Jian Yong, Cai Zheng, Ding Yinghui, Zhang Zhichao, Mo Gengshen, Zhou Xinlan, Xu Weiyuan, Yan Zhihan, Carniato Fabio, Ye Fangfu, Botta Mauro, Dai Lixiong
Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China.
J Med Chem. 2025 Jul 24;68(14):14254-14270. doi: 10.1021/acs.jmedchem.4c03122. Epub 2025 Jul 10.
The safety issues of MRI contrast agents in clinical practice have raised significant concerns, which can lead to adverse effects such as nephrogenic systemic fibrosis and metal deposition in the brain. Herein, we designed two innovative chiral pyclen-based octadentate Gd(III) complexes, and . Compared to the achiral , these chiral complexes exhibited substantial enhancements in relaxivity, by 52.0% and 36.9%, respectively. They also demonstrated improvements in thermodynamic stability and kinetic inertness. DFT calculations revealed that the strong coordination of pendant arm oxygen atoms with the Gd(III) ion contributes to the observed kinetic inertness. Variable-temperature O NMR measurements showed that and possess shorter inner-sphere water residence lifetimes, resulting in water exchange rates approximately twice as high as that of . imaging and biodistribution studies further highlighted their distinct clearance pathways: exhibited dual hepatic and renal clearance, whereas was exclusively cleared via the renal route.
磁共振成像（MRI）造影剂在临床实践中的安全性问题引发了重大关注，这些问题可能导致诸如肾源性系统性纤维化和脑部金属沉积等不良反应。在此，我们设计了两种基于手性吡咯烷的创新八齿钆（III）配合物， 和 。与非手性的 相比，这些手性配合物的弛豫率分别显著提高了52.0%和36.9%。它们在热力学稳定性和动力学惰性方面也有改善。密度泛函理论（DFT）计算表明，侧链臂氧原子与钆（III）离子的强配位作用有助于观察到的动力学惰性。变温氧核磁共振测量表明， 和 的内球水停留寿命较短，导致水交换率约为 的两倍。成像和生物分布研究进一步突出了它们不同的清除途径： 表现出肝脏和肾脏双重清除，而 仅通过肾脏途径清除。
