A complete mechanistic study of the solution dynamics of [Eu(DOTAM)(H 2 O)] 3+ is performed through 1 H and 17 O NMR variable pressure and temperature studies. An unambiguous understanding of the water exchange was possible thanks to the first 17 O NMR observation of the bound water signal on both the M-and m-isomers (M:). The water exchange on m is about 50 times faster than on M, and even though the equilibrium constant K ) [M]/[m] equals 4.5, the contribution of m to the overall exchange rate is 90%. These results can be transferred to an aqueous solution since they agree with the overall exchange rate obtained by 17 O NMR for an aqueous solution of [Gd(DOTAM)(H 2 O)] 3+ . 2D-EXSY and variable temperature and pressure 1 H NMR experiments reveal that the interconversion between the M and m isomers happens mainly through a rotation of the amide arms in an interchange activated mechanism. (Interconversion rates measured by magnetization transfer: M f m: k a 250 ) 60 ( 10 s -1 ; m f M: k a 250 ) 260 ( 50 s -1 . Activation volumes: M f m: ∆V q ) -0.5 ( 0.3 cm 3 mol -1 , m f M: ∆V q ) -0.5 ( 0.7 cm 3 mol -1 and reaction volume ∆V°) 0 ( 1 cm 3 mol -1 ). In light of a simultaneous fitting of the water exchange and interconversion NMR data (M f m: ∆H q ) 39.1 ( 1.9 kJ mol -1 , ∆S q ) -52.1 ( 7.4 J K -1 mol -1 , k 250 ) 68 ( 5 s -1 ), as well as an interpretation of the activation and reaction volumes, we deduce a correlation between the two processes. A nonhydrated complex is proposed as a common intermediate for both the water exchange and the arm rotation processes, but only one M f m interconversion happens while two to three water exchanges take place.

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1H NMR line-shape analysis and magnetisation-transfer experiments at variable temperature and pressure have been used to elucidate the solution dynamics of both M and m isomers of three [Eu(dota-tetraamide)(H2O)]3+ complexes. The direct 1H NMR observation of the bound water signal allows the water-exchange rates on each isomer to be measured individually. They are definitely independent of the ligand for both M and m isomers (M: k298(ex)=9.4+/-0.2 x 10(3) s(-1) for [Eu(dotam)(H2O)]3+, 8.2+/-0.2 x 10(3) s(-1) for [Eu(dtma)(H2O)]3+ and 11.2+/-1.4 x 10(3) s(-1) for [Eu(dotmam)-(H2O)]3+; m: k298(ex)=474+/-130 x 10(3) s(-1) for [Eu(dotam)(H2O)3+, 357+/-92 x 10(3) s(-1) for [Eu(dtma)(H2O)3+), and proceed through a dissociative mechanism (M isomers: deltaV++ = +4.9 cm3 mol(-1) for [Eu(dotam)(H2O)]3+ and + 6.9 cm3 mol(-1) for [Eu(dtma)(H2O)]3+). The overall water exchange only depends on the M/m isomeric ratio. The m isomer, which exchanges more quickly, is favoured by a-substitution of the ring nitrogen. Therefore the synthesis of DOTA-like ligands, which predominantly form complexes in the m form, should be a sufficient condition to ensure faster water exchange on potential Gd(III)-based contrast agents. Furthermore the activation parameters for the water-exchange and isomerisation processes are both compatible with a nonhydrated complex as intermediate.

Taking advantage of the Curie contribution to the relaxation of the protons in the Tb(III) complex, and the quadrupolar relaxation of the 17O and 2H nuclei on the Eu(III) complex, the effect of the internal motion of the water molecule bound to [Ln(DOTAM)(H2O)]3+ complexes was quantified. The determination of the quadrupolar coupling constant of the bound water oxygen chi(Omicron)(1 + eta(Omicron)2/3)1/2 = 5.2 +/- 0.5 MHz allows a new analysis of the 17O and 1H NMR data of the [Gd(DOTA)(H2O)]- complex with different rotational correlation times for the Gd(III)-O(water) and Gd(III)-H(water) vectors. The ratio of the rotational correlation times for the Ln(III)-H(water) vector and the overall rotational correlation time is calculated tau(RH)/tau(RO) = 0.65 +/- 0.2. This could have negative consequences on the water proton relaxivity, which we discuss in particular for macromolecular systems. It appears that the final effect is actually attenuated and should be around 10% for such large systems undergoing local motion of the chelating groups.

The parameters governing the water proton relaxivity of the [Gd(EGTA-BA-(CH2)12)]nn+ polymeric complex were determined through global analysis of 17O NMR, EPR and nuclear magnetic relaxation dispersion (NMRD) data [EGTA-BA2- = 3,12-bis(carbamoylmethyl)- 6,9-dioxa-3,12-diazatetradecanedioate(2-)]. The Lipari-Szabo approach that distinguishes the global motion of the polymer (tau g) from the local motion of the Gd(III)-water vector (tau l) was necessary to describe the 1H and 17O longitudinal relaxation rates; therefore for the first time it was included in the global simultaneous analysis of the EPR, 17O NMR and NMRD data. The polymer consists on average of only five monomeric units, which limits the intramolecular hydrophobic interactions operating between the (CH2)12 groups. Hence the global rotational correlation time is not very high (tau g298 = 3880 +/- 750 ps) compared to the corresponding DTPA-BA-based polymer (about 15 monomeric units), where tau g298 = 6500 ps. As a consequence, the relaxivity is limited by the rotation, which precludes the advantage obtained from the fast exchanging chelating unit (kex298 = 2.2 +/- 0.1 x 10(6) s-1).

The tripodal ligand (alpha,alpha',alpha' 'nitrilotri(6-methyl-2-pyridinecarboxylic acid)) (H(3)tpaa) forms a Gd(III) complex which has a relaxivity (r(1p) = 13.3 mM(-1) s(-1) at 25 degrees C and at 60 MHz) remarkably higher than those of the currently clinically used contrast agents based on octacoordinate polyaminocarboxylate complexes (3.5-4.7 mM(-1) s(-1)) and a reasonably good thermodynamic stability. The crystal structure of the ligand and of its La, Nd, Eu, Gd, Tb, Ho, Tm, Yb, and Lu complexes have been determined by X-ray crystallography. The neutral H(3)tpaa molecule adopts, in the solid state, a preorganized tripodal conformation in which the three H(3)tpaa arms are located on the same side of the molecule, ready to bind a metal ion in a heptadentate coordination mode. The structures of the Ln(III) complexes vary along the series for their nuclearity and number of water molecules coordinated to the metal, and a tetrameric structure is observed for the La(3+) ion (9- and 10-coordinate metal centers), dimeric structures are formed from the Nd(3+) ion through the Yb(3+) ion (9-coordinate), and a monomeric structure results for Lu(3+) (8-coordinate). The relaxivity studies presented here suggest that the high relaxivity of the Gd(tpaa) complex is mainly the consequence of a shorter bound water proton-Gd(III) distance associated with a probable water coordination equilibrium between tris(aqua) and bis(aqua) complexes, giving raise to a mean number of coordinated water molecules q > 2. Both effects are strongly related to the ligand flexibility, which allows for a large volume available for water binding. The observed rapid water exchange rate is probably due to the presence of a low-energy barrier between 10-, 9-, and 8- coordinate geometries. Although the low solubility of the Gd complex of tpaa prevents its practical application as an MRI contrast agent, the straightforward introduction of substituents on the pyridine rings allows us to envisage ligands with a higher water solubility, containing functional groups leading to macromolecular systems with very high relaxivity.

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