Quantitative relationship between in vivo receptor occupancy of psychotropic and the change of glucose utilization in brain

精神药物体内受体占有率与脑葡萄糖利用变化的定量关系

基本信息

批准号：
63571017
负责人：
SAWADA Yasufumi
金额：
$ 1.28万
依托单位：
Tokyo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1988
资助国家：
日本
起止时间：
1988 至 1989
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63571017/
关键词：
Benzodiazepine clonazepam deoxyglucose glucose zolpidem metabolism brain デオキシグルコースグルコース

项目摘要

To evaluate the relationship between the pharmacological effect of benzodiazepine (BZP) and BZP receptor binding in the conscious mouse brain, a response of the glucose utilization (GU) to clonazepam (CNZ) or zolpidem was measured as an index for the pharmacological effect. GU was measured by the simultaneous use of [14C]2-deoxyglucose (2DG), the glucose analogue which can be phosphorylated in the brain, and [3H]3-0-methylglucose (3MG), the nonmetabolizable glucose analogue. The distribution volume of unphosphorylated 2DG in the brain was not significantly different from that of 3MG (VM), indicating that the phosphorylation rate of 2DG can be estimated by subtracting VM from apparent volume of distribution of 2DG. By this double tracer technique, it is possible to determine GU within 10 min after administration of both tracers. Pharmacological and pathophysiological changes of the isotope correction factor (lumped constant) can also be estimated by this technique.In the cerebral cortex … More , GU decreased to 70-80 % at 60 min after i.v. administration of CNZ (0.005-1.0 mg/kg), and this effect was completely diminished by the administration of a benzodiazepine antagonist, Ro-15-1788 (5 mg/kg). The maximum effect of CNZ on GU (about 30 % decrease) was found at 0.1 mg/kg of CNZ, but increasing the dose to 1 mg/kg bad very little additional effect. In vivo BZP receptor occupancy, measured using [3H]Ro-15-1788, increased from less than 10 % at a dose of 0.005 mg/kg up to essentially 100 % at doses of 1 mg/kg or greater. ID50 in dose response curve of the receptor occupancy for CNZ and ED50 in that of decrease in GU were 0.3 mg/kg and 0.007 mg/kg, respectively. A nonlinear and hyperbolic relationship was observed between the receptor occupancy and the response for the glucose metabolic rate, indicating that BZP exerts the maximum glucose metabolic change at a low fractional receptor occupancy (30-40%). In zolpidem similar results were also obtained. By using positron emission tomography, these techniques can be applied to living human brain, which makes it possible to determine the optimal doses of BZP in the effective therapeutic drug monitoring. Less

为了评估意识小鼠脑中苯二氮卓（BZP）（BZP）（BZP）和BZP受体结合的药理作用之间的关系，将葡萄糖利用率（GU）对氯硝西epam（CNZ）或Zolpidem的响应作为药理学作用的指标衡量。通过同时使用[14C] 2-脱氧葡萄糖（2DG），可以在大脑中磷酸化的葡萄糖类似物以及[3H] 3-0-甲基葡萄糖（3mg），不可固化的葡萄糖类似物来测量GU。大脑中未磷酸化的2DG的分布体积与3mg（VM）没有显着差异，表明可以通过从2DG的明显分布体积中减去VM来估计2DG的磷酸化速率。通过这种双重示踪剂技术，可以在两种示踪剂给药后10分钟内确定GU。同位素校正因子的药理和病理生理变化（总计）。常数）也可以通过此技术来估计。在大脑皮层中……更多，在静脉注射后60分钟时，GU下降到70-80％。施用CNZ（0.005-1.0 mg/kg），通过苯二氮卓类拮抗剂RO-15-1788（5 mg/kg）的给药完全降低了这种影响。在0.1 mg/kg的CNZ处发现CNZ对GU的最大影响（约30％），但将剂量增加到1 mg/kg不良的效果很少。使用[3H] RO-15-1788测量的体内BZP受体占用率从0.005 mg/kg的剂量下增加了10％，达到1 mg/kg或更高剂量的100％。 CNZ和ED50的剂量反应曲线中的ID50分别为0.3 mg/kg和0.007 mg/kg。观察到受体占用率与葡萄糖代谢率的反应之间观察到非线性和双曲线关系，这表明BZP在低分数受体占用率（30-40％）下施加最大的葡萄糖代谢变化（30-40％）。在Zolpidem中，还获得了相似的结果。通过使用阳性发射断层扫描，可以将这些技术应用于活人的大脑，这使得可以在有效的治疗药物监测中确定BZP的最佳剂量。较少的