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

Abstract

Abstract The search for more biocompatible alternatives to Gd 3+ ‐based MRI agents, and the interest in 52 Mn for PET imaging call for ligands that form inert Mn 2+ chelates. Given the labile nature of Mn 2+ , high inertness is challenging to achieve. The strongly preorganized structure of the 2,4‐pyridyl‐disubstituted bispidol ligand L 1 endows its Mn 2+ complex with exceptional kinetic inertness. Indeed, MnL 1 did not show any dissociation for 140 days in the presence of 50 equiv. of Zn 2+ (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 MnL 1 (4.28 m m −1 s −1 at 25 °C, 20 MHz) is remarkable for a monohydrated, small Mn 2+ chelate. In vivo MRI experiments in mice and determination of the tissue Mn content evidence rapid renal clearance of MnL 1 . Additionally, L 1 could be radiolabeled with 52 Mn and the complex revealed good stability in biological media.