Classical molecular dynamics simulations with a force field adapted to the family of Gd(3+) polyaminocarboxylate complexes have been successfully applied on two macrocyclic ([Gd(DOTA)(H(2)O)](-) and [Gd(DO3A)(H(2)O)(2)]) and two acyclic ([Gd(DTPA)(H(2)O)](2-) and [Gd(EGTA)(H(2)O)](-)) complexes in aqueous solution (DOTA=1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane, DO3A=1,4,6-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane, DTPA=1,1,4,7,7-pentakis(carboxymethyl)-1,4,7-triazaheptane, EGTA=1,1,10,10-tetrakis(carboxymethyl)-1,10-diaza-4,7-dioxadecane). In both macrocylic complexes the Gd(3+) coordination polyhedron remains close to a monocapped square antiprism (MSA) during the entire simulation time. For the stereolabile acyclic complexes different interconverting sets of geometries are observed: three sets close to tricapped trigonal prisms (TTP) for [Gd(EGTA)(H(2)O)](-) and three sets intermediate between MSA and TTP (distorted C(2v) symmetry) for [Gd(DTPA)(H(2)O)](2-). The fast conformational changes observed in the acyclic complexes might weaken the hydration of the second water shell and therefore disfavour the outer-sphere relaxivity. Moreover, the motions of the chelate observed in both acyclic complexes involve the reorientation of the symmetry elements over time. This reorientation, occurring on a picosecond timescale, can be associated with the correlation time for modulation of the zero field splitting and might participate in the electron spin relaxation mechanisms of the Gd(3+) ion. The internal motion of the inner-sphere water molecule can be quantified by the ratio tau(R)(GD-HW)/tau(R)(GD-OW) which increases slightly from 0.7 for the acyclic to 0.8 for the macrocyclic complexes. This increase for the macrocylic chelates is favourable for a higher relaxivity and can be related to their rigidity. The water exchange rate on the four complexes has been related to the steric constraint of the ligand on the inner-sphere water molecule(s), which is inversely proportional to a geometrical descriptor, the solid angle psi. A range of psi values is given (2<

Multiple experiments (17O NMR, 1H NMR, and EPR) have been performed in the past to understand the microscopic parameters that control the magnetic relaxation rate enhancement induced by paramagnetic molecules on neighboring water protons, the so-called relaxivity. The generally accepted theories of the electron spin relaxation of S = 7/2 ions such as Gd3+ (Solomon-Bloembergen-Morgan or simplified Hudson-Lewis) are unsatisfactory for a simultaneous analysis. Recently, an improved theory, where the electron spin relaxation is due to the combination of a static (thus explicitly linked to the molecular structure) and a dynamic zero field splitting, has been developed and tested on experimental EPR data. The model has also been extended beyond the electronic Redfield limit using Monte Carlo simulations. Using the aqua ion [Gd(H2O)8]3+ as a test case, we present here the first simultaneous analysis of 17O NMR, 1H NMR, and EPR relaxation data using this rigorous approach of the electron spin relaxation. We discuss the physical meaning of the calculated parameters. The consequences on future experiments are also considered, especially regarding the analysis of nuclear magnetic relaxation dispersion (NMRD) profiles in the study of Gd3+ complexes.

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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-) r<==>[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, DeltaH(0)=+4.0+/-0.2 kJ mol(-1), DeltaS(0)=+6.1+/-0.5 J K(-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(298)(is)=73.0+/-0.5 s(-1), DeltaH++(is)=75.3+/-1.9 kJ mol(-1), DeltaS++(is)= +43.1+/-5.8 J K(-1) mol(-1) and DeltaV++(is)=+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)(ex)=(0.40+/-0.02)x10(6) s(-1), and that it proceeds through a dissociative interchange I(d) mechanism, DeltaV( not equal )=+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.

The hydration state of a series of [Ln(DO2A)(H2O)n]+ complexes in aqueous solution at pH = 6.4–7.0 was studied by measuring the lanthanide‐induced 17O shifts (LIS) of water [Ln includes elements from Ce to Yb; DO2A = 1,7‐bis(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane]. Their contact contribution, obtained from Reilley plots, indicated a decrease in the inner‐sphere water coordination number of the [Ln(DO2A)(H2O)n]+ complexes from n = 3 (Ce–Eu), to n = 2 (Tb–Yb). A temperature‐dependent UV/Vis absorption study of the 578–582 nm 7F0 → 5D0 transition band of [Eu(DO2A)(H2O)n]+ in aqueous solution showed that this complex is present in an equilibrium between eight‐ and nine‐coordinate species with n = 2 and n = 3, respectively. The hydration equilibrium parameters (2 ↔ 3), K2–3298= 4.0 ± 0.2, ΔH2–30 = –12.1 ± 1 kJ mol–1 and ΔS 2–30 = –28.9 ± 3 J mol–1 K–1,correspond to an average hydration number of 2.65–2.85 in the temperature range 273–363 K. A variable temperature, multiple field 17O NMR study combined with direct EPR measurements of the transverse electronic relaxation rates has been used to obtain the parameters characterizing water exchange, rotation and electronic relaxation, all influencing the proton relaxivity of [Gd(DO2A)(H2O)2–3]+. The small increase in the water exchange rate of [Gd(DO2A)(H2O)2–3]+ (k ex298 = (10 ± 5) × 106s–1) relative to that of[Gd(DOTA)(H2O)]– (4.8 × 106 s–1) is a consequence of an unfavorable interplay of charge and hydration equilibria. The value of τ R298 = 40 ± 1 ps is short, and the electronic relaxation rate (1/T2e ≈︁ 1.2 × 1010 s–1) is fast relative to [Gd(DOTA)(H2O)]– (1.3–2.4 × 109 s–1 for B = 0.34 T). These parameters negate to some extent the expected increase in proton relaxivity of the [Gd(DO2A)(H2O)2–3]+ complex.

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Abstract:The increasing use of contrast agents in magnetic resonance imaging (MRI) for medical diagnosis is due to the ability, called relaxivity, of these paramagnetic compounds to accelerate the relaxation of the surrounding water proton spins. A new classical force field for molecular dynamics simulations of Gd 3+ polyaminocarboxylates has recently been published, which allows the study of the chelate internal mobility. We present two selected examples where such motions can affect relaxivity. Knowing the relationship between the bound water proton and oxygen mobility is important for the combined analysis of multinuclear NMR studies, and we show that they differ significantly. Next, we observe symmetry changes over time in the Gd 3+ coordination polyhedron of the acyclic complexes. We propose that such rearrangements can play a role in the electron spin relaxation of Gd 3+ chelates, an important result considering the uncertainty still attached to this particular factor.