Reactive oxygen species (ROS) are hypothesized to play a key role in the pathogenesis of myriad organ related disease. In this regard, we are developing redox active iron complexes as contrast agents to non-invasively image and quantify ROS using MRI. Complexes of high-spin Fe3+ are potent MR relaxation agents that generate positive MRI contrast, whereas complexes of Fe2+ are much weaker relaxation agents. Using the chelate Fe-PyC3A as an unoptimized prototype, we demonstrated that we could generate over an order of magnitude MR signal turn on by ROS mediated oxidation of Fe2+-PyC3A to Fe3+-PyC3A and this ROS-mediated “turn on” generates strong, selective contrast enhancement of acutely inflamed tissue in a murine model of pancreatitis. We are currently working to further optimize redox active Fe complexes to selectively react with different ROS. We hypothesize that we can control ROS specificity by fine tuning the Fe3+/Fe2+ redox potential. To test this hypothesis, we screened a focused library of over ten structurally related iron complexes as ROS responsive contrast agents. The Fe3+ and Fe2+ complexes were isolated independently and characterized by HPLC, MS, cyclic voltammetry, and UV-Vis. We also quantified the rates of Fe2+ to Fe3+ oxidation in the presence of O2 and ROS and assayed for aerobic redox cycling under ROS forcing conditions using the thiobarbituric acid reactive substances spectrophotometric assay. Our data demonstrates that by carefully tuning the redox potentials, we can develop Fe2+ complexes that are indefinitely resistant to aerobic oxidation but are rapidly “activated” to the Fe3+ “on state” by ROS like hydrogen peroxide. Implications for design of ROS-sensing MRI contrast agents will be discussed.

Structure-reactivity relationships governing iron-based and reactive oxygen species specific MRI contrast agents

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.