Redox-responsive Fe(II)/Fe(III) MRI probes with pentadentate or hexadentate macrocyclic ligands

Abstract

Fe(II) complexes of TACN (1,4,7-triazacyclononane) containing two 6-methyl-2-picolyl pendant groups are studied as redox-responsive agents for monitoring peroxide produced in inflammation. One Fe(II) complex has a pentadentate ligand with a sixth coordination site for binding water as confirmed by x-ray crystallography ([FeII(MPB)(CF3SO3)](CF3SO3)) and by 17O NMR studies in solution. The other complex is formed with a hexadentate ligand (FeII(MPH)) and also has an inner-sphere water ligand in solution as shown by variable temperature 17O NMR studies. FeII(MPB) is inert towards oxidation under ambient levels of O2 in aqueous solution at pH 7.4 over 24 hours whereas FeII(MPH) is resistant to oxidation over 4 hours. FeII(MPB) oxidizes rapidly (> 3 min) upon addition of one equivalent of peroxide or in the presence of 0.1 U/mL glucose oxidase (GOX). With one equivalent of peroxide in buffered solutions, the major product is FeIII(MPB), most likely as a buffer or hydroxide complex, but with a 10-fold excess of peroxide, a Fe(III) phenolate complex is produced as supported by electronic absorbance spectroscopy and analysis of products by high resolution mass spectrometry. The r1 relaxivity for the FeIII(MPB) (r1 = 0.71 mM-1s-1) is increased by 14-fold over the FeII complex at 1.4 T, 34 °C and pH 7.4. Oxidation of FeII(MPH) by addition of one equivalent of peroxide or by GOX is complete within a few minutes and produces a 7-fold increase in relaxivity. Changes in relaxivity are reversed by addition of ascorbate. FeII(MPB) is one of the first reported examples of a Fe(II) macrocyclic MRI probe that is unreactive to O2 but reacts rapidly with micromolar concentrations of peroxide for increased selectivity in monitoring inflammation.