Dual-Site Chiral Engineering of a Fully Alkyl-Substituted Gd-DOTA Yields a High-Performance and Safe Hepatobiliary...

Safety concerns associated with the release of a tiny amount of gadolinium (Gd³⁺) from clinically used gadolinium-based contrast agents (GBCAs) underscore the need for ultrastable alternatives for magnetic resonance imaging (MRI). Here we report Gd-L2, a fully alkyl-substituted, chiral Gd-DOTA derivative incorporating a tetraethyl-substituted cyclen backbone and α-arm methyl groups. This dual-site chiral design enhances both kinetic inertness and relaxivity, providing a structurally robust platform for hepatobiliary MRI contrast enhancement. Gd-L2 exhibits an OATP-mediated hepatic uptake, enabling selective liver accumulation followed by efficient renal clearance. In orthotopic hepatocellular carcinoma (HCC) mouse models, the complex achieves pronounced tumor margin delineation, highlighting its potential for early HCC detection. Collectively, this work establishes a nonaromatic molecular engineering strategy for the development of next-generation hepatobiliary MRI contrast agents that combine high stability, enhanced performance, and targeted functionality.