An NMR relaxometry approach for quantitative investigation of the transchelation of gadolinium ions from GBCAs to a competing macromolecular chelator

Gadolinium-based contrast agents (GBCAs) have been used in clinical Magnetic Resonance Imaging (MRI) for more than 30 years. However, there is increasing evidence that their dissociation in vivo leads to long-term depositions of gadolinium ions in the human body. In vitro experiments provide critical insights into kinetics and thermodynamic equilibria of underlying processes, which give hints towards the in vivo situation. We developed a time-resolved MRI relaxometry-based approach that exploits distinct relaxivities of Gd(3+) in different molecular environments. Its applicability to quantify the transmetallation of GBCAs, the binding of Gd(3+) to competing chelators, and the combined transchelation process is demonstrated. Exemplarily, the approach is applied to investigate two representative GBCAs in the presence of Zn(2+) and heparin, which is used as a model for a macromolecular and physiologically occurring chelator. Opposing indirect impacts of heparin on increasing the kinetic stability but reducing the thermodynamic stability of GBCAs are observed. The relaxivity of resulting Gd-heparin complexes is shown to be essentially increased compared to that of the parent GBCAs so that they might be one explanation for observed long-term MRI signal enhancement in vivo. In forthcoming studies, the presented method could help to identify the most potent Gd-complexing macromolecular species.