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成像在药物开发和评价中的新视角

• 批准号: 12557007
• 负责人: YANAI Kazuhiko
• 金额: $ 8.19万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557007/
• 关键词: Knockout mice; PET; drug development; histamine; acetylcholine esterase; ^<11>C-donepezil; activation study; pain perception; 痛みの受客; けいれんキンドリング; アレキシサイミア; PET; モルヒネ; carbn-11; ヒスタミンH_1,H_2受容体; ダブルノックアウトマウス; ストレス; セロトニン; モルセネ; ^<11>C

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

敲除小鼠和正电子发射断层扫描（PET）是评估体内药物有效性的独特方法。使用最近开发的新技术，我们开发了几种新方法来评估小鼠和人体体内的药物效应。为了研究敲除小鼠，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镇痛药，因为与组胺相关的敲除小鼠表现出对各种化学刺激的伤害感受，并增强了吗啡诱导的抗伤害感受。我们还证明，在组胺H1受体敲除小鼠，组氨酸脱羧酶缺乏的小鼠和肥大细胞缺陷小鼠中，甲状腺素化唑醇的糖脂显着增强，这表明慢性治疗脑培训H1阻滞剂可能会在患者的慢性癫痫发作。为了开发PET技术，特定的 ^<11> C-或 ^<18> f标记的放射性示例用于选择性标记几种受体是新合成的……更尺寸通过新的合成方法尺寸。 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-fuoropoxytan(histamine H3 antagonist).作为一种新的标记方法，合成了4- [18F]氟苄基卤化物和[^<11> c]甲基三叶酸酯，并用于标记放射性氨基氨基甲酯。我们还使用三维宠物系统开发了几种在人脑中成像的新方法。我们开发的人类神经药理学的PET方法如下：受体结合参数的非侵入性测量； H_2^<15> O和3D-PET的脑激活研究； ^<11> C-配体激活研究，用于测量神经递质释放。为了了解个人角色的大脑机制，我们使用3D-PET和H_2^<15> o来阐明了通过在脑检查中的面部表情通过面部表情的大脑处理的显着差异。对于神经受体研究，我们检查了抑郁症和精神分裂症患者中组胺能神经传递的替代方法。两种精神疾病的大脑中H1受体结合物得到显着改善。较少的

项目成果

K.Yanai, et al.: "Histamine H_1 receptor-mediated inhibition of pottassium-evoked release of"Behavioral Brain Res.. (In press). (2001)

K.Yanai 等人：“组胺 H_1 受体介导的钾诱发释放抑制”行为脑研究（正在出版）。

M.Endou, et al.: "Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats."Brain Res.. (In press). (2001)

M.Endou 等人：“食物匮乏的活动压力降低了大鼠组胺能神经元系统的活动。”Brain Res..（正在出版）。

Z.Chen, Z.Li, E.Sakurai, J.I.Mobarakeh, H.Ohtsu, T.Watanabe, T.Watanabe, K.Iinuma and K Yanai: "Chemical kindling induced by pentylenetetrazol in histamine H_1 receptor gene knockout mice(H_1KO), histidine decarboxylase-deficient mice(HDC^<-/->) and mast

Z.Chen、Z.Li、E.Sakurai、J.I.Mobarakeh、H.Ohtsu、T.Watanabe、T.Watanabe、K.Iinuma 和 K Yanai：“组胺 H_1 受体基因敲除小鼠 (H_1KO) 中戊四氮诱导的化学点燃

Takahiko Watanabe, Henk Timmerman, Kazuhiko Yanai: "Histamine Research in the New Millennium"Amsterdam, Elsevier Science B.V. 521 (2001)

Takahiko Watanabe、Henk Timmerman、Kazuhiko Yanai：“新千年的组胺研究”阿姆斯特丹，Elsevier Science B.V. 521 (2001)

M.Endou, K.Yanai, et al.: "Food-deprived activity stress decreased the activity of the histaminergic neuron system in rats"Brain Research. 891. 32-41 (2001)

M.Endou、K.Yanai 等人：“食物剥夺的活动压力降低了大鼠组胺能神经元系统的活性”《大脑研究》。