Jászberényi Zoltán, Sour Angélique, Tóth Eva, Benmelouka Meriem, Merbach André E
Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, ISIC, BCH, CH-1015 Lausanne, Switzerland.
Dalton Trans. 2005 Aug 21(16):2713-9. doi: 10.1039/b506702b. Epub 2005 Jul 12.
In the objective of optimizing water exchange rate on stable, nine-coordinate, monohydrated Gd(III) poly(amino carboxylate) complexes, we have prepared monopropionate derivatives of DOTA4- (DO3A-Nprop4-) and DTPA5- (DTTA-Nprop5-). A novel ligand, EPTPA-BAA(3-), the bisamylamide derivative of ethylenepropylenetriamine-pentaacetate (EPTPA5-) was also synthesized. A variable temperature 17O NMR study has been performed on their Gd(III) 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, k(ex)(298), are 8.0 x 10(7) s(-1), 6.1 x 10(7) s(-1) and 5.7 x 10(7) 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 Gd(III) complex. The k(ex) values on the propionate complexes are, however, lower than those obtained for [Gd(EPTPA)(H2O)]2- and [Gd(TRITA)(H2O)]- which contain one additional CH(2) 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.
为了优化稳定的九配位单水合钆（III）聚（氨基羧酸盐）配合物的水交换率，我们制备了DOTA4-（DO3A-Nprop4-）和DTPA5-（DTTA-Nprop5-）的单丙酸酯衍生物。还合成了一种新型配体EPTPA-BAA(3-)，即乙二胺丙三胺五乙酸（EPTPA5-）的双戊酰胺衍生物。对它们的钆（III）配合物进行了变温17O NMR研究，对于[Gd(DTTA-Nprop)(H2O)]2-和[Gd(EPTPA-BAA)(H2O)]，该研究结合了多场EPR和NMRD测量。[Gd(DTTA-Nprop)(H2O)]2-、[Gd(DO3A-Nprop)(H2O)]-和[Gd(EPTPA-BAA)(H2O)]的水交换率k(ex)(298)分别为8.0×10(7) s(-1)、6.1×10(7) s(-1)和5.7×10(7) s(-1)，只要其他参数（电子弛豫和旋转）也得到优化，这些值都处于达到最大质子弛豫率的狭窄最佳范围内。在DTPA5-或DOTA4-中用丙酸臂取代乙酸会导致水结合位点周围的空间压缩增加，从而导致钆（III）配合物上的水交换加速。然而，丙酸配合物的k(ex)值低于[Gd(EPTPA)(H2O)]2-和[Gd(TRITA)(H2O)]-的k(ex)值，与母体[Gd(DTPA)(H2O)]2-和[Gd(DOTA)(H2O)]-相比，这两种配合物的胺主链中多了一个CH(2)单元。除了具有最佳的水交换率外，[Gd(DTTA-Nprop)(H2O)]2-具有，并且[Gd(DO3A-Nprop)(H2O)]-预计具有足够的热力学稳定性。这些特性共同使其成为开发高弛豫率大分子MRI造影剂（磁共振成像造影剂）的主要候选物。
