Rational Design of Gd-DOTA-Type Contrast Agents for Hepatobiliary Magnetic Resonance Imaging

Abstract

The safety risks of gadolinium (Gd³⁺)-based contrast agents (GBCAs) arise from their inevitable leakage of Gd³⁺, and the pursuit of more stable GBCAs for magnetic resonance imaging (MRI) has drawn increasing attention. Yet, Gd-EOB-DTPA and Gd-BOPTA are the only two authorized GBCAs for liver diagnosis in spite of their weak stability. In this study, one of the pendent arms of the most inert commercial Gd-DOTA was decorated with phenyl moieties, in which obvious enhancements of both kinetic and thermodynamic stability were achieved. <b>Gd-L</b>_<b>4</b> with a para-substituted OBn group was observed with ready hepatocellular uptake, with significant contrast provided in diagnosing orthotopic hepatocellular carcinoma, and its hepatobiliary secretion accounted for more than 50% of the injection dose in mice. In this study, <b>Gd-L</b>_<b>4</b> was found with comparable performance in liver MRI diagnosis to that of commercial Gd-EOB-DTPA and was thus deemed as an ideal candidate for further clinical applications.