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首页> 外文期刊>Chemistry: A European journal >Gd~(III) complexes with fast water exchange and high thermodynamic stability: potential building blocks for high-relaxivity MRI contrast agents
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Gd~(III) complexes with fast water exchange and high thermodynamic stability: potential building blocks for high-relaxivity MRI contrast agents

机译：具有快速水交换和高热力学稳定性的Gd〜（III）配合物：高弛豫度MRI造影剂的潜在组成部分

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摘要

On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd~(III) poly(aminocarboxylate) complexes, we succeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA~(5-) ligand (DTPA = (diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA~(5-)) or two (DPTPA~(5-)) ethylene bridges, or one backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop~(5-)). The ligand EPTPA~(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO_2~(5-)) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature ~(17)O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa-bz-NO_2)(H_2O)]~92-) and [Gd(eptpa)(H_2O)]~(2-) than on [Gd(dtpa)(H_2O)]~(2-) (kappa_(ex)~(298) = 150 X 10~6, 330 X 10~6, and 3.3 X 10~6 s~(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd~(III)-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure ~(17)O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H_2O)]~(2-) (DELTAV = (+6.6 +- 1.0) cm~3 mol~(-1). In contrast to [Gd(eptpa)(H_2O)]~(2-), an interchange mechanism is proved for the macrocyclic [Gd(trita)(H_2O)]~- (DELTAV =(-1.5 +- 1.0) cm~3 mol~(-1)), which has one more CH_2 group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H_2O)]~-, and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA~(5-) is substituted by a propionate, the water exchange rate on the Gd~(III) complex increases by a factor of 10 (kappa_(ex)~(298) = 31 x 10~6 S~(-1)). The [Gd(dptpa)]~(2-) chelate has no inner-sphere water molecule. The protonation constants of the EPTPA-bz-NO_2~(5-) and DPTPA~(5-) ligands and the stability constants of their complexes with Gd~(III), Zn~(II), Cu~(II) and Ca~(II) were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa-bz-NO_2)(H_2O)]~(2-) is reduced to a slight extent in comparison with [Gd(dtpa)(H_2O)]~(2-), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H_2O)]~- are potential building blocks for the development of high-relaxivity macromolecular agents.
机译：基于九配位的一水合Gd〜（III）聚氨基羧酸盐配合物内球的结构考虑，我们成功地通过诱导水结合位点附近的空间压缩来促进水交换。我们通过替换一个（EPTPA〜（5-））或两个（DPTPA〜（），来修饰常见的DTPA〜（5-）配体（DTPA =（二亚乙基三胺-N，N，N'，N“，N”-五乙酸） 5-））乙烯桥，或一个通过丙烯桥的主链，或一个通过丙酸酯臂的配位乙酸酯（DTTA-prop〜（5-））。配体EPTPA〜（5-）还被硝基苄基连接基团官能化（ EPTPA-bz-NO_2〜（5-））可以使螯合物与大分子偶联，由〜（17）O NMR和EPR联合研究确定的水交换速率比EPTPA-bz-NO_2〜（5-））高两个数量级。 [Gd（eptpa-bz-NO_2）（H_2O）]〜92-）和[Gd（eptpa）（H_2O）]〜（2-）比[Gd（dtpa）（H_2O）]〜（2-）（kappa_ （ex）〜（298）= 150 X 10〜6、330 X 10〜6和3.3 X 10〜6 s〜（-1））。这对于获得基于Gd〜（III）的大环MRI造影剂的最大质子弛豫性是最佳的。通过变压〜（17）O NMR光谱测量的水交换的活化体积证明了[Gd（eptpa）（H_2O）]〜（2-）的解离交换机理（DELTAV =（+6.6 +-1.0 ）cm〜3 mol〜（-1）。与[Gd（eptpa）（H_2O）]〜（2-）相比，证明了大环[Gd（trita）（H_2O）]〜-（DELTAV =（-1.5 +-1.0）cm〜3 mol〜（-1）），其中大环中的CH_2基团比市售MRI造影剂[Gd（dota）（H_2O）]〜-多，并且胺主链的延长也导致了非常快的水交换。当DTPA〜（5-）的一种乙酸盐被丙酸酯替代时，Gd〜（III）络合物上的水交换速率增加了10倍（kappa_ （ex）〜（298）= 31 x 10〜6 S〜（-1））[Gd（dptpa）]〜（2-）螯合物没有内圈水分子，EPTPA-bz的质子化常数测定了-NO_2〜（5-）和DPTPA〜（5-）的配体以及它们与Gd〜（III），Zn〜（II），Cu〜（II）和Ca〜（II）的配合物的稳定性常数。 pH电位计。尽管与[Gd（dtpa）（H_2O）]〜（2-）相比，[Gd（eptpa-bz-NO_2）（H_2O）]〜（2-）的热力学稳定性有所降低，但它是稳定的足以在医学诊断中用作MRI造影剂。因此，该螯合物和[Gd（H 2 O）]-都是开发高弛豫性大分子试剂的潜在组成部分。

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