An overly anionic metal coordination environment eliminates the T1-weighted response of quinol-containing MRI contrast agent sensors to H2O2

A hexadentate anionic ligand with two redox-active quinol groups was synthesized and tested as a component for a MRI contrast agent. Although the ligand binds more strongly to Mn(II) than a previously reported ligand and can be used to prepare a Mn(II) complex that does not react with O2, its Mn(II) complex does not display a T1-weighted relaxivity response to H2O2. [Display omitted] •A more anionic version of a diquinol ligand used for redox-responsive MRI contrast agents was prepared.•The ligand binds to Mn(II) approximately 50 times more strongly than a related ligand with a lesser anionic charge.•The Mn(II) complex reacts with hydrogen peroxide, but not air.•Hydrogen peroxide oxidizes the metal ion in the complex, preventing a T1-weighted relaxivity response. A previously reported quinol- and Mn(II)-containing MRI contrast agent sensor for H2O2 has the drawback of releasing the metal ion upon oxidation of the organic ligand. The release of potentially neurotoxic Mn(II) limits the sensor’s in vivo applicability. We prepared N,N′-bis(2,5-dihydroxybenzyl)ethanediamine-N,N′-diacetic acid (H6qc1) as a substitute ligand that could potentially remain bound to the metal ion after oxidation of the quinol portions to more weakly metal-binding para-quinones. The carboxylic acid groups deprotonate at ambient pH, providing a more anionic coordination environment that stabilizes its Mn(II) complex in water. Although the more anionic coordination sphere doesn’t introduce air sensitivity, it does render the metal center more susceptible to oxidation by hydrogen peroxide, as evidenced by electron paramagnetic resonance. The oxidation of the metal to less paramagnetic Mn(III) is proposed to lower the r1 enough to completely counter any increase in T1-weighted relaxivity that would result from improved aquation.