A Macrocyclic Ligand Framework That Improves Both the Stability and -Weighted MRI Response of Quinol-Containing HO Sensors.

Previously prepared Mn(II)- and quinol-containing magnetic resonance imaging (MRI) contrast agent sensors for HO relied on linear polydentate ligands to keep the redox-activatable quinols in close proximity to the manganese. Although these provide positive -weighted relaxivity responses to HO that result from oxidation of the quinol groups to -quinones, these reactions weaken the binding affinity of the ligands, promoting dissociation of Mn(II) from the contrast agent in aqueous solution. Here, we report a new ligand, 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane, that consists of two quinols covalently tethered to a cyclam macrocycle. The macrocycle provides stronger thermodynamic and kinetic barriers for metal-ion dissociation in both the reduced and oxidized forms of the ligand. The Mn(II) complex reacts with HO to produce a more highly aquated Mn(II) species that exhibits a 130% greater , quadrupling the percentile response of our next best sensor. With a large excess of HO, there is a noticeable induction period before quinol oxidation and enhancement occurs. Further investigation reveals that, under such conditions, catalase activity initially outcompetes ligand oxidation, with the latter occurring only after most of the HO has been depleted.