Facile Synthesis of a Bis‐ α ‐aryl‐Substituted Pyclen‐Based Heptadentate Lanthanide Chelator for Ultra‐Robust and High‐Contrast MRI Agents and for Radiopharmaceuticals
Pak‐Lun Lam, Yik‐Hoi Yeung, Hei‐Yui Kai, Yujie Xie, Zhengxiao Liu, Stuart J. Elliott, Edward R. H. Walter, Feilong Liu, Wanqi Zhou, Yue Wu, Ju Jiao, Ho‐Fai Chau, Ga‐Lai Law, Nicholas J. Long, Jean‐Claude G. Bünzli, Ka‐Leung WongABSTRACT
Owing to safety concerns associated with previous gadolinium‐based magnetic resonance imaging (MRI) agents, pyclen‐based Gd chelates are emerging as promising alternatives. However, the development of pyclen‐based chelators has been hindered by synthetic challenges. In this work, we report two new pyclen‐based chelators featuring α ‐aryl‐substituents on two of the acetate arms. Using the Petasis reaction, two lanthanide chelators 3a and 3b were synthesized in just two steps from pyclen. 3a‐Gd exhibits superior coordination stability and relaxivity compared to previously reported Gd 3+ chelates of comparable molecular weight. It also has low cytotoxicity and produces a strong, long‐lasting in vivo MRI signal, enabling real‐time monitoring of tissues/organs, as demonstrated in heart, liver, and kidney imaging of mice. Additionally, the chelator also shows improved coordination kinetics for In 3+ , Tb 3+ , Lu 3+ , and Y 3+ , highlighting its potential for the development of a new class of next‐generation radiopharmaceuticals.