Relaxation-Based In Vivo Discrimination of Oxidized and Reduced States of a Redox-Switchable 19F MRI Probe
Résumé
MRI assessment of the tissue redox state is important for revealing and understanding various pathologies, and redox responsive imaging probes capable of generating discrete and quantifiable signals both in their reduced and oxidized forms can provide enhanced detection reliability. The small fluorinated, redox-active FeL1 chelate is a prototype of such agents. L1 forms stable and inert complexes with both Fe2+ and Fe3+ions, and the redox potential of the Fe3+ L1/Fe2+L1 couple (+240 mV vs. NHE) is adapted to biological redox sensing. Fe2+L1 undergoes instantaneous oxidation in the presence of H2O2, and Fe3+L1 is reduced by cysteine, glutathione and ascorbate. Fe2+L1 and Fe3+L1 have very different proton relaxivities (0.1 mM -1 s -1 and 2.83 mM -1 s -1 , respectively, 60 MHz, 298 K), as well as 19F relaxation times (T1 = 71-130 ms; T2 = 60-117 ms and T1 = 2.43 ms; T2 = 1.81 ms, respectively, 400 MHz, 298 K), in accordance with the different paramagnetic relaxation enhancement capacity of the two iron redox states. Upon applying specific MRI pulse sequences adapted to the relaxation rate (RARE for Fe2+L1 and UTE for Fe3+L1, combined with appropriate acquisition parameters), both redox forms are detected in 19F MR phantom images with good sensitivity and signal-to-noise ratios linearly dependent on probe concentration. Fe2+L1 and Fe3+L1 can be readily visualized and unambiguously discriminated based on their 19 F relaxation times in living mice, following intramuscular injection. The possibility to monitor the redox switch in 1 H MRI as well is an additional advantage of this bioresponsive probe.
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