A Macrocyclic Ligand Framework That Improves Both the Stability and T₁-Weighted MRI Response of Quinol-Containing...

Previously prepared Mn(II)- and quinol-containing magnetic resonance imaging (MRI) contrast agent sensors for H₂O₂ relied on linear polydentate ligands to keep the redox-activatable quinols in close proximity to the manganese. Although these provide positive T₁-weighted relaxivity responses to H₂O₂ that result from oxidation of the quinol groups to p-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 H₂O₂ to produce a more highly aquated Mn(II) species that exhibits a 130% greater r₁, quadrupling the percentile response of our next best sensor. With a large excess of H₂O₂, there is a noticeable induction period before quinol oxidation and r₁ enhancement occurs. Further investigation reveals that, under such conditions, catalase activity initially outcompetes ligand oxidation, with the latter occurring only after most of the H₂O₂ has been depleted.