Pharmacological PET receptor imaging and its application to drug development

正电子发射断层扫描（PET）是一种独特的方法来检查脑化学非侵入性人类。使用PET技术，特定的神经化学系统，如多巴胺能和组胺能神经元系统，在活体人脑中进行测量。用<11><18>新的合成方法合成了用于选择性标记几种受体的特异性~（13）C或~（13）F标记放射性示踪剂。我们还开发了几种新的方法成像在人脑中使用三维PET系统。我们开发的用于人类神经药理学的PET方法如下：受体结合参数的无创测量; H_2^ O和3D-PET的脑激活研究<15>;<11>用于测量神经递质释放的^C-配体激活研究。至于药理学应用，我们使用PET技术评价抗组胺药的镇静特性。抗组胺药是用于缓解过敏性疾病症状的有效药物。抗组胺药的安全性问题 ...更多信息 因为它们在当前医疗实践中广泛使用。PET用于更好地了解抗组胺药对中枢神经系统的药理作用。年轻男性志愿者<11>口服或静脉注射抗组胺药后，用[^ C]-多塞平（一种有效的H1拮抗剂）检查H1受体结合率。在其他研究中，认知表现也在服用抗组胺药前后进行了速示检查。由抗组胺药引起的人类额叶皮层中的H1受体占用与临床试验中报告的嗜睡发生率值显著相关，并且占用与受损的认知表现成正比。为了解抗组胺药引起“嗜睡和认知障碍”的脑机制，应用3D-PET和H_2^ O测定了d-氯苯那敏（d-chlorpheniramine，d-氯苯那敏）治疗前后大鼠作业过程中局部脑血流量（rCBF）<15>的变化。给药后，双侧颞中回、中脑和扣带回前部的rCBF显著降低。这些发现表明，H1受体阻断剂会影响大脑中注意和认知系统的活动。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