Burai László, Tóth Eva, Sour Angélique, Merbach André E
Laboratoire de Chimie Inorganique et Bioinorganique, Ecole Polytechnique Fédérale de Lausanne, EPFL-BCH, Switzerland.
Inorg Chem. 2005 May 16;44(10):3561-8. doi: 10.1021/ic048645d.
Chiral, bifunctional poly(amino carboxylate) ligands are commonly used for the synthesis of macromolecular, Gd(III)-based MRI contrast agents, prepared in the objective of increasing relaxivity or delivering the paramagnetic Gd(III) to a specific site (targeting). Complex formation with such ligands results in two diastereomeric forms for the complex which can be separated by HPLC. We demonstrated that the diastereomer ratio for Ln(III) DTPA derivatives (approximately 60:40) remains constant throughout the lanthanide series, in contrast to Ln(III) EPTPA derivatives, where it varies as a function of the cation size with a maximum for the middle lanthanides (DTPA(5-) = diethylenetriaminepentaacetate; EPTPA(5-) = ethylenepropylenetriaminepentaacetate). The interconversion of the two diastereomers, studied by HPLC, is a proton-catalyzed process (k(obs) = k(1)[H(+)]). It is relatively fast for Gd(EPTPA-bz-NH(2))(H(2)O) but slow enough for Gd(DTPA-bz-NH(2))(H(2)O) to allow investigation of pure individual isomers (isomerization rate constants are k(1) = (3.03 +/- 0.07) x 10(4) and 11.6 +/- 0.5 s(-1) M(-1) for Gd(EPTPA-bz-NH(2))(H(2)O)(-) and Gd(DTPA-bz-NH(2))(H(2)O), respectively). Individual water exchange rates have been determined for both diastereomers of Gd(DTPA-bz-NH(2))(H(2)O) by a variable-temperature (17)O NMR study. Similarly to Ln(III) EPTPA derivatives, k(ex) values differ by a factor of 2 (k(ex)(298) = (5.7 +/- 0.2) x 10(6) and (3.1 +/- 0.1) x 10(6) s(-1)). This variance in the exchange rate has no consequence on the proton relaxivity of the two diastereomers, since it is solely limited by fast rotation. However, such difference in k(ex) will affect proton relaxivity when these diastereomers are linked to a slowly rotating macromolecule. Once the rotation is optimized, slow water exchange will limit relaxivity; thus, a factor of 2 in the exchange rate can lead to a remarkably different relaxivity for the diastereomer complexes. These results have implications for future development of Gd(III)-based, macromolecular MRI contrast agents, since the use of chiral bifunctional ligands in their synthesis inevitably generates diastereomeric complexes.
手性双功能聚（氨基羧酸盐）配体通常用于合成基于钆（III）的大分子磁共振成像（MRI）造影剂，其制备目的是提高弛豫率或将顺磁性钆（III）递送至特定部位（靶向）。与这类配体形成配合物会产生两种非对映异构体形式的配合物，可通过高效液相色谱（HPLC）分离。我们证明，与镧系元素（III）EPTPA衍生物不同，镧系元素（III）DTPA衍生物的非对映异构体比例（约为60:40）在整个镧系元素系列中保持恒定，镧系元素（III）EPTPA衍生物的非对映异构体比例随阳离子大小而变化，在中间镧系元素时达到最大值（DTPA(5-) = 二乙烯三胺五乙酸；EPTPA(5-) = 乙二胺丙胺五乙酸）。通过HPLC研究的两种非对映异构体的相互转化是一个质子催化过程（k(obs) = k(1)[H(+)]）。对于Gd(EPTPA-bz-NH(2))(H(2)O)来说相对较快，但对于Gd(DTPA-bz-NH(2))(H(2)O)足够慢，从而能够研究纯的单个异构体（对于Gd(EPTPA-bz-NH(2))(H(2)O)和Gd(DTPA-bz-NH(2))(H(2)O)，异构化速率常数分别为k(1) = (3.03 ± 0.07) x 10(4)和11.6 ± 0.5 s(-1) M(-1)）。通过变温(17)O核磁共振研究确定了Gd(DTPA-bz-NH(2))(H(2)O)两种非对映异构体各自的水交换速率。与镧系元素（III）EPTPA衍生物类似，k(ex)值相差2倍（k(ex)(298) = (5.7 ± 0.2) x 10(6)和(3.1 ± 0.1) x 10(6) s(-1)）。这种交换速率的差异对两种非对映异构体的质子弛豫率没有影响，因为它仅受快速旋转的限制。然而，当这些非对映异构体与缓慢旋转的大分子相连时，k(ex)的这种差异将影响质子弛豫率。一旦旋转得到优化，缓慢的水交换将限制弛豫率；因此，交换速率相差2倍可能导致非对映异构体配合物的弛豫率有显著差异。这些结果对基于钆（III）的大分子MRI造影剂的未来发展具有启示意义，因为在其合成中使用手性双功能配体不可避免地会产生非对映异构体配合物。
