The study for imaging, in vivo, brain mitochondrial. dysfunction using positron emission tomography

越来越多的证据表明，线粒体在许多脑部疾病中起着关键作用。因此，对线粒体功能进行分析，为脑部疾病的诊断提供重要信息。另一方面，正电子发射断层扫描(PET)是研究脑功能的有价值的工具。然而，目前还没有合适的PET示踪剂来直接分析线粒体的功能。在这项研究中，我们使用~&lt；11&gt；C-丙酮酸作为正电子发射计算机断层扫描的示踪剂，并试图分析脑内线粒体的功能。线粒体解偶联剂--乙酰氰基-4-(三氟甲氧基)苯肼(FCCP，10μM)可在20分钟内引起培养的海马神经元线粒体膜电位的损伤。FCCP能显著降低线粒体的放射性，提示11&gt；C-丙酮酸可用于体外分析线粒体功能。我们还利用纹状体内注射琥珀酸脱氢酶抑制剂3-硝基丙酸(3-NP)介导的兴奋性毒性模型，研究了丙酮酸的可行性。体内研究表明：1)丙酮酸可用于检测动物模型中线粒体功能障碍；2)丙酮酸可用作PET示踪剂如下：a)静脉注射11&gt；C‘-丙酮酸；b)注射后10-20分钟，进行PET扫描和PET图像分析。最后，我们用正电子发射计算机断层扫描仪研究了可逆性大脑中动脉闭塞后应用丙酮酸的可能性。11&gt；C-丙酮酸表现出与氟代脱氧葡萄糖(18&gt；F-FDG)相似的模式。基于这些结果，我们得出结论，作为一种PET示踪剂，11&gt；C-丙酮酸在体内外检测脑线粒体功能障碍方面是有价值的。

Mounting evidences indicate that the mitochondria play a key role in many diseases of the brain. To analyze mitochondrial function, therefore, provides the important information for diagnosis of the brain diseases. On the other hand, positron emission tomography (PET) is a valuable tool for the study of brain function. However, there is no suitable PET tracer for direct analysis of mitochondrial function. In this study, we employed ^<11>C-pyruvate as a PET tracer, and attempted to analyze mitochondrial function in the brain.A mitochondrial uncoupler, carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP, 10 μM) induced, within 20 min, the impairment of mitochondrial membrane potential in the cultured hippocampal neurons. FCCP significantly decreased ^<11>C-pyruvate radioactivity indicating that ^<11>C-pyruvate may be useful for analyzing mitochondrial function in vitro. We also studied the feasibility of ^<11>C-pyruvate using in vivo rat model of excitotoxicity mediated by intrastriatal injection of 3-nitropropionic acid (3-NP), a succinate dehydrogenase inhibitor. The in vivo study suggests that : 1) ^<11>C-pyruvate can be useful for detecting the mitochondrial dysfunction in the animal model ; and 2) ^<11>C-pyruvate can be used as a PET tracer as follows : a) ^<11>C'-pyruvate intravenously injected ; and b) 10-20 min after injection, PET scan performed and PET mages analyzed. Finally we examined the possibility of ^<11>C-pyruvate using PET scanner following reversible middle cerebral artery occlusion in monkey. ^<11>C-pyruvate showed the similar pattern as indicated by ^<18>F-fluorodeoxyglucose (^<18>F-FDG). Based on these results, we conclude that, as a PET tracer, ^<11>C-pyruvate is valuable to detect the brain mitochondrial dysfunction in vitro and in vivo.