast agent applications, if its stable and inert complexation can be achieved. Toward this goal, four pyridine and one carboxylate pendants have been introduced in coordinating positions on the bispidine platform to yield ligand L3. Thanks to its rigid and preorganized structure and perfect size match for Mn2+, L3 provides remarkably high thermodynamic stability (log KMnL = 19.47), selectivity over the major biological competitor Zn2+ (log(KMnL/KZnL) = 4.4), and kinetic inertness. Solid-state X-ray data show that [MnL3(MeOH)](OTf)2 has an unusual eight-coordinate structure with a coordinated solvent molecule, in contrast to the six-coordinate structure of [ZnL3](OTf), underlining that the coordination cavity is perfectly adapted for Mn2+, while it is too large for Zn2+. In aqueous solution, 17O NMR data evidence one inner sphere water and dissociatively activated water exchange (kex298 = 13.5 × 107 s–1) for MnL3. Its water proton relaxivity (r1 = 4.44 mM–1 s–1 at 25 °C, 20 MHz) is about 30% higher than values for typical monohydrated Mn2+ complexes, which is related to its larger molecular size; its relaxation efficiency is similar to that of clinically used Gd3+-based agents. In vivo MRI experiments realized in control mice at 0.02 mmol/kg injected dose indicate good signal enhancement in the kidneys and fast renal clearance. Taken together, MnL3 is the first chelate that combines such excellent stability, selectivity, inertness and relaxation properties, all of primary importance for MRI use.

中文翻译:

Mn2+ Bispidine 复合物兼具出色的稳定性、惰性和 MRI 效率

作为必需的金属离子和有效的弛豫剂,如果能够实现稳定和惰性的络合,Mn 2+有望在磁共振成像 (MRI) 造影剂应用中取代 Gd 3+ 。为实现这一目标,已将四个吡啶和一个羧酸酯悬垂物引入双spidine 平台上的配位位置以产生配体L 3。由于其刚性和预先组织的结构以及与 Mn 2+的完美尺寸匹配,L 3提供了非常高的热力学稳定性(log K MnL = 19.47),对主要生物竞争者 Zn 2+的选择性(log (K MnL / KZnL ) = 4.4) 和动力学惰性。固态X射线数据显示[MnL 3 (MeOH)](OTf) 2具有不寻常的八配位结构和配位溶剂分子,与[ZnL 3 ](OTf)的六配位结构形成对比,强调配位腔非常适合 Mn 2+ ,而对于 Zn 2+来说太大了。在水溶液中,17 O NMR 数据证明 MnL 3存在一个内球水和解离活化水交换 ( k ex 298 = 13.5 × 10 7 s –1 ) 。其水质子弛豫率 ( r 1= 4.44 mM –1 s –1 at 25 °C, 20 MHz) 比典型的一水合 Mn 2+络合物的值高约 30%,这与其较大的分子大小有关;其弛豫效率与临床上使用的Gd 3+基药物相似。以 0.02 mmol/kg 注射剂量在对照小鼠中实现的体内MRI 实验表明肾脏信号增强良好且肾脏清除速度快。总之,MnL 3是第一个结合了如此出色的稳定性、选择性、惰性和弛豫特性的螯合物,所有这些特性对于 MRI 使用都是最重要的。
更新日期:2022-11-29
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