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.