OCCUPANCY OF EXTRASTRIATAL D2 RECEPTORS BY CLOZAPINE

描述：(逐字摘自申请者的摘要)抗精神病药物的作用 典型的抗精神病药是通过阻断多巴胺D2型受体介导的。 有人提出，这些药物的抗精神病作用是由 在锥体外区阻断皮质和边缘多巴胺D2受体 部位效应是由纹状体背外侧D2受体阻断所介导的。至 DATE、MOST和SPECT对抗精神病药物阻断D2受体的研究 已经检查了纹状体。有许多研究表明， 氯氮平的非典型分布至少部分是通过选择性地 对皮质和边缘多巴胺能神经传递的影响。我们的团队已经 [18F]N-烯丙基-5-氟丙基吡啶作为PET放射性配体的研制 人类纹状体外D2受体的可视化研究。我们的第一阶段和早期阶段 II IND研究表明，该配体允许良好的可视化和 人纹状体外D2受体的定量测定。我们建议使用[18F] N-烯丙基-5-氟丙哌啶PET研究评价15例精神分裂症 受试者停止服药，并在氟哌啶醇单一治疗6周后，AS 以及15名精神分裂症患者停药后8周 氯氮平单一疗法。这些研究的数据将允许对以下方面进行评估 无论是氯氮平、S还是氟哌啶醇(一种典型的抗精神病药物)， 选择性地占据纹状体外的多巴胺D2受体，以及是否局部 D2受体的占用可能与抗精神病作用有关。次要的 目标包括检查精神病理症状复合体，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.