Insights into the Responding Modes of Highly Potent Gadolinium-Based Magnetic Resonance Imaging Probes Sensitive to Zinc Ions

Zn ions (Zn2+) play an important biological role in many diseases; hence, an imaging method for monitoring the Zn2+ distribution in tissues could provide important clinical insights. Recently, we reported a potent Zn-sensitive probe based on the Gd-DO3A (DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-tricarboxylic acid), modified tyrosine. and di(2-picolyl)amine chelator for this metal cation, which generates an outstanding magnetic resonance imaging (MRI) response. Here we further explored the origin of this unprecedented response and expanded the choice of potential MRI probes by preparing the free acid version of the initial MRI sensor. We report a detailed investigation of the 1H NMR dispersion, 17O NMR, and isothermal titration calorimetry properties of these two MRI probes upon interaction with Zn2+. The performed experiments confirm selective interaction of the MRI probes and target metal cation, which causes substantial changes in the coordination sphere of the paramagnetic center. It also evidenced some aggregation, which enhances the relaxivity response. Interestingly, conversion of the methyl ester to the free carboxylic acid of the tyrosine moiety changes the nature of the aggregates and leads to a smaller relaxivity response. The probes interact with human serum albumin (HSA) in the absence of Zn2+, which leads to a possible modification of the coordination sphere of Gd3+ or a substantial change in the exchange rate of second-sphere water molecules. In the presence of Zn2+, the interaction with HSA is very weak, demonstrating the importance of the Zn2+ coordination sphere in the behavior of these systems