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

为了评价苯二氮卓（BZP）的药理作用与清醒小鼠脑BZP受体结合之间的关系，以氯硝西泮（CNZ）或唑吡坦对葡萄糖利用（GU）的反应为指标，测定其药理作用。GU是通过同时使用[14C]2-脱氧葡萄糖（2DG）和[3H]3-0-甲基葡萄糖（3MG）来测量的，[14C]2-脱氧葡萄糖（2DG）是葡萄糖类似物，可以在大脑中磷酸化，[3H]3-0-甲基葡萄糖（3MG）是不可代谢的葡萄糖类似物。未磷酸化的2DG在脑内的分布体积与3MG （VM）的分布体积没有显著差异，说明2DG的磷酸化速率可以通过2DG的表观分布体积减去VM来估计。通过这种双示踪剂技术，可以在给予两种示踪剂后10分钟内确定GU。同位素校正因子（集总常数）的药理学和病理生理变化也可以通过该技术估计。在大脑皮层…More，在静脉注射CNZ （0.005-1.0 mg/kg）后60分钟，GU下降到70- 80%，而给药苯二氮卓类拮抗剂Ro-15-1788 （5 mg/kg）完全减少了这种影响。CNZ在0.1 mg/kg时对GU的影响最大（约降低30%），但将剂量增加到1mg /kg时几乎没有附加效应。使用[3H]Ro-15-1788测量的体内BZP受体占用率从0.005 mg/kg剂量下的不到10%增加到1mg /kg或更高剂量时的基本100%。CNZ受体占用量的ID50和GU受体占用量的ED50分别为0.3 mg/kg和0.007 mg/kg。受体占用率与糖代谢率的响应呈非线性双曲线关系，表明BZP在低受体占用率（30-40%）时产生最大的糖代谢变化。唑吡坦也得到了类似的结果。通过使用正电子发射断层扫描，这些技术可以应用于活体人脑，这使得确定BZP的最佳剂量在有效的治疗药物监测中成为可能。少

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