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 Mn-52 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 L-1 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 degrees 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 degrees 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, L-1 could be radiolabeled with Mn-52 and the complex revealed good stability in biological media.