Department of Pathology, University of Melbourne, Victoria 3010, Australia; Mental Health Research Institute, Parkville, Victoria 352, Australia.
ACS Chem Neurosci. 2010 Nov 17;1(11):720-7. doi: 10.1021/cn100068x. Epub 2010 Sep 30.
Apoptotic cell death via activation of the caspase family of cysteine proteases is a common feature of many neurodegenerative diseases including Creutzfeldt-Jakob disease. Molecular imaging of cysteine protease activities at the preclinical stage may provide valuable mechanistic information about pathophysiological pathways involved in disease evolution and in response to therapy. In this study, we report synthesis and characterization of a near-infrared (NIR) fluorescent contrast agent capable of noninvasively imaging neuronal apoptosis in vivo, by conjugating a NIR cyanine dye to Val-Ala-Asp-fluoromethylketone (VAD-fmk), a general inhibitor of active caspases. Following intravenous administration of the NIR-VAD-fmk contrast agent, in vivo fluorescence reflectance imaging identified significantly higher levels of active caspases in the brain of mice with advanced but preclinical prion disease, when compared with healthy controls. The contrast agent and related analogues will enable the longitudinal study of disease progression and therapy in animal models of many neurodegenerative conditions.
细胞凋亡是许多神经退行性疾病的共同特征，包括克雅氏病（Creutzfeldt-Jakob disease）。在临床前阶段对半胱氨酸蛋白酶活性进行分子成像，可能为疾病演变过程中涉及的病理生理途径以及对治疗的反应提供有价值的机制信息。在这项研究中，我们报告了一种近红外（NIR）荧光对比剂的合成和特性，该对比剂通过将 NIR 花青染料与 Val-Ala-Asp-氟甲基酮（VAD-fmk）连接，可用于非侵入性地在体内成像神经元凋亡，VAD-fmk 是活性半胱天冬酶的通用抑制剂。静脉内给予 NIR-VAD-fmk 对比剂后，与健康对照组相比，在患有晚期但临床前朊病毒病的小鼠的大脑中，体内荧光反射成像可识别出明显更高水平的活性半胱天冬酶。该对比剂和相关类似物将使许多神经退行性疾病动物模型中的疾病进展和治疗的纵向研究成为可能。
