Redox-activated manganese-based MR contrast agent

Abstract

Here we report a simple Mn coordination complex with utility as a redox-sensitive MR probe. The HBET ligand stabilizes both the Mn(2+) and Mn(3+) oxidation states. In the presence of glutathione (GSH), low relaxivity Mn(III)-HBET is converted to high relaxivity Mn(II)-HBET with a 3-fold increase in relaxivity, and concomitant increase in MR signal. Alternately, hydrogen peroxide can convert Mn(II)-HBET to Mn(III)-HBET with a reduction in MR signal.

Figure 1

Ligand structure strongly influences the redox potential of the Mn^III/Mn^II couple. Conversion of carboxylato to phenolato donors shifts the half-cell potential by 617 mV in favor of the higher oxidation state.

Figure 2

(a) Cyclic voltammogram at 100 mV/s for 25 mM Mn^II-HBET in 25 mM pH 7.4 Tris buffer, 500 mM KNO₃, and K₄Fe(CN)₆ as an internal standard. Potentials reported vs NHE. (b) Cottrell plot of Mn²⁺/Mn³⁺ couple - i_a (green) and i_c (blue) vs √ν, where ν = scan rate.

Figure 3

Left: T₁-weighted MR image recorded at 4.7 T of tubes containing pure water, 0.5 mM Mn^III-HBET and 0.5 mM Mn^II-HBET in pH 7.4 TRIS buffer. Right: relaxivities measured at room temperature at 4.7 T.

Figure 4

(a) Reduction of 0.5 mM Mn^III-HBET to Mn^II-HBET by 10 mM GSH in TRIS buffer (pH 7.4, 37 °C) results in increased proton relaxation rate (1/T₁, left axis) and concomitant decrease in mole fraction of Mn^III-HBET (right axis) as determined by characteristic UV absorbance at 375 nm. (b) Reduction of 0.5 mM MnIII-HBET by 1 mM GSH at 26 °C monitored by LC-MS. No long-lived intermediate species were observed in the reduction process.