Insights into the Responding Modes of Highly Potent Gadolinium-Based Magnetic Resonance Imaging Probes Sensitive to Zinc Ions
Résumé
Zinc ions (Zn 2+) play an important biological role in many diseases, hence an imaging method for monitoring the Zn 2+ 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 DPA (di-(2-picolyl)amine) chelator for this metal cation, which generates outstanding magnetic resonance imaging (MRI) response. Here we further explored the origin of this unprecedented response and expanded the choice of the potential MRI probes by preparing the free acid version of the initial MRI sensor. We report a detailed investigation of the 1 H nuclear magnetic relaxation dispersion (NMRD), 17 O NMR and isothermal titration calorimetry properties of these two MRI probes upon interacting with Zn 2+. The performed experiments confirm the selective interaction of the MRI probes and the 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 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 Zn 2+ , which leads to a possible modification of the coordination sphere of Gd 3+ or a substantial change in the exchange rate of second sphere water molecules. In the presence of Zn 2+ , the interaction with HSA is very weak, demonstrating the importance of the Zn 2+ coordination sphere in the behavior of these systems.
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