OCCUPANCY OF EXTRASTRIATAL D2 RECEPTORS BY CLOZAPINE

描述：（逐字引用申请人摘要）抗精神病作用 典型的精神抑制剂的作用是通过阻断多巴胺D2型受体介导的。 有人提出，这些药物的抗精神病作用是介导的， 通过阻断皮质和边缘多巴胺D2受体， 位点效应由背外侧纹状体D2受体阻断介导。到 迄今为止，大多数抗精神病药物阻断D2受体的PET和SPECT研究 检查了纹状体有很多研究表明， 氯氮平的非典型特征至少部分是由选择性 对皮质和边缘多巴胺能神经传递的影响。我们集团 开发了[18F] N-烯丙基-5-氟丙基吡必利作为PET放射性配体， 可视化的纹状体外D2受体在人。我们的第一阶段和早期阶段 II IND研究表明，这种配体允许极好的可视化和 人纹状体外D2受体的定量。我们建议使用[18F] 15例精神分裂症患者的N-烯丙基-5-氟丙基吡必利PET研究 受试者停止药物治疗和氟哌啶醇单药治疗6周后， 以及15名精神分裂症受试者停止药物治疗， 氯氮平单药治疗。这些研究的数据将有助于评价 无论是将氯氮平与氟哌啶醇（一种典型的精神抑制剂）进行比较， 选择性地占据纹状体外多巴胺D2受体， D2受体的占据可能与抗精神病作用有关。二次 目标包括检查精神病理学症状复合体，即， 积极的，消极的，混乱的，以及认知异常， 精神分裂症与D2受体的区域水平有关。

DESCRIPTION: (Verbatim from the Applicant's Abstract) The antipsychotic effects of typical neuroleptics are mediated by blockade of dopamine D2 type receptors. It has been proposed that the antipsychotic effects of these drugs are mediated by blockade of cortical and limbic dopamine D2 receptors while extrapyramidal site effects are mediated by dorsolateral striatal D2 receptor blockade. To date, most PET and SPECT studies of antipsychotic drug blockade of D2 receptors have examined the striatum. There are a number of studies which suggest that the atypical profile of clozapine is mediated at least in part by selective effects on cortical and limbic dopaminergic neurotransmission. Our group has developed [18F] N-allyl-5-fluoropropylepidepride as a PET radioligand for visualization of extrastriatal D2 receptors in man. Our Phase I and early Phase II IND studies demonstrate that this ligand allows excellent visualization and quantitation of extrastriatal D2 receptors in man. Wed propose to use [18F] N-allyl-5-fluoropropylepidepride PET studies to evaluate 15 schizophrenic subjects off medication and following 6 weeks of haloperidol monotherapy, as well as 15 schizophrenic subjects off medication and following 8 weeks of clozapine monotherapy. The data from these studies will allow evaluation as to whether clozapine, s compared to haloperidol (a typical neuroleptic), selectively occupies extrastriatal dopamine D2 receptors, and whether regional occupancy of D2 receptors can be related to antipsychotic effects. Secondary goals include examining if psychopathological symptom complexes, i.e., positive, negative, and disorganization, as well as cognitive abnormalities in schizophrenia are related to regional levels of D2 receptors.