Towards rational design of fast water-exchanging Gd(dota-like) contrast agents? Importance of the M/m ratio

H-1 NMR line-shape analysis and magnetisation-transfer experiments at varia ble temperature and pressure have been used to elucidate the solution dynam ics of both M and m isomers of three [Eu(dota-tetraamide)(H2O)](3+) complex es. The direct H-1 NMR observation of the bound water signal allows the wat er-exchange rates on each isomer to be measured individually. They are defi nitely independent of the ligand for both M and m isomers (M: k(ex)(298) = 0.2 x 10(3)s(-1) for [Eu(dotam)(H2O)](3+), 8.2 +/- 02 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: k(ex)(298) = 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 dissociat ive mechanism (M isomers: DeltaV(double dagger) = + 4.9 cm(3) mol(-1) for [ Eu(dotam)(H2O)](3+) and + 6.9 cm(3) mol(-1) for [Eu(dtma)(H2O)](3+)). The o verall 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 ni trogen. Therefore the synthesis of DOTA-like ligands, which predominantly f orm complexes in the m form, should be a sufficient condition to ensure fas ter water exchange on potential Gd-III-based contrast agents. Furthermore t he activation parameters for the water-exchange and isomerisation processes are both compatible with a nonhydrated complex as intermediate.