Adding a Second Quinol to a Redox-Responsive MRI Contrast Agent Improves Its Relaxivity Response to H₂O₂

Abstract

The overproduction of reactive oxygen species has been linked to a wide array of health disorders. The ability to noninvasively monitor oxidative stress in vivo could provide substantial insight into the progression of these conditions and, in turn, could facilitate the development of better diagnosis and treatment options. A mononuclear Mn(II) complex with the redox-active ligand N,N'-bis(2,5-dihydroxybenzyl)-N,N'-bis(2-pyridinylmethyl)-1,2-ethanediamine (Hqtp2) was made and characterized. A previously prepared Mn(II) complex with a ligand containing a single quinol subunit was found to display a modest T-derived relaxivity response to HO. The introduction of a second redox-active quinol both substantially improves the relaxivity response of the complex to HO and reduces the cytotoxicity of the sensor but renders the complex more susceptible to transmetalation. The addition of HO partially oxidizes the quinol subunits to para-quinones, concomitantly increasing the r from 5.46 mM s to 7.17 mM s. The oxidation of the ligand enables more water molecules to coordinate to the metal ion, providing an explanation for the enhanced relaxivity. That the diquinol complex is only partially oxidized by HO is attributed to its activity as an antioxidant; the complex can both catalytically degrade superoxide and serve as a hydrogen atom donor.

Quinol-containing ligands enable high superoxide dismutase activity by modulating coordination number, charge, oxidation states and stability of manganese complexes throughout redox cycling

“…Previously, our labs developed and characterized three waterand air-stable Mn(II) complexes with redox-active organic ligands (Scheme 1) that respond to H 2 O 2 with changes in their T 1 -weighted relaxivity (r 1 ). [22][23][24] Consequently, the Mn(II) complexes can serve as redox-responsive contrast agents for magnetic resonance imaging (MRI). Notably, the MRI responses result from the oxidation of the organic component, rather than the metal, distinguishing these from redox-responsive probes developed by the Caravan group.…”

“…22 The other two compounds, [Mn(H 2 -qp1)(MeCN)] 2+ (2, MeCN ¼ acetonitrile) and [Mn(H 4 qp2)Br 2 ] (3), feature quinol subunits which are oxidized to para-quinone groups upon their reactions with H 2 O 2 (Scheme 2). 23,24 In the reduced form of the ligands, the quinols can deprotonate and bind tightly to Mn(II) ions as quinolates; in the oxidized form, conversely, the neutral para-quinones have much weaker metal binding affinities and appear to be displaced by water molecules. 24 The better aquation of the Mn(II) ion is proposed to increase r 1 and thereby enhance MRI contrast.…”

“…23,24 In the reduced form of the ligands, the quinols can deprotonate and bind tightly to Mn(II) ions as quinolates; in the oxidized form, conversely, the neutral para-quinones have much weaker metal binding affinities and appear to be displaced by water molecules. 24 The better aquation of the Mn(II) ion is proposed to increase r 1 and thereby enhance MRI contrast.…”

Metal-based redox-responsive MRI contrast agents

“…Most literature examples of redox responsive contrast agents involving manganese take advantage of the different oxidation states of this metal, as can been seen in the next section. Albeit, Goldsmith and collaborators 62,63,64 reported a series of non-cyclic Mn II complexes that contain ligands with an increasing number of peripheral redox-active hydroxyl groups as H2O2 sensors (Figure 12). While the monohydrated and heptacoordinate Mn II complex 21 is stable in the presence of oxygen, addition of H2O2 leads to an intermolecular oxidative cross-coupling reaction between two carbon atoms of the 2-hydroxy-5-methylbenzyl rings, yielding a binuclear complex.…”

Drawing on biology to inspire molecular design: a redox-responsive MRI probe based on Gd(iii)-nicotinamide

“…1 Numerous complexes have been developed for chemical stimuli such as enzymatic activity, 2,3 Ca 2+ , Cu 2+ , Zn 2+ , 4,5 or neurotransmitters, 6 or characteristics of the chemical environment such as pH, 7 redox state, 8 or temperature. 9 Currently reported approaches to achieving redox-responsive MRI systems include using redox-active metals such as cobalt, 10 copper, 11 and manganese, 12 and europium, 13 selfassembly triggered ligands, 14 or appended functional groups such as quinols, 15 thiols 16 and merocyanine/spyrooxazine. 17 Local changes in biological redox potential play an important role in signal transduction, influencing many cellular functions.…”