Tuning the Redox Sensitivity of Mn ^II /Mn ^III -Bispidine MRI Probes by the Introduction of a Phenolate Donor

In the objective of exploiting the Mn II/III redox couple combined with the bispidine scaffold for the development of redox-responsive magnetic resonance imaging (MRI) probes, we have designed and synthesized H 3 L1 ligand, featuring a phenol pendant arm. This novel ligand is hypothesized to lower the Mn II/III redox potential relative to previously reported derivatives, while retaining the high kinetic inertness and good relaxivity properties characteristic of Mn II bispidine complexes. The [Mn II L1(H 2 O)] - complex exhibits high thermodynamic stability (log K Mn II L1 = 14.2), notable kinetic inertness (dissociation half-life, t 1/2 = 20.4 h at pH 6 in the presence of 50 equiv of Zn II ), and high relaxivity ( r 1 = 3.91 mM –1 s –1 at 60 MHz, 25 °C, pH 7), highlighting the suitability of the Mn II complex as a platform for MRI probe development. Electrochemical studies revealed a significantly lower oxidation potential ( E 1/2 = 306 mV vs SCE) compared to other Mn-bispidine chelates, enabling successful synthesis of the oxidized [Mn III L1] form in methanol. Although the aqueous stability of the +III oxidation state remains limited and highly dependent on water content, these results demonstrate that the incorporation of a phenolate donor effectively tunes the Mn II/III redox properties of the bispidine scaffold.