A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals.
A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals.
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DOI：
10.1002/cmmi.1672
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发表时间：
2016-03
影响因子：
--
通讯作者：
Pagel MD
中科院分区：
文献类型：
--
作者：
Hingorani DV;Montano LA;Randtke EA;Lee YS;Cárdenas-Rodríguez J;Pagel MD
CatalyCEST MRI可以通过监测造影剂被酶裂解后与水的化学交换的变化来检测酶活性。这些分子通常使用顺磁性金属，并与另外的非响应性参比分子一起递送。为了改进这种用于分子成像的方法，合成并表征了具有酶响应性和酶不响应性CEST信号的单一抗磁性剂。来自芳基酰胺的CEST信号在用组织蛋白酶B裂解二肽基配体后消失，而水杨酸部分在很大程度上对酶活性无反应。来自相同试剂的两个CEST信号的比率比较允许酶活性的浓度无关测量。水杨酸部分的化学交换速率在酶催化后没有变化，这进一步验证了该部分是酶不响应的。水杨酸部分的化学交换速率的温度依赖性是非Arrhenius，表明水杨酸的两步化学交换机制。低饱和功率下的良好检测灵敏度有助于临床转化，沿着非金属MRI造影剂的潜在低毒性。该试剂的模块化设计构成了一种平台技术，该技术扩展了catalyCEST MRI用于分子成像的试剂种类。
CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non-responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non-Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging.