Detection of enzymatic activity by PARACEST MRI:: A general approach to target a large variety of enzymes
Detection of enzymatic activity by PARACEST MRI:: A general approach to target a large variety of enzymes
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DOI：
10.1002/anie.200800809
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Toth, Eva
中科院分区：
文献类型：
--
作者：
Chauvin, Thomas;Durand, Philippe;Toth, Eva
对生理响应诊断探针的搜索是当前磁共振成像（MRI）造影剂发展的重要驱动力。顺磁性化学交换饱和转移（PARACEST）试剂有望作为传感器用于测量其生物环境的各种参数（pH、温度、代谢物或金属离子浓度）。[1-5]PARACEST探针非常适合分子成像，因为与基于Gd 3+的MRI试剂相反，造影剂可以随意打开和关闭。[6，7]它们含有顺磁移动的移动的质子，与大量水缓慢交换。这些质子的照射通过化学交换影响水质子的磁共振信号。影响交换的因素将对水信号产生可检测的影响。PARACEST成像的一个缺点是其灵敏度适中;通常需要药物的毫摩尔浓度[8]，并且在低浓度下无法检测靶分子。前PARACEST试剂的酶促活化可以避免这个问题，因为大量试剂的转化可以通过多个酶催化循环来实现。因此，即使在低酶浓度下，酶活性的PARACEST检测也是可能的。从这个角度来看，Yoo等人最近开发了一种检测caspase-3的PARACEST探针。[9，10]在这里，我们报告了第一个代表性的新的，多功能平台的PARACEST代理设计用于特异性检测各种酶。分子设计是基于偶联酶特异性底物的镧系元素螯合单元通过一个自分解间隔（方案1）。在底物的酶促裂解后，
The search for physiologically responsive diagnostic probes is an important driving force in the current development of contrast agents for magnetic resonance imaging (MRI). Paramagnetic chemical exchange saturation transfer (PARACEST) agents hold promise as sensors for measuring various parameters of their biological environment (pH, temperature, metabolite or metal ion concentration).[1–5] PARACEST probes are ideally suited for molecular imaging since, as opposed to Gd3+-based MRI agents, the contrast can be switched on and off at will.[6, 7] They contain paramagnetically shifted mobile protons in slow exchange with bulk water. The irradiation of these protons affects the magnetic resonance signal of water protons through the chemical exchange. Factors influencing the exchange will have a detectable effect on the water signal. One drawback of PARACEST imaging is its modest sensitivity; typically millimolar concentrations of the agent are required,[8] and PARACEST detection of target molecules is not possible at low concentration. Enzymatic activation of a pro-PARACEST agent can circumvent this problem, as the transformation of a large amount of the agent can be realized through multiple enzyme-catalyzed cycles. Hence, PARACEST detection of enzyme activity can be possible even at low enzyme concentrations. In this perspective, Yoo et al. have recently developed a PARACEST probe that detects caspase-3.[9, 10]Here we report the first representative of a new, versatile platform of PARACEST agents designed for specific detection of a wide variety of enzymes. The molecular design is based on coupling an enzyme-specific substrate to a lanthanide-chelating unit through a self-immolative spacer (Scheme 1). After enzymatic cleavage of the substrate, the