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Imaging of Dysfunctional Elastogenesis in Atherosclerosis Using an Improved Gadolinium-Based Tetrameric MRI Probe Targeted to Tropoelastin
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2021-10-18 , DOI: 10.1021/acs.jmedchem.1c01286
Federico Capuana 1 , Alkystis Phinikaridou 2 , Rachele Stefania 1 , Sergio Padovan 3 , Begoña Lavin 2, 4 , Sara Lacerda 5 , Eyad Almouazen 6 , Yves Chevalier 6 , Laurence Heinrich-Balard 7 , René M Botnar 2, 8 , Silvio Aime 9 , Giuseppe Digilio 10
Affiliation  

Dysfunctional elastin turnover plays a major role in the progression of atherosclerotic plaques. Failure of tropoelastin cross-linking into mature elastin leads to the accumulation of tropoelastin within the growing plaque, increasing its instability. Here we present Gd4-TESMA, an MRI contrast agent specifically designed for molecular imaging of tropoelastin within plaques. Gd4-TESMA is a tetrameric probe composed of a tropoelastin-binding peptide (the VVGS-peptide) conjugated with four Gd(III)-DOTA-monoamide chelates. It shows a relaxivity per molecule of 34.0 ± 0.8 mM–1 s–1 (20 MHz, 298 K, pH 7.2), a good binding affinity to tropoelastin (KD = 41 ± 12 μM), and a serum half-life longer than 2 h. Gd4-TESMA accumulates specifically in atherosclerotic plaques in the ApoE–/– murine model of plaque progression, with 2 h persistence of contrast enhancement. As compared to the monomeric counterpart (Gd-TESMA), the tetrameric Gd4-TESMA probe shows a clear advantage regarding both sensitivity and imaging time window, allowing for a better characterization of atherosclerotic plaques.

中文翻译:

使用针对原弹性蛋白的改进的基于钆的四聚体 MRI 探针对动脉粥样硬化中功能失调的弹性生成进行成像

功能失调的弹性蛋白更新在动脉粥样硬化斑块的进展中起主要作用。原弹性蛋白交联成成熟弹性蛋白的失败导致原弹性蛋白在生长斑块内的积累,增加了其不稳定性。在这里,我们介绍了 Gd 4 -TESMA,一种专为斑块内原弹性蛋白分子成像而设计的 MRI 造影剂。Gd 4 -TESMA 是一种四聚体探针,由与四种 Gd(III)-DOTA-单酰胺螯合物缀合的原弹性蛋白结合肽(VVGS-肽)组成。它显示出每分子 34.0 ± 0.8 mM –1 s –1 (20 MHz, 298 K, pH 7.2) 的弛豫度,对原弹性蛋白 ( K D= 41 ± 12 μM),血清半衰期超过 2 小时。Gd 4 -TESMA 在 ApoE –/–斑块进展小鼠模型的动脉粥样硬化斑块中特异性积累,对比度增强持续 2 小时。与单体对应物 (Gd-TESMA) 相比,四聚体 Gd 4 -TESMA 探针在灵敏度和成像时间窗口方面显示出明显的优势,从而可以更好地表征动脉粥样硬化斑块。
更新日期:2021-10-28
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