Exploring occupancy of dopamine D3 receptor by buspirone in humans using positron

使用正电子探索丁螺环酮对人体多巴胺 D3 受体的占据

• 批准号: 8534759
• 负责人: Isabelle Boileau
• 金额: $ 13.23万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534759
• 关键词: Affect; Agonist; Anti-Anxiety Agents; Area; Basic Science; Behavior; Binding; Brain imaging; Buspirone; Clinical; DRD2 gene; Data; Dopamine; Dose; Drug Addiction; Drug Targeting; Emerging Technologies; FDA approved; Globus Pallidus; Goals; Human; Image; Injection of therapeutic agent; Intervention; Lead; Life; Ligands; Measurable; Measurement; Measures; Pharmaceutical Preparations; Pharmacotherapy; Placebos; Plasma; Positron; Positron-Emission Tomography; Property; Proteins; Public Health; Relative (related person); Safety; Serotonin; Substantia nigra structure; Testing; Therapeutic; Tobacco Dependence; Translations; Validation; addiction; dopamine D3 receptor; image processing; imaging probe; improved; in vivo; interest; neurochemistry; pre-clinical; putamen; radiotracer; receptor; tool

DESCRIPTION (provided by applicant): Drug addiction is a US public health and safety concern, urging improved treatment approaches such as targeted pharmacotherapies. Preclinical data have provided evidence that dopamine D3 receptor (DRD3) antagonism decreases addiction-relevant behaviour. Buspirone is an FDA-approved anxiolytic which acts as a serotonin partial agonist but has been recently identified as a DRD3 antagonist. Imaging with positron emission tomography (PET) permits the measurement of neurochemicals in vivo. PET has become a powerful tool for neuroscientists to visualize and localize receptors and estimate receptor occupancy by drug ligands. The process of imaging requires the injection of a positron-emitting radiotracer (e.g. [11C]-(+)-PHNO) that binds to the protein of interest (e.g. dopamine D3 receptors) followed by the measurement of this binding using the PET scanner. [11C]-(+)-PHNO is the only ligand allowing to measure dopamine D3 receptors occupancy in humans. Here, we will determine if buspirone significantly occupies the DRD3 at therapeutic doses in humans. These studies will allow for the translation of basic science discoveries into clinical validation. Our long term goal will be to determine the possible use of buspirone as an intervention for tobacco dependence.

描述（由申请人提供）：药物成瘾是美国公共卫生和安全问题，迫切需要改进治疗方法，如靶向药物治疗。临床前数据提供了证据表明多巴胺D3受体（DRD 3）拮抗作用可降低成瘾相关行为。丁螺环酮是FDA批准的抗焦虑药，其作为5-羟色胺部分激动剂，但最近被确定为DRD 3拮抗剂。正电子发射断层扫描（PET）成像允许测量体内的神经化学物质。PET已成为神经科学家可视化和定位受体并估计药物配体对受体的占用的有力工具。成像过程需要注射与目标蛋白（例如多巴胺D3受体）结合的正电子发射放射性示踪剂（例如[11 C]-（+）-PHNO），然后使用PET扫描仪测量这种结合。[11 C]-（+）-PHNO是唯一允许测量人类多巴胺D3受体占有率的配体。在这里，我们将确定丁螺环酮在人体治疗剂量下是否显著占据DRD 3。这些研究将使基础科学发现转化为临床验证。我们的长期目标将是确定丁螺环酮作为烟草依赖干预的可能用途。

项目成果

Neuronal circuitry underlying the impact of D3 receptor ligands in drug addiction.

• DOI: 10.1016/j.euroneuro.2014.08.017
• 发表时间: 2015-09
• 期刊: EUROPEAN NEUROPSYCHOPHARMACOLOGY
• 影响因子: 5.6
• 作者: Le Foll, Bernard;Di Ciano, Patricia
• 通讯作者: Di Ciano, Patricia

Recent methods for measuring dopamine D3 receptor occupancy in vivo: importance for drug development.

测量体内多巴胺D3受体占用率的最新方法：对药物开发的重要性。

• DOI: 10.3389/fphar.2014.00161
• 发表时间: 2014
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Le Foll B;Wilson AA;Graff A;Boileau I;Di Ciano P
• 通讯作者: Di Ciano P

Psychiatric Disorders as Vulnerability Factors for Nicotine Addiction: What Have We Learned from Animal Models?

• DOI: 10.1007/978-3-319-13482-6_6
• 发表时间: 2015-01-01
• 期刊: NEUROPHARMACOLOGY OF NICOTINE DEPENDENCE
• 作者: Balfour, David J. K.;Munafo, Marcus R.
• 通讯作者: Munafo, Marcus R.

Dopamine D4 receptors in psychostimulant addiction.

• DOI: 10.1016/b978-0-12-420118-7.00008-1
• 发表时间: 2014
• 期刊: Advances in pharmacology (San Diego, Calif.)
• 作者: Di Ciano, Patricia;Grandy, David K;Le Foll, Bernard
• 通讯作者: Le Foll, Bernard

Dopamine D3 receptor is necessary for ethanol consumption: an approach with buspirone.

• DOI: 10.1038/npp.2014.51
• 发表时间: 2014-07
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology