Unprecedented Kinetic Inertness for a Mn2+‐Bispidine Chelate: A Novel Structural Entry for Mn2+‐Based Imaging Agents

The search for more biocompatible alternatives to Gd³⁺‐based MRI agents, and the interest in ⁵²Mn for PET imaging call for ligands that form inert Mn²⁺ chelates. Given the labile nature of Mn²⁺, high inertness is challenging to achieve. The strongly preorganized structure of the 2,4‐pyridyl‐disubstituted bispidol ligand L₁ endows its Mn²⁺ complex with exceptional kinetic inertness. Indeed, MnL₁ did not show any dissociation for 140 days in the presence of 50 equiv. of Zn²⁺ (37 °C, pH 6), while recently reported potential MRI agents MnPyC3A and MnPC2A‐EA have dissociation half‐lives of 0.285 h and 54.4 h under similar conditions. In addition, the relaxivity of MnL₁ (4.28 mm ^?1 s^?1 at 25 °C, 20 MHz) is remarkable for a monohydrated, small Mn²⁺ chelate. In vivo MRI experiments in mice and determination of the tissue Mn content evidence rapid renal clearance of MnL₁. Additionally, L₁ could be radiolabeled with ⁵²Mn and the complex revealed good stability in biological media.