Mn²⁺ Bispidine Complex Combining Exceptional Stability, Inertness, and MRI Efficiency

As an essential metal ion and an efficient relaxation agent, Mn²⁺ holds a great promise to replace Gd³⁺ in magnetic resonance imaging (MRI) contrast agent applications, if its stable and inert complexation can be achieved. Toward this goal, four pyridine and one carboxylate pendants have been introduced in coordinating positions on the bispidine platform to yield ligand L³. Thanks to its rigid and preorganized structure and perfect size match for Mn²⁺, L³ provides remarkably high thermodynamic stability (log K_MnL = 19.47), selectivity over the major biological competitor Zn²⁺ (log(K_MnL/K_ZnL) = 4.4), and kinetic inertness. Solid-state X-ray data show that [MnL³(MeOH)](OTf)₂ has an unusual eight-coordinate structure with a coordinated solvent molecule, in contrast to the six-coordinate structure of [ZnL³](OTf), underlining that the coordination cavity is perfectly adapted for Mn²⁺, while it is too large for Zn²⁺. In aqueous solution, ¹⁷O NMR data evidence one inner sphere water and dissociatively activated water exchange (k_ex²⁹⁸ = 13.5 × 10⁷ s^-1) for MnL³. Its water proton relaxivity (r₁ = 4.44 mM^-1 s^-1 at 25 °C, 20 MHz) is about 30% higher than values for typical monohydrated Mn²⁺ complexes, which is related to its larger molecular size; its relaxation efficiency is similar to that of clinically used Gd³⁺-based agents. In vivo MRI experiments realized in control mice at 0.02 mmol/kg injected dose indicate good signal enhancement in the kidneys and fast renal clearance. Taken together, MnL³ is the first chelate that combines such excellent stability, selectivity, inertness and relaxation properties, all of primary importance for MRI use.