We present the results of new and previously published 17O NMR, EPR, and NMRD studies of aqueous solutions of the Gd3+ octaaqua ion and the commercial MRI contrast agents [Gd(DTPA)(H2O)]2- (MAGNEVIST, Schering AG, DTPA = 1,1,4,7,7-pentakis(carboxymethyl)-1,4,7-triazaheptane), [Gd(DTPA-BMA)(H2O)] (OMNISCAN, Sanofi Nycomed, DTPA-BMA = 1,7-bis[(N-methylcarbamoyl)methyl]-1,4,7-tris(carboxymethyl)-1,4,7-triazaheptane), and [Gd(DOTA)(H2O)]- (DOTAREM, Guerbet, DOTA = 1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane). High-field EPR measurements at different concentrations give evidence of an intermolecular dipole−dipole electronic relaxation mechanism that has not previously been described for Gd3+ complexes. For the first time, the experimental data from the three techniques for each complex have been treated using a self-consistent theoretical model in a simultaneous multiple parameter least-squares fitting procedure. The lower quality of the fits compared to separate fits of the data for each of the three techniques shows that the increase in the number of adjustable parameters is outweighed by the increased constraint on the fits. The parameters governing the relaxivity of the complexes are thus determined with greater confidence than previously possible. The same approach was used to study two dimeric Gd3+ complexes [pip{Gd(DO3A)(H2O)}2] and [bisoxa{Gd(DO3A)(H2O)}2] (pip(DO3A)2 = bis(1,4-(1-(carboxymethyl)-1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl-1,4-diazacyclohexane, bisoxa(DO3A)2 = bis(1,4-(1-(carboxymethyl)-1,4,7,10-tetraaza-4,7,10-tris(carboxymethyl)-1-cyclododecyl))-1,10-diaza-3,6-dioxadecane) that are being developed as potential second-generation MRI contrast agents. These dimeric complexes are expected to have higher relaxivities than the monomeric contrast agents, due to their longer rotational correlation times. The results of this study show that further relaxivity gain for these complexes will be hindered by the slow rate of water exchange on the complexes. High-field EPR measurements suggest that there is a previously unrecorded intramolecular dipole−dipole mechanism of electronic relaxation, but that this additional contribution to electronic relaxation is of minor importance compared to the limiting effect of water exchange rates in the determination of proton relaxivity in MRI applications.

A variable-temperature, -pressure, and -ionic strength 1 H NMR study of the DOTA complexes of different trivalent cations (Sc, Y, La, Ce f Lu) (DOTA ) 1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)cyclododecane) yielded data that are in contradiction with the hitherto used model of only two enantiomeric pairs of diastereoisomers that differ in the ligand conformations. A two-isomer equilibrium cannot explain the newly observed apparent reversal of the isomer ratio at the end of the series. As both conformers may lose their inner sphere water molecule, a coordination equilibrium may be superimposed on this conformational equilibrium, as shown by large positive reaction volumes for the isomerization of [Ln(DOTA)(

Macrocyclic Gd"' complexes attached to dendrimers represent a new class of potential MRI contrast agents. They have an extended lifetime in the blood pool, which is indispensable for their application in magnetic resonance angiography, and high relaxivities, which reduce the dose required to produce quality images. We performed a variable-temperature and -pressure "0 NMR study in aqueous solution and at 14.

The structure and dynamics of the lanthanide(III) complexes of DTPA-BGLUCA3- (DTPA-bis(glucamide)), DTPA-BENGALAA3- (DTPA-bis(ethylenegalactamine−amide)), DTPA-BEA3- (DTPA-bis(ethanolamide)), and DTPA-BPDA3- (DTPA-bis(propanediolamide)) in water have been investigated. These complexes are of relevance as potential MRI contrast agents. 13C relaxation times of the Nd(III) complexes show octadentate binding of the organic ligand via the three amines, the three carboxylates, and the two amide oxygens. 17O NMR measurements indicate that the coordination sphere is completed by one water ligand. Eight diastereomeric pairs of isomers are observed for the DTPA-bis(sugaramides). Data sets obtained from variable-temperature and -pressure 17O NMR at 9.4 T and variable-temperature 1H nuclear magnetic relaxation dispersion (NMRD) on the Gd(III) complexes were fitted simultaneously to give insight into the parameters governing the water 1H relaxivity. The water exchange rates, k ex 298, on [Gd(DTPA-BPDA)(H2O)], [Gd(DTPA-BGLUCA)(H2O)] and [Gd(DTPA-BENGALAA)(H2O)] are 3.6 ± 0.3, 3.8 ± 0.2, and 2.2 ± 0.1 × 105 s-1, and the activation volumes are +6.7, +6.8, and +5.6 cm3 mol-1 (±0.2 cm3 mol-1), respectively, indicating a strongly dissociatively activated mechanism. The sugar moieties have no significant influence on the coordination of the Gd(III) ion and on the parameters governing the relaxivity, apart from the expected increase in the rotational correlation time. The relaxivity under the usual MRI conditions is limited by the water exchange rate and the electronic relaxation. The data obtained are used to explain the relaxivity of conjugates of polysaccharides and Gd(DTPA).

The structures and intramolecular dynamics of [Ln(EGTA)(H2O)]- (Ln = La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+, Lu3+ and EGTA4- = 3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecanedioate(4−)) in aqueous solution have been investigated by variable temperature 1H and 13C NMR. The quantitative analysis of the proton hyperfine shifts and considerations about the stereochemical nonrigidity indicate the occurrence of a structural change along the lanthanide series with the crossover between Sm and Eu. Changes of coordination number from 10 to 9 to 8 are proposed to occur across the series. The experimental data from 17O NMR, EPR and NMRD studies for the Gd3+ complex are treated using a self-consistent theoretical model in a simultaneous multiple parameter least-squares fitting procedure (Powell, D. H.; Ni Dhubhghaill, O. M.; Pubanz, D.; Helm, L.; Lebedev, Y. S.; Schlaepfer, W.; Merbach, A. E. J. Am. Chem. Soc. 1996, 118, 9333). An intermolecular dipole−dipole electronic relaxation mechanism that has very recently been described for Gd3+ complexes (Powell et al., op. cit.) is included in the data treatment. The high water exchange rate of [Gd(EGTA)(H2O)]- of k ex 298= (3.1 ± 0.2) × 107 s-1 is explained in terms of a limiting dissociative exchange mechanism (ΔV ⧧ = +10.5 ± 1.0 cm3mol-1), favored by the steric constraints on the water binding site that are revealed by the study on the solution structure.

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Variable temperature NMR spectroscopy studies of lanthanide(III) complexes with 1,4,7,10-tetraazacyclododecane-N,N',N",N'-tetraacetic acid (DOTA) provide evidence of the presence of two isomeric forms in aqueous solution. An NMR study was performed in order to gain structural information on the two isomeric species, using a fitting procedure of calculated to experimental dipolar contributions to the paramagnetic shifts. The two isomers show to have identical macrocyclic ring conformations and differ only in the coordination or orientation of the acetate arms of the ligand, yielding either square prismatic and square anti-prismatic coordination geometries, or octadentate and heptadentate coordinations of the ligand relative to the lanthanide ion. Analysis of the dipolar shifts is consistent with both types of acetate conformational equilibria.

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