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

为了评价苯二氮(BZP)的药理作用与清醒小鼠脑内BZP受体结合的关系，以葡萄糖利用(GU)对氯硝西潘(CNZ)或唑吡坦的反应作为药理作用的指标。同时使用脑内可磷酸化的葡萄糖类似物[14C]2-脱氧葡萄糖(2DG)和非代谢葡萄糖类似物[~3H]3-0-甲基葡萄糖(3 Mg)测定GU。未磷酸化的2DG在脑内的分布体积与3 mg(Vm)的分布体积无显著差异，表明从2DG的表观分布体积减去Vm可估算2DG的磷酸化速率。通过这种双示踪技术，可以在两种示踪剂注射后10分钟内测定GU。这种技术还可以估计同位素校正因子(集总常数)的药理学和病理生理学变化。在大脑皮层中，…静脉注射后60min，GU下降至70-80%。该作用可被苯二氮类拮抗剂Ro-15-1788(5 mg/kg)完全减弱。CNZ在0.1 mg/kg剂量时对胃溃疡的影响最大(下降约30%)，但将剂量增加到1 mg/kg时，附加作用很小。在体内，用[~3H]Ro-15-1788测量的BZP受体占有率从0.005 mg/kg剂量时的不到10%增加到1 mg/kg或更高剂量时的基本上100%。CNZ受体占位的量效曲线ID_(50)为0.3 mg/kg，GU减少的ED_(50)为0.007 mg/kg。受体占有率与葡萄糖代谢率之间存在非线性和双曲线关系，表明BZP在较低的受体占有率(30-40%)时葡萄糖代谢变化最大。在唑吡坦中也得到了类似的结果。通过正电子发射断层扫描，这些技术可以应用于活体人脑，这使得在有效的治疗药物监测中确定BZP的最佳剂量成为可能。较少

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