Towards Binuclear Polyaminocarboxylate MRI Contrast Agents? Spectroscopic and MD Study of the Peculiar Aqueous Behavior of the LnIII Chelates of OHEC (Ln=Eu, Gd, and Tb): Implications for Relaxivity

We report the study of binuclear LnIII chelates of OHEC (OHEC=octaazacyclohexacosane-1,4,7,10,14,17,20,23-octaacetate). The interconversion between two isomeric forms, which occurs in aqueous solution, has been studied by NMR, UV/Vis, EPR, and luminescence spectroscopy, as well as by classical molecular dynamics (MD) simulations. For the first time we have characterized an isomerization equilibrium for a LnIII polyaminocarboxylate complex (LnIII=Y, Eu, Gd and Tb) in which the metal centre changes its coordination number from nine to eight, such that: [Ln2(ohec)(H2O)2]2−⇄[Ln2(ohec)]2−+2 H2O. The variable temperature and pressure NMR measurements conducted on this isomerization reaction give the following thermodynamic parameters for EuIII: K298=0.42±0.01, ΔH0=+4.0±0.2 kJ mol−1, ΔS0=+6.1±0.5 J K−1 mol−1 and ΔV0=+3.2±0.2 cm3 mol−1. The isomerization is slow and the corresponding kinetic parameters obtained by NMR spectroscopy are: k=73.0±0.5 s−1, ΔH=75.3±1.9 kJ mol−1, ΔS=+43.1±5.8 J K−1 mol−1 and ΔV=+7.9±0.7 cm3 mol−1. Variable temperature and pressure 17O NMR studies have shown that water exchange in [Gd2(ohec)(H2O)2]2− is slow, k=(0.40±0.02)×106 s−1, and that it proceeds through a dissociative interchange Id mechanism, ΔV≠=+7.3±0.3 cm3 mol−1. The anisotropy of this oblong binuclear complex has been highlighted by MD simulation calculations of different rotational correlation times. The rotational correlation time directed on the Gd–Gd axis is 24 % longer than those based on the axes orthogonal to the Gd–Gd axis. The relaxivity of this binuclear complex has been found to be low, since 1) only [Gd2(ohec)(H2O)2]2−, which constitutes 70 % of the binuclear complex, contributes to the inner-sphere relaxivity and 2) the anisotropy of the complex prevents water molecules from having complete access to both GdIII cages; this decreases the outer-sphere relaxivity. Moreover, EPR measurements for the GdIII and for the mixed GdIII/YIII binuclear complexes have clearly shown that the two GdIII centres interact intramolecularly; this enhances the electronic relaxation of the GdIII electron spins.