We are developing biochemically responsive MRI contrast agents that capitalize on the transition metal properties of Mn. The Mn(III) and Mn(II) oxidation states are magnetically distinct and we have exploited this behavior to develop contrast agents that provide an exceptionally large MRI “turn off” and “turn on” effect in response to oxidation state interchange mediated by oxidative stresses (H2O2/peroxidase) and biochemical reductants (L-cysteine) respectively. Our prototype ligand, termed JED, is capable of isomerizing between binding motifs that are selective for Mn(III) or Mn(II) and is the first ligand to support persistent and isolable complexes of either oxidation state in biological milieu. Mn-JED was also used to demonstrate that redox active Mn can provide larger “activatable” MR signal modulation than is possible with Gd at any MR field strength. However, the complex exhibits poor solubility which limits formulation at the high concentrations required for bolus injection of MRI contrast, and requires isolation of diastereomerically pure ligand which adds challenges to scale-up for in vivo testing. We will describe our efforts to develop water soluble and achiral Mn complexes that (1) can support both Mn(III) and Mn(II) in biological medium, and (2) provide biochemically responsive MR contrast that is equal or greater to Mn-JED. We will discuss the synthesis, chemical reactivity, biophysical properties (NMR, CV, protein binding, thermodynamic stability, kinetic inertness), and MR contrasting efficacy of these new complexes.

New chelators capable of supporting multiple Mn oxidation states for biochemically responsive MRI contrast agent

256th National Meeting (2018)

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