Comprehensive Magnetic Resonance Imaging Relaxometry of Gadolinium‐Based Contrast Agents: A Systematic Study of Transmetallation and Transchelation Processes With Zinc Ions and Heparin

Gadolinium-based contrast agents (GBCAs) are essential in medical imaging, but concerns remain about their long-term safety. An increasing number of studies indicate that gadolinium can accumulate in human tissues. The initial step is transmetallation, whereby endogenous ions displace Gd(III) ions from its chelate. Subsequently, a transchelation process allows ion binding to macromolecules, such as glycosaminoglycans (GAGs), and tissue deposits may form. However, the clinical impact and potential connection to gadolinium deposition disease remain uncertain and require further research. In this study, magnetic resonance imaging relaxometry was employed to investigate the molecular interactions of eight clinically relevant GBCAs with Zn(II) ions and GAGs. Taking advantage of the characteristic relaxivity changes of Gd(III) ions in different environments enabled detection and quantification of free Gd(III) ions, as well as of the macromolecule-bound species. The investigation revealed distinct relaxivity patterns of Gd-accessible water that are specific for each GBCA, highlighting differences in intrinsic stability when challenged by competing ions or alternative chelators. Evaluation of transitions between equilibrium states enables comparative assessment of reaction kinetics for deeper insights into the observables of GBCA behavior. Thus, relaxometry emerges as a robust analytical platform, offering valuable guidance for improving existing contrast agents and designing safer, more stable alternatives.