Towards Rational Design of Fast Water-Exchanging Gd(dota-Like) Contrast Agents? Importance of the M/m Ratio

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Abstract
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: k =9.4±0.2×103 s−1 for [Eu(dotam)(H2O)]3+, 8.2±0.2×103 s−1 for [Eu(dtma)(H2O)]3+ and 11.2±1.4×103 s−1 for [Eu(dotmam)(H2O)]3+; m: k =474±130×103 s−1 for [Eu(dotam)(H2O)]3+, 357±92×103 s−1 for [Eu(dtma)(H2O)]3+), and proceed through a dissociative mechanism (M isomers: ΔV ‡=+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 α‐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 GdIII‐based contrast agents. Furthermore the activation parameters for the water‐exchange and isomerisation processes are both compatible with a nonhydrated complex as intermediate.

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