A Trans-1,2-Diphenyl-Substituted EDTA Platform for High-Relaxivity Mn(II) MRI Probes.

Abstract

The development of high-performance Mn(II)-based MRI contrast agents requires the simultaneous optimisation of thermodynamic stability, kinetic inertness, water-exchange kinetics and rotational dynamics. Herein, we report a trans-1,2-diphenyl-substituted EDTA ligand that provides a simple yet effective molecular platform to address these requirements. The corresponding Mn(II) complex exhibits enhanced conditional stability and kinetic inertness compared with the parent [Mn(EDTA)]^2- while preserving the fast inner-sphere water-exchange regime characteristic of EDTA-based chelates. Relaxometric and ¹⁷O NMR investigations demonstrate that the complex retains the favourable dynamic properties of the parent scaffold in solution. Supramolecular recognition studies with poly-β-cyclodextrin and human serum albumin (HSA), combined with Lipari-Szabo analysis of the bound-state ¹H NMRD profiles, reveal that the trans-oriented phenyl groups promote dual-site binding, efficiently minimising residual internal motions and strengthening the coupling between the local dynamics of the Mn(II) chelate and the global tumbling of the protein. Consequently, the HSA adduct reaches a relaxivity of 62 mM^-1 s^-1 at 30 MHz and 298 K, among the highest reported for albumin-bound Mn(II) complexes. These findings establish a general molecular design strategy for developing targeted Mn(II)-based MRI probes and nanoscale contrast agents with enhanced relaxometric performance.