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

We report the study of binuclear Ln III 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 Ln III polyaminocarboxylate complex (Ln III =Y, Eu, Gd and Tb) in which the metal centre changes its coordination number from nine to eight, such that: [Ln 2 (ohec)(H 2 O) 2 ] 2− ⇄[Ln 2 (ohec)] 2− +2 H 2 O. The variable temperature and pressure NMR measurements conducted on this isomerization reaction give the following thermodynamic parameters for Eu III : K 298 =0.42±0.01, Δ H 0 =+4.0±0.2 kJ mol −1 , Δ S 0 =+6.1±0.5 J K −1  mol −1 and Δ V 0 =+3.2±0.2 cm 3  mol −1 . The isomerization is slow and the corresponding kinetic parameters obtained by NMR spectroscopy are: k ${{298\hfill \atop {\rm is}\hfill}}$ =73.0±0.5 s −1 , Δ H ${{{\ne}\hfill \atop {\rm is}\hfill}}$ =75.3±1.9 kJ mol −1 , Δ S ${{{\ne}\hfill \atop {\rm is}\hfill}}$ =+43.1±5.8 J K −1  mol −1 and Δ V ${{{\ne}\hfill \atop {\rm is}\hfill}}$ =+7.9±0.7 cm 3  mol −1 . Variable temperature and pressure 17 O NMR studies have shown that water exchange in [Gd 2 (ohec)(H 2 O) 2 ] 2− is slow, k ${{298\hfill \atop {\rm ex}\hfill}}$ =(0.40±0.02)×10 6 s −1 , and that it proceeds through a dissociative interchange I d mechanism, Δ V ≠ =+7.3±0.3 cm 3  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 [Gd 2 (ohec)(H 2 O) 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 Gd III cages; this decreases the outer‐sphere relaxivity. Moreover, EPR measurements for the Gd III and for the mixed Gd III /Y III binuclear complexes have clearly shown that the two Gd III centres interact intramolecularly; this enhances the electronic relaxation of the Gd III electron spins.