Comparison of rat dopamine D2 receptor occupancy for a series of antipsychotic drugs measured using radiolabeled or nonlabeled raclopride tracer
Comparison of rat dopamine D2 receptor occupancy for a series of antipsychotic drugs measured using radiolabeled or nonlabeled raclopride tracer
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DOI：
10.1016/j.lfs.2005.11.031
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发表时间：
2006-05-22
期刊：
影响因子：
6.1
通讯作者：
Phebus, Lee A.
中科院分区：
文献类型：
--
作者：
Barth, Vanessa N.;Chernet, Eyassu;Phebus, Lee A.
迄今为止，临床前脑受体占有率测量已经通过使用闪烁光谱学或断层成像定量放射性标记的示踪配体的脑分布来进行。对于啮齿动物等较小的动物，大多数研究采用组织解剖和闪烁光谱法。这些测量也可以使用液相色谱结合质谱检测来完成，以测量示踪分子的脑分布，从而避免了对放射性配体的需要。为了验证基于质谱的受体占有率的方法，我们研究了多巴胺D2受体的剂量占有率曲线的一些抗精神病药物在平行实验中使用质谱或放射性配体为基础的方法。在平行实验中，使用放射性标记或未标记的拉氯肽示踪剂，生成8种抗精神病化合物的口服剂量占用曲线。当比较这两种方法生成的曲线并测定ED 50值时，获得了非常相似的数据。ED 50值分别为（mg/kg）：氯丙嗪5.1和2.7，氯氮平41和40-，氟哌啶醇0.2和0.3，奥氮平2.1和2.2，利培酮0.1和0.4，螺哌隆0.5和0.4;硫利达嗪9.2和9.5，齐拉西酮1.4和2.1（分别为未标记和放射性标记的雷氯必利示踪剂）。这两种技术的体内应用导致可比数据的观察结果增加了基于质谱的受体占有率测定方法的验证状态。(c)2006年爱思唯尔公司All rights reserved.
Preclinical brain receptor occupancy measures have heretofore been conducted by quantifying the brain distribution of a radiolabeled tracer ligand using either scintillation spectroscopy or tomographic imaging. For smaller animals like rodents, the majority of studies employ tissue dissection and scintillation spectroscopy. These measurements can also be accomplished using liquid chromatography coupled to mass spectral detection to measure the brain distribution of tracer molecules, obviating the need for radioligands. In order to validate mass spectroscopy-based receptor occupancy methods, we examined dopamine D2 receptor dose-occupancy curves for a number of antipsychotic drugs in parallel experiments using either mass spectroscopy or radioligand-based approaches. Oral dose-occupancy curves were generated for 8 antipsychotic compounds in parallel experiments using either radiolabeled or unlabeled racloptide tracer. When curves generated by these two methods were compared and ED50 values determined, remarkably similar data were obtained. Occupancy ED50 values were (mg/kg): chlorpromazine, 5.1 and 2.7; clozapine, 41 and 40-, haloperidol, 0.2 and 0.3; olanzapine, 2.1 and 2.2; risperidone, 0.1 and 0.4; spiperone, 0.5 and 0.4; thioridazine 9.2 and 9.5, and ziprasidone 1.4 and 2.1 (unlabeled and radiolabeled raclopride tracer, respectively). The observation that in vivo application of both techniques led to comparable data adds to the validation state of the mass spectroscopy-based approach to receptor occupancy assays. (c) 2006 Elsevier Inc. All rights reserved.