Fine-tuning water exchange on GdIII poly(amino carboxylates) by modulation of steric crowding

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Abstract
In the objective of optimizing water exchange rate on stable, nine-coordinate, monohydrated GdIII poly(amino carboxylate) complexes, we have prepared monopropionate derivatives of DOTA4− (DO3A-Nprop4−) and DTPA5− (DTTA-Nprop5−). A novel ligand, EPTPA-BAA3−, the bisamylamide derivative of ethylenepropylenetriamine-pentaacetate (EPTPA5−) was also synthesized. A variable temperature 17O NMR study has been performed on their GdIII complexes, which, for [Gd(DTTA-Nprop)(H2O)]2− and [Gd(EPTPA-BAA)(H2O)] has been combined with multiple field EPR and NMRD measurements. The water exchange rates, kex 298, are 8.0 × 107 s−1, 6.1 × 107 s−1 and 5.7 × 107 s−1 for [Gd(DTTA-Nprop)(H2O)]2−, [Gd(DO3A-Nprop)(H2O)]− and [Gd(EPTPA-BAA)(H2O)], respectively, all in the narrow optimal range to attain maximum proton relaxivities, provided the other parameters (electronic relaxation and rotation) are also optimized. The substitution of an acetate with a propionate arm in DTPA5− or DOTA4− induces increased steric compression around the water binding site and thus leads to an accelerated water exchange on the GdIII complex. The kex values on the propionate complexes are, however, lower than those obtained for [Gd(EPTPA)(H2O)]2− and [Gd(TRITA)(H2O)]− which contain one additional CH2 unit in the amine backbone as compared to the parent [Gd(DTPA)(H2O)]2− and [Gd(DOTA)(H2O)]−. In addition to their optimal water exchange rate, [Gd(DTTA-Nprop)(H2O)]2− has, and [Gd(DO3A-Nprop)(H2O)]− is expected to have sufficient thermodynamic stability. These properties together make them prime candidates for the development of high relaxivity, macromolecular MRI contrast agents.

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