The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia
The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia
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DOI：
10.1038/sj.npp.1300931
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发表时间：
2006-05-01
影响因子：
7.6
通讯作者：
Bartenstein, P
中科院分区：
文献类型：
--
作者：
Gründer, G;Landvogt, C;Bartenstein, P
正电子发射断层扫描（PET）研究显示，临床使用剂量的氯氮平在人纹状体中对D - 2/D - 3多巴胺受体的占有率低于60%。在此，对精神分裂症患者体内氯氮平对D - 2/D - 3多巴胺受体的占有率进行了测定，以验证氯氮平优先结合纹状体外多巴胺受体这一假设。共有15名接受氯氮平治疗的精神分裂症住院患者接受了[F - 18]氟潘立酮PET扫描。受体占有率计算为相对于7名正常志愿者所测未阻断值的结合潜能降低百分比。皮质（颞下回55%）的D - 2/D - 3受体平均占有率在统计学上显著高于纹状体区域（壳核36%，尾状核43%，p < 0.005）。虽然在纹状体和皮质中可达到的最大受体占有率E - max均接近100%，但壳核中达到E - max的50%（ED50）时的血浆浓度（950纳克/毫升）远高于颞下回（333纳克/毫升）。在较宽的血浆浓度范围内，氯氮平优先结合皮质D - 2/D - 3受体。在极高的血浆水平时，这种选择性会丧失。当血浆氯氮平浓度在350 - 400纳克/毫升范围内时，皮质受体占有率接近60%，这与氯氮平的抗精神病疗效阈值相对应。氯氮平的纹状体外结合可能与其抗精神病作用的相关性比纹状体结合更大。然而，为了证实这一发现，还需要对未治疗状态和治疗状态进行个体内比较的进一步研究。
Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D-2/D-3 dopamine receptors in human striatum. Here, the occupancy of D-2/D-3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [F-18]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D-2/D-3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p < 0.005). While the maximum attainable receptor occupancy E-max approached 100% both in the striatum and cortex, the plasma concentration at 50% of E-max (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D-2/D-3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.