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首页> 外文期刊>Chemistry: A European journal >Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity
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Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity

机译：包含两个具有白蛋白结合亲和力的顺磁性中心的潜在MRI造影剂的合成，表征和药代动力学评估

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A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N",N"-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37° C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear cyadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the non-covalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (K-a) was found to be 10(4) m(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40% more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.
机译：合成并评估了两亲性螯合配体的双核（（III）配合物，其中包含两个由双吲哚衍生物桥接的二亚乙基三胺-N，N，N'，N“，N” -N“-五乙酸酯（DTPA）部分作为潜在的磁共振成像（MRI）造影剂。核磁弛豫色散（NMRD）测量表明，在20 MHz和37° C双核g（III）络合物比[Gd（DTPA）]具有更高的弛豫度（6.8对3.9 s（-1）mmol（-1））。相对于[Gd（DTPA）]，双核（III）配合物的较高弛豫度可能与其减少的运动和更大的旋转相关时间有关。在人血清白蛋白（HSA）的存在下，非共价结合的双核复合物的弛豫度值增加至每mmol Gd3 + 15.2 s（-1），这是由于其与该蛋白的相互作用较强。发现与HSA（K-a）的结合常数的拟合值为10（4）m（-1）。由于其与HSA的相互作用，与市售的[Gd（DTPA）]造影剂相比，双核复合物具有更长的血浆消除半衰期以及对血管腔的更好限制。研究了锌（II）对双核g（III）配合物的重金属化。生物分布研究表明，该复合物通过肾脏途径和可能通过肝胆途径排出。体内研究表明，正常剂量的complex（III）配合物的一半比[Gd（DTPA）]更有效地增强了肝脏组织中的对比度约40％。测试了双核g（III）复合物作为潜在的坏死抗性造影剂（NACA），但尽管与HSA结合，但未显示出坏死抗性，这表明与白蛋白的结合并不是靶向坏死的关键参数。

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