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 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)(H2O)(2)](2-) reversible arrow [Ln(2)(ohec)](2-) +2H(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, DeltaH(0)=+4.0+/-0.2 kJ mol(-1), DeltaS(0) = +6.1+/-0.5 JK(-1)mol(-1) and DeltaV(0)=+3.2+/-0.2 cm 3 mol(-1). The isomerization is slow and the corresponding kinetic parameters obtained by NMR spectroscopy are: k(is)(298) = 73.0+/-0.5s(-1), DeltaH(is)(double dagger) = 75.3+/-1.9 kJ mol(-1), DeltaS(is)(double dagger) = +43.1+/-5.8 is JK(-1)mol(-1) and DeltaV(is)(double dagger) = +7.9+/-0.7 cm(3) mol(-1). Variable temperature and pressure 17 0 NMR studies have shown that water exchange in [Gd-2(ohec)(H2O)(2)](2-) is slow, k(ex)(298) = (0.40 +/- 0.02) x 10(6) s(-1), and that it proceeds through a dissociative interchange I, mechanism, DeltaV(double dagger) = +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)(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 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.