Pharmacological PET receptor imaging and its application to drug development

正电子发射断层扫描(PET)是一种独特的无创检测人脑化学物质的方法。利用PET技术，在活人的大脑中测量了特定的神经化学系统，如多巴胺能和组胺能神经元系统。用新的合成方法合成了选择性标记多种受体的特异性放射性示踪剂~(11)或~(18)F。我们还开发了几种使用三维PET系统在人脑中进行成像的新方法。我们开发的用于人类神经药理学的PET方法如下：无创测量受体结合参数；用H_2^&lt；15&gt；O和3D-PET进行脑激活研究；^&lt；11&gt；C-配体激活研究，以测量神经递质的释放。至于药理应用，我们使用正电子发射计算机断层扫描技术来评估抗组胺药物的镇静性能。抗组胺药是缓解过敏性疾病症状的有效药物。抗组胺药物…的安全性问题更重要的是，因为它们在当前的医疗实践中被广泛使用。PET被用来更好地了解抗组胺药物对中枢神经系统的药理作用。在口服或静脉注射抗组胺药物后，研究了服用强效H1拮抗剂多塞平的年轻男性志愿者的H1受体占有率。在其他研究中，在服用抗组胺药物之前和之后，也用速测仪测量了认知能力。抗组胺药物引起的人类额叶皮质H1受体占有率与临床试验中报道的嗜睡发生率显著相关，并且占有率与认知能力受损成正比。为了解抗组胺药物引起的“嗜睡和认知障碍”的脑机制，用3D-PET和H_2^&lt；15&gt；O测量了给药前后的局部脑血流量(RCBF)。给药后双侧颞中回、中脑和扣带前回的局部脑血流量明显减少。这些发现表明，H1受体的阻断会影响大脑中注意力和认知系统的活动。较少

Positron emission tomography(PET) is a unique method to examine brain chemistry non-invasively in humans. Using PET techniques, specific neurochemical systems, such as dopaminergic and histaminergic neuronal systems, were measured in the living human brain. Specific ^<11>C-or ^<18>F-labelled radiotracers for selective labeling of several receptors were newly synthesized by new synthetic methods. We also developed several new methods of imaging in the human brain using 3-demensional PET system. Our developed PET methods for human neuropharmacology are as follows : Non-invasive measurement of receptor binding parameters ; cerebral activation study with H_2^<15>O and 3D-PET ; ^<11>C-ligand activation study to measure neurotransmitter release. As for pharmacological applications, we used PET techniques for evaluating sedative properties of antihistamines. Antihistamines are the efficacious drugs to be used for the symptomatic relief of allergic diseases. The safety issue of antihistamines … More is of central importance because of their widespread use in current medical practice. PET was used to better understand the pharmacological effects of antihistamines on the central nervous system. The H1 receptor occupancy was examined in young male volunteers with [^<11>C]-doxepin(a potent H1 antagonist) after the oral or intravenous administration of antihistamines. In other studies, the cognitive performance was also measured tachistoscopically before and after taking antihistamines. The H1 receptor occupancy in the human frontal cortex caused by antihistamines is significantly correlated with the reported values of incidence of sleepiness in clinical trials, and the occupancy is well proportional to the impaired cognitive performance. To understand the brain mechanism of antihistamine-induced "sleepiness and impaired cognition", the regional cerebral blood flow (rCBF) during the task was measured using 3D-PET and H_2^<15>O before and after administration of d-chlorpheniramine. After its administration, the rCBF was significantly decreased on the bilateral middle temporal gyrus, midbrain and anterior cingulate. These findings suggest that H1 receptor blockade would be affected on the activity of the attention and cognitive system in the brain. Less