Imaging dopamine-2 (D2) receptor sites in schizophrenia

精神分裂症中多巴胺 2 (D2) 受体位点的成像

• 批准号: 7069574
• 负责人: RAJESH NARENDRAN
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069574
• 关键词: amphetamines; apomorphine; baboons; binding sites; bioimaging /biomedical imaging; brain imaging /visualization /scanning; carbon; clinical research; dopamine; dopamine agonists; dopamine antagonists; dopamine receptor; drug screening /evaluation; human subject; magnetic resonance imaging; neurotransmitter transport; pharmacokinetics; positron emission tomography; psychopathology; raclopride; radiation therapy dosage; radiotracer; receptor binding; schizophrenia

DESCRIPTION (provided by applicant): The dopamine hypothesis of schizophrenia proposed that positive symptoms of the illness are associated with hyperactivity of dopamine transmission. This hypothesis was recently supported by the observation in three studies that the amphetamine-induced reduction in [123[] IBZM and [11C]raclopride binding potential (BP) was elevated in patients with schizophrenia. The larger displacement of the antagonists [123I]IBZM or [11C]raclopride following amphetamine challenge in patients with schizophrenia might result from a larger increase in dopamine synaptic concentration following amphetamine (i.e. presynaptic factors) or from an increased affinity of D2 receptors for dopamine (i.e. postsynaptic factors), or from some combination of both factors. Available data and current methods do not allow to tease apart the respective contributions of these factors, because of the lack of in vivo methods to measure affinity of 132 receptors for agonists. In spite of the fact that D2 antagonist benzamide radioligands such as [123I]BZM and [11C]raclopride have contributed tremendously to our understanding of endogenous synaptic dopamine concentrations, they have been plagued by their relatively low sensitivity and ceiling effect (following psychostimulant challenges) which are presumably related to the fact that antagonist D2 radioligands bind to both high and low affinity states. The endogenous agonist dopamine is expected to compete efficiently with a D2 agonist ligand such as [11C]NPA than binds preferentially to the high affinity configuration unlike antagonist ligand such as []23I]IBZM or [1lC]raclopride that fail to distinguish between affinity states. We present preliminary evidence supporting the hypothesis that the D2 agonist radioligands [11C]NPA will provide a superior tool to study changes in intrasynaptic dopamine in the living brain. This application proposes to characterize the in vivo binding of [1tC]NPA in baboons (contribution of high and low agonist affinity sites to in vivo binding), to determine the whole body dosimetry, file an IND and to characterize this radiotracer in healthy human subjects (test/retest reliability and vulnerability to endogenous dopamine) which would lead to the eventual application of this radiotracer to study the high affinity D2 receptor sites in schizophrenia. The overall goal of this study is to develop and validate a method that will make it possible to characterize the pre- or post-synaptic nature of the dysregulation of dopamine transmission revealed by the amphetamine challenge in patients with schizophrenia.

描述（由申请人提供）：精神分裂症的多巴胺假说提出，该疾病的阳性症状与多巴胺传递过度活跃有关。最近三项研究的观察结果支持了这一假设，即精神分裂症患者中苯丙胺诱导的[123[]IBZM 和[11C]雷氯必利结合电位 (BP) 降低升高。精神分裂症患者接受安非他明后，拮抗剂 [123I]IBZM 或 [11C]雷氯必利的位移较大，可能是由于安非他明（即突触前因子）后多巴胺突触浓度增加较大，或 D2 受体对多巴胺的亲和力增加所致。即突触后因素），或两种因素的某种组合。由于缺乏体内方法来测量 132 受体对激动剂的亲和力，现有数据和当前方法无法区分这些因素各自的贡献。 尽管 D2 拮抗剂苯甲酰胺放射性配体（例如 [123I]BZM 和 [11C]雷氯必利）对我们对内源性突触多巴胺浓度的理解做出了巨大贡献，但它们一直因其相对较低的灵敏度和天花板效应（在精神兴奋剂挑战之后）而受到困扰。这可能与拮抗剂 D2 放射性配体结合高亲和力状态和低亲和力状态有关。内源性激动剂多巴胺预计会与 D2 激动剂配体（例如 [11C]NPA）有效竞争，而不是优先结合高亲和力构型，这与无法区分亲和状态的拮抗剂配体（例如 []23I]IBZM 或 [11C]雷氯必利）不同。我们提供了初步证据支持以下假设：D2 激动剂放射性配体 [11C]NPA 将为研究活体大脑中突触内多巴胺的变化提供优越的工具。 本申请旨在表征狒狒中 [1tC]NPA 的体内结合（高和低激动剂亲和力位点对体内结合的贡献），以确定全身剂量测定，提交 IND 并在健康人类受试者中表征该放射性示踪剂（测试/再测试的可靠性和对内源性多巴胺的脆弱性）这将导致最终应用这种放射性示踪剂来研究精神分裂症中的高亲和力 D2 受体位点。本研究的总体目标是开发和验证一种方法，该方法将能够表征精神分裂症患者安非他明激发所揭示的多巴胺传递失调的突触前或突触后性质。