Synthesis and characterization of a Gd(III) based contrast agent responsive to thiol containing compounds
Synthesis and characterization of a Gd(III) based contrast agent responsive to thiol containing compounds
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DOI：
10.1039/b705088g
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Aime, Silvio
中科院分区：
文献类型：
--
作者：
Carrera, Carla;Digilio, Giuseppe;Aime, Silvio
一种新的Gd（III）配合物与修改的DO 3A样螯合笼已被合成和其特征在于作为一个候选的造影剂响应组织中的游离巯基的浓度（基本上由还原型谷胱甘肽，GSH）。新化合物（称为Gd-DO 3AS-Act）带有以2-吡啶基-二硫基结尾的柔性连接基，其可以迅速与游离硫醇（XSH）反应以形成Gd-DO 3AS-SX形式的混合二硫化物。化合物Gd-DO 3AS-Act的特征在于高达8.1 mM（-1）s（-1）的毫摩尔弛豫率（在20 MHz、25 ℃和pH 7.4下）。在与GSH反应时，形成Gd-DO 3AS-SG共价加合物，并且毫摩尔弛豫率下降至4.1 mM（-1）s（-1）。这种弛豫率的降低被解释的基础上形成的分子内配位键之间的谷胱甘肽羧基基团和Gd（III）的中心，降低顺磁中心的水合状态。1H-1-NMR色散曲线与O-17-NMR横向弛豫时间对温度曲线一起证实Gd（III）中心的水合从Gd-DO 3AS-Act到Gd-DO 3AS-SG加合物强烈减少。在聚β-环糊精存在下，Gd-DO 3AS-Act与GSH反应所产生的弛豫率差异可提高至60%。
A novel Gd(III) complex with a modified DO3A-like chelating cage has been synthesized and characterized as a candidate contrast agent responsive to the concentration of free thiols in tissues ( essentially represented by reduced glutathione, GSH). The novel compound ( called Gd-DO3AS-Act) bears a flexible linker ending with a 2-pyridyl-dithio group, that can promptly react with free thiols ( XSH) to form mixed disulfides of the form Gd-DO3AS-SX. Compound Gd-DO3AS-Act is characterized by a millimolar relaxivity as high as 8.1 mM(-1) s(-1) ( at 20 MHz, 25 degrees C and pH 7.4). Upon reaction with GSH, the Gd-DO3AS-SG covalent adduct is formed and the millimolar relaxivity drops to 4.1 mM(-1) s(-1). Such a decrease in relaxivity is explained on the basis of the formation of an intramolecular coordinative bond between one of the glutathionyl carboxyl groups and the Gd( III) centre, lowering the hydration state of the paramagnetic centre. H-1-NMR dispersion profiles together with O-17-NMR transverse relaxation time versus temperature profiles confirm that the hydration of the Gd( III) centre is strongly reduced ongoing from Gd-DO3AS-Act to the Gd-DO3AS-SG adduct. The relaxivity difference brought about by the reaction of Gd-DO3AS-Act with GSH can be enhanced up to 60% in the presence of poly-beta-cyclodextrin.