Structure–Redox–Relaxivity Relationships for Redox Responsive Manganese-Based Magnetic Resonance Imaging Probes

A library of 10 Mn-containing complexes capable of switching reversibly between the Mn­(II) and Mn­(III) oxidation states was prepared and evaluated for potential usage as MRI reporters of tissue redox activity. We synthesized <i>N</i>-(2-hydroxybenzyl)-<i>N</i>,<i>N</i>′,<i>N</i>′-ethylenediaminetriacetic acid (HBET) and <i>N</i>-(2-hydroxybenzyl-<i>N</i>,<i>N</i>′,<i>N</i>′-<i>trans</i>-1,2-cyclohexylenediaminetriacetic acid (CyHBET) ligands functionalized (−H, −OMe, −NO₂) at the 5-position of the aromatic ring. The Mn­(II) complexes of all ligands and the Mn­(III) complexes of the 5-H and 5-NO₂ functionalized ligands were synthesized and isolated, but the Mn­(III) complexes with the 5-OMe functionalized ligands were unstable. ¹H relaxivity of the 10 isolable complexes was measured at pH 7.4 and 37 °C, 1.4 T. Thermodynamic stability, pH-dependent complex speciation, hydration state, water exchange kinetics of the Mn­(II) complexes, and pseudo-first order reduction kinetics of the Mn­(III) complexes were studied using a combination of pH-potentiometry, UV–vis spectroscopy, and ¹H and ¹⁷O NMR measurements. The effects of ligand structural and electronic modifications on the Mn­(II/III) redox couple were studied by cyclic voltammetry. The Mn­(II) complexes are potent relaxation agents as compared to the corresponding Mn­(III) species with [Mn^II(CyHBET)­(H₂O)]^2– exhibiting a 7.5-fold higher relaxivity (3.3 mM^–1 s^–1) than the oxidized form (0.4 mM^–1 s^–1). At pH 7.4, Mn­(II) exists as a mixture of fully deprotonated (ML) and monoprotonated (HML) complexes and Mn­(II) complex stability decreases as the ligands become more electron-releasing (pMn for 10 μM [Mn^II(CyHBET–<b>R</b>′)­(H₂O)]^2– decreases from 7.6 to 6.2 as <b>R</b>′ goes from −NO₂ to −OMe, respectively). HML speciation increases as the electron-releasing nature of the phenolato-<i>O</i> donor increases. The presence of a water coligand is maintained upon conversion from HML to ML, but the water exchange rate of ML is faster by up to 2 orders of magnitude (<i>k</i>_ex³¹⁰ for H­[Mn^II(CyHBET)­(H₂O)]⁻ and [Mn^II(CyHBET)­(H₂O)]^2– are 1.2 × 10⁸ and 1.0 × 10¹⁰ s^–1, respectively). The Mn­(II/III) redox potential can be tuned over a range of 0.30 V (<i>E</i>_1/2 = 0.27–0.57 V) through electronic modifications to the 5-substituent of the aromatic ligand component. However, care must be taken in tuning the ligand electronics to avoid Mn­(III)–ligand autoredox. Taken together, these results serve to establish criteria for optimizing Mn­(III) versus Mn­(II) relaxivity differentials, complex stability, and Mn­(II/III) redox potential