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

基本信息

项目摘要

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疾病的阳性症状与多巴胺传播的多动症有关。最近在三项研究中观察到,苯丙胺引起的[123 [] IBZM和[11C] raclopride结合潜力(BP)的降低升高,这一假设得到了支持。拮抗剂[123i] IBZM或[11c] racphiride在精神分裂症患者中挑战后的较大位移可能是由于苯丙胺突触浓度较大的增加而导致的,而苯丙胺突触浓度的升高(即,肿瘤前)(即,因多巴胺的d2受体的增加而增加了多巴胺(即,均为sssssssssednics)的邻级痛苦因素(即,均具有增加的因素)。由于缺乏测量132受体对激动剂的亲和力的体内方法,可用的数据和当前方法不允许分开这些因素的各自贡献。 尽管事实是D2拮抗剂苯甲酰胺放射素,例如[123i] bzm和[11c] raclopide,这对我们对内源性突触多巴胺浓度的理解做出了巨大贡献,但它们已被其相对较低的敏感性和较高的敏感性和较高的敏感性(在心理刺激性的挑战)中受到仇恨的态度而受到群体的影响。亲和力国家。预计内源性激动剂多巴胺将与D2激动剂配体有效竞争,例如[11C] NPA,而不是优先与高亲和力构型结合,与[[] 23i] ibzm或[1lc] raclide不同,无法区分亲和力状态。我们提供了支持以下假设:D2激动剂放射线[11C] NPA将为研究活大脑中鼻内多巴胺的变化提供卓越的工具。 该应用建议表征狒狒[1TC] NPA在体内结合(高和低激动剂亲和力对体内结合的贡献),以确定整个身体的剂量,并在健康的受试者中对这种放射性受试者进行归档,并表征人类对健康的可靠性和弱点对内源性的影响,从而导致了这种范围内基质的DOPERIAS,从而使该群体具有这种影响,从而导致了该群体的范围),从而使这些受试者具有这种影响力,从而使该受试者具有较高的影响力)精神分裂症中的亲和力D2受体位点。这项研究的总体目的是开发和验证一种方法,该方法将使精神分裂症患者的苯丙胺挑战揭示的多巴胺传播失调前或后突触的性质。

项目成果

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RAJESH NARENDRAN其他文献

RAJESH NARENDRAN的其他文献

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{{ truncateString('RAJESH NARENDRAN', 18)}}的其他基金

PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction
可卡因成瘾过程中皮质多巴胺传输的 PET 成像
  • 批准号:
    9722779
  • 财政年份:
    2018
  • 资助金额:
    $ 17.25万
  • 项目类别:
Imaging beta-amyloid in middle age alcoholics as a mechanism that increases their risk for Alzheimer’s disease
中年酗酒者中的β-淀粉样蛋白是一种增加其患阿尔茨海默病风险的机制
  • 批准号:
    9718353
  • 财政年份:
    2016
  • 资助金额:
    $ 17.25万
  • 项目类别:
In vivo imaging of corticotropin releasing factor-nociceptin receptor interactions
促肾上腺皮质激素释放因子-伤害感受肽受体相互作用的体内成像
  • 批准号:
    9198085
  • 财政年份:
    2016
  • 资助金额:
    $ 17.25万
  • 项目类别:
PET Imaging of neurochemical transmission in cocaine use disorders
可卡因使用障碍中神经化学传递的 PET 成像
  • 批准号:
    10459233
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:
PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction
可卡因成瘾过程中皮质多巴胺传输的 PET 成像
  • 批准号:
    8118277
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:
Imaging Cortical Dopamine Transmission in Alcohol Dependence
酒精依赖中皮质多巴胺传输的成像
  • 批准号:
    8132972
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:
PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction
可卡因成瘾过程中皮质多巴胺传输的 PET 成像
  • 批准号:
    9193064
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:
PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction
可卡因成瘾过程中皮质多巴胺传输的 PET 成像
  • 批准号:
    7790857
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:
PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction
可卡因成瘾过程中皮质多巴胺传输的 PET 成像
  • 批准号:
    7934671
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:
PET Imaging of Cortical Dopamine Transmission in Cocaine Addiction
可卡因成瘾过程中皮质多巴胺传输的 PET 成像
  • 批准号:
    9024494
  • 财政年份:
    2009
  • 资助金额:
    $ 17.25万
  • 项目类别:

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