NMDA受体显像剂^(99m)Tc-PQQ酯的药物动力学研究

The study of pharmacokinetics of NMDA receptor imaging agent ^(99m)Tc-PQQ ester

用药物动力学定域模型及向量分析方法研究99mTc-PQQ酯(99mTc-4,5-dioxo-4,5-dihydro-1H-pyrrolo(2,3-f)quinoline-2,7,9-tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester)在小鼠血和脑中的药物动力学,以用于研究NMDA受体(N-methyl-D-aspartate receptor)显像。随机选取8组18 22 g的小鼠(每组5只,一组用于血药动力学,其他用于脑药动力学),从尾静脉注入99mTc-PQQ酯(0.2mL,10 MBq),血药动力学组于注射后5、15、30、60、120、180、360 min从尾静脉抽取10μL血样;其他组于注射后同样的时间间隔处死,取脑组织(海马、额叶、顶叶、小脑、枕叶、纹状体、脑桥和延髓、颞叶和丘脑)并称重,用γ-counter测放射性计数。用药物动力学定域模型计算动力学方程和参数、构作解空间、进行向量分析。动物实验数据表明,99mTc-PQQ酯能在海马、额叶和顶叶中浓聚。根据药物动力学定域模型计算,动力学方程分别为:海马C=0.24e 0.042t+0.28e 0.0045t,额叶C=0.22e 0.042 t+0.27e 0.0045t,顶叶C=0.24e 0.042t+0.21e 0.0045t,小脑C=0.23e 0.042t+0.11e 0.0045t,枕叶C=0.17e 0.042t+0.14e 0.0045t,纹状体C=0.11e 0.042t+0.17e 0.0045t,脑桥和延髓C=0.10e 0.042t+0.18e 0.0045t,颞叶C=0.14e 0.042t+0.14e 0.0045t,丘脑C=0.14e 0.042t+0.09e 0.0045t。血药动力学参数计算为:k12=0.0173 min 1,k21=0.0096min 1,ke=0.0196 min 1,CL=0.13 ID%g 1.min 1,AUC=753.68 ID%g 1.min,t1/2α=16.50 min,t1/2β=155.35 min等。对应于各脑组织向量的模与99mTc-PQQ酯在各脑组织中的最高浓度成线性关系,回归方程为y=1.3287x 0.0229,R2=0.9487。解空间和向量分析表明,99mTc-PQQ酯在海马、额叶和顶叶中的动力学行为相似,但与其在其他脑组织中的动力学行为有一定差异。药物动力学研究结果表明,99mTc-PQQ酯能在某些脑组织(如海马、额叶和顶叶)中浓聚。该药物在脑组织中有利的摄取和适宜的滞留证实了其能在体内与NMDA受体结合。

To study pharmacokinetics of 99mTc-PQQ ester （99mTc-4,5-dioxo-4,5-dihydro- 1H-pyrrolo （2,3-f） quinoline-2,7,9-tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester） in the blood and the brain of mice with pharmacokinetics local model and vector analysis. 99mTc-PQQ ester can be used to image NMDA receptor. 99mTc-PQQ ester （0.2 mL, 10 MBq） was injected through tail vein into the mice （18-22 g）, which were divided into 8 groups （five per group, one group for the blood and the other for the brain） randomly. 10 ~tL blood samples were withdrawn from the tail vein at 5, 15, 30, 60, 120, 180 and 360 min post-injection. The other groups of mice were sacrificed at the same time intervals post-injection, and tissues of the brain（thalamencephalon, hippocampus, frontal cortex, parietal cortex, temporal cortex, occipital cortex, pons and medulla oblongata, striatum and cerebellum） were removed and weighed. Radioactivities were counted with the y-counter. Kinetic equations and parameters were calculated by pharmacokinetics local model, and pharmacokinetics data were studied by solution space and vector analysis method. Experimental data showed that 99mTc-PQQ ester could accumulated in the hippocampus, frontal cortex and parietal cortex. According to the calculation of pharmacokinetics local model, kinetic equations were： hippocampus C=0.24e-0.0420t＋0.28e-0.00446t, frontal cortex C=0.22e 0.042t＋0.27e 0.00446t, parietal cortex C=0.24e-0.042t-0.21 e- 0.00446t, cerebellum C=0.23e 0.0420t＋0.11 e-0.00446t, occipital cortex C=0.17e0.0429t＋0.14e-0.00446t, striatum C= 0.11e-0.0420t＋0.17e-0.0446t, pons and medulla oblongata C=0.10e0.0420t＋0.18e-0.0446t, temporal cortex C= 0.14e0.0420t＋0.14e-0.00446t and thalamencephalon C=0.14e-0.0420t＋0.09e-0.00446t, respectively. Pharmacokinetics parameters of the blood were also calculated, k12 0.0173 min-1, k21 0.0096 min-1, ke 0.0196 min-1, CL 0.13 ID%g 1 rain-1, AUC 753.68 ID%g-1 rain, 11/2a 16.50min and t1/2β 155.35 min, respectively. There was a linear relationship between vector modules corresponding to brain tissues and the highest concentrations of 99mTc-PQQ ester in the brain tissues, and the linear regression equation was y=1.3287x-0.0229, R2=0.9487. Results of solution space and vector analysis method indicated that kinetic action of 99mTc-PQQ ester in the hippocampus, frontal cortex and parietal cortex was similar, and was different from that of the other brain tissues. The study of pharmacokinetics shown that 99mTc-PQQ ester can accumulated in some brain tissues of mice, such as hippocampus, frontal cortex and parietal cortex. The favourable uptake and suitable retention in these brain tissues confirmed that it can combine with NMDA receptor in vivo.