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）是评估体内给药疗效的独特方法。利用最近开发的新技术，我们开发了几种新的方法来评估小鼠和人体内的药理作用。在基因敲除小鼠的研究中，我们发现了组胺能神经元的一些新功能。H1阻滞剂可以作为轻度镇痛药，因为组胺相关基因敲除小鼠对各种化学刺激的痛觉减少，吗啡诱导的抗痛觉增强。我们还证明，戊四唑点燃在组胺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显著增强，这表明慢性治疗脑穿透H1阻滞剂可能导致慢性癫痫患者。对于PET技术的发展，新合成了特定的^<11>C-或^<18> f标记的放射性示踪剂，用于选择性标记几种受体。新开发的示踪剂如下：^<11>C-donepezil（乙酰胆碱酯酶抑制剂），^<18>F-TAK147（乙酰胆碱酯酶抑制剂），^<18> f -氟胆碱（胆碱类似物），和^<18> f -氟proxytan（组胺H3拮抗剂）。合成了4-[18F]氟酰卤化物和[^<11>C]三氟酸甲酯作为一种新的标记方法，用于放射性药品的标记。我们还开发了几种新的方法，利用三维PET系统在人脑成像。我们开发的用于人类神经药理学的PET方法有：无创测量受体结合参数；H_2^<15>和3D-PET脑活化研究^< 11bb0 c -配体激活研究测量神经递质释放。为了进一步了解人格特质的脑机制，我们利用3D-PET和H_2^<15>厘清述情障碍患者面部表情对情绪的脑加工的显著差异。对于神经受体的研究，我们检查了抑郁症和精神分裂症患者组胺能神经传递的变化。两种精神疾病患者的大脑中H1受体结合明显减少。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