1H-NMRD and 17O-NMR assessment of water exchange and rotational dynamics of two potential MRI agents: MP-1177 (an extracellular agent) and MP-2269 (a blood pool agent).
Résumé
The parameters that govern water proton magnetic relaxation (e.g. water exchange rates, and rotational and electronic correlation times) of representatives of two classes of Gd(III) complexes have been estimated, using two different approaches and the results compared with those derived for known analogs. The complexes studied are: (i) the non-ionic GdDTPA-bis(-methoxyethyl-amide) [Gd(DTPA-BMEA)], a typical small-molecule extracellular MR agent, and (ii) the ionic Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-L-aspartyl-lysine-deriv ed-DTPA [GdL]4-, a prototype MR blood pool agent, which binds to serum albumin in vivo through non-covalent hydrophobic interactions. An 17O-NMR study of [Gd(DTPA-BMEA)] gives a water exchange rate constant of k(ex)298 = (0.39 +/- 0.02) x 10(6) s(-1), identical to that for the bismethylamide analog [Gd(DTPA-BMA)]. Both approaches yield longer rotational correlation times for [Gd(DTPA-BMEA)], consistent with its higher molecular weight. An 17O-NMR study of [GdL]4- gives a water exchange rate constant of k(ex)298 = (4.2 +/- 0.1) x 10(6) s(-1), identical to that for [Gd(DTPA)]2-. The water exchange rate on [GdL]4- did not decrease considerably when bound to albumin, the lowest limit is k(ex,GdL-BSA) = k(ex,GdL)/2. Both approaches yield identical rotational correlation times for [GdL]4-, however, it was difficult to derive a consistent rotational constant for the albumin-bound [GdL]4- using the different approaches (values ranged between 1.0 and 23.0 ns).