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

Abstract

The search for more biocompatible alternatives to Gd³⁺ -based MRI agents, and the interest in ⁵² Mn 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 ⁵² Mn and the complex revealed good stability in biological media.

Keywords: 52Mn; MRI; contrast agents; kinetic inertness; manganese.