The new perspectives of knockout mice and positron emission temography in the development and evaluation of drugs

基因敲除小鼠和正电子发射断层扫描(PET)是评价体内给药效果的独特方法。利用最近开发的新技术，我们开发了几种新的方法来评估在小鼠和人类体内的药理作用。在对基因敲除小鼠的研究中，我们发现了组胺能神经元的几个新功能。H1阻滞剂可以用作温和的止痛剂，因为组胺相关的基因敲除小鼠对各种化学刺激的伤害性反应减少，而吗啡诱导的抗伤害性反应增强。我们还发现，在组胺H1受体敲除小鼠、组氨酸脱羧酶缺陷小鼠和肥大细胞缺陷小鼠中，戊四氮点燃显著增加，这表明慢性治疗脑穿透性H1阻滞剂可能会在患者中发展为慢性癫痫。为了发展正电子发射计算机断层扫描技术，合成了新的…。通过新的合成方法获得更大的尺寸。新开发的示踪剂有：C-多奈哌齐(乙酰胆碱酯酶抑制剂)、F-TAK147(乙酰胆碱酯酶抑制剂)、F-氟胆碱(胆碱类似物)和F-呋喃丙烷(组胺H3拮抗剂)。作为一种新的标记方法，合成了4-[18F]氟苯卤化物和[^&lt；11&gt；C]三氟酸甲酯，并将其用于放射性药物的标记。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。为了了解个性特征的大脑机制，我们使用3D-PET和H_2^&lt；15&gt；O阐明了述情障碍患者面部表情对情绪的大脑处理的显著差异。在神经受体研究方面，我们检测了抑郁症和精神分裂症患者组胺能神经传递的变化。两种精神疾病患者脑内H1受体结合量均显著降低。较少

Knockout mice and positron emission tomography (PET) are unique methods to evaluate the efficacy of administered drugs in vivo. Using recently-developed new technologies, we developed several new methods to evaluate pharmacological effects in vivo in mice and humans. For studies of knockout mice, we discovered several new functions of the histaminergic neurons. H1 blockers can be used as mild analgesics because histamine-related knockout mice showed reduced nociception to various chemical stimuli and enhanced morphine-induced antinociception. We also demonstrated that pentylenetetrazol-kindling were significantly augmented in histamine H1 receptor knockout mice, histidine decarboxylase deficient mice and mast cell deficient mice, suggesting that chronic treatment of brain-penetrating H1 blockers could develop chronic epilepsy in patients. For the development of PET techniques, specific ^<11>C- or ^<18>F-labelled radiotracers for selective labeling of several receptors were newly synthe … More sized by new synthetic methods. Newly-developed tracers are as follows: ^<11>C-donepezil(acetylcholine esterase inhibitor), ^<18>F-TAK147(acetylcholine esterase inhibitor), ^<18>F-fluorocholine (choline analog), and ^<18>F-fuoroproxytan(histamine H3 antagonist). As a new labeling method, 4-[18F]fluorobenzyl halides and [^<11>C]methyl triflate were synthesized and used to label radioplmramaceuticals. 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 neurotransmiter release. To understand the brain mechanism of personal characters, we clarified the significant difference in brain processing of emotion by facial expressions in alexithymia using 3D-PET and H_2^<15>O. For neuroreceptor studies, we examined the alternation of histaminergic neurotransmission in depressive and schizophrenic patients. H1 receptor bindings were significantly decreased in brains of both psychiatric diseases. Less