DOPAMINE TRANSPORTER OCCUPANCY BY NOVEL PYROVALERONE ANALOGS, A PET STUDY

新型吡咯戊酮类似物对多巴胺转运蛋白的占用，宠物研究

• 批准号: 8358000
• 负责人: Bertha K Madras
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358000
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Affect; Affinity; Binding; Cells; Central Nervous System Diseases; Cocaine Dependence; Corpus striatum structure; Dose; Drug Kinetics; Exhibits; Funding; Grant; Hour; Human; In Vitro; Injection of therapeutic agent; Macaca mulatta; Measures; National Center for Research Resources; New England; Norepinephrine; Pharmaceutical Preparations; Positron-Emission Tomography; Primates; Principal Investigator; Property; Research; Research Infrastructure; Resources; Route; Serotonin; Site; Source; Structure; Testing; Therapeutic; Therapeutic Uses; Time; United States National Institutes of Health; analog; base; cost; design; dopamine transporter; in vivo; inhibitor/antagonist; lipophilicity; monoamine; novel; pyrovalerone

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AIMS: Compounds that affect dopamine transporter (DAT) function have therapeutic potential to treat cocaine addiction, and other CNS disorders. They also have abuse potential, depending on structure, potency, dose, pharmacokinetic properties and route of administration. The stimulant pyrovalerone is a relatively high affinity DAT inhibitor with limited therapeutic use because of abuse liability. To develop medications with reduced abuse liability, we designed pyrovalerone analogs and assessed in vitro potencies at monoamine transporters (dopamine, serotonin, norepinephrine) and in vivo occupancy of the DAT. METHODS: DAT affinity was determined in HEK-293 cells transfected with the human DAT. DAT occupancy (reduction in binding potential) was measured with PET imaging of the DAT probe (11C)CFT ((11C)WIN 35,428) and anesthetized rhesus monkeys. After acquisition of baseline DAT levels, the test compound was administered and PET imaging performed with a second injection of (11C)CFT one hour later. RESULTS: Novel pyrovalerone analogs exhibited high to moderate DAT potency (3.1 - 216 nM) and moderate to high DAT:SERT selectivity. All compounds (1 mg/kg) occupied 59 percent or more of DAT sites in the striatum. Several compounds with high affinity for the DAT in vitro showed lower DAT occupancy than lower affinity compounds, within the time frame of the PET session. DAT occupancy correlated with lipophilicity (logP values) and not with DAT affinity. CONCLUSIONS: For pyrovalerone analogs, lipophilicity, but not in vitro affinity, predicts in vivo DAT occupancy, Several compounds displayed rapid DAT onset, findings relevant both for therapeutic potential or abuse liability.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 目的：影响多巴胺转运蛋白 (DAT) 功能的化合物具有治疗可卡因成瘾和其他中枢神经系统疾病的潜力。它们还具有滥用潜力，具体取决于结构、效力、剂量、药代动力学特性和给药途径。兴奋剂吡咯戊酮是一种相对高亲和力的 DAT 抑制剂，由于滥用的可能性，其治疗用途有限。为了开发减少滥用倾向的药物，我们设计了吡咯戊酮类似物，并评估了单胺转运蛋白（多巴胺、血清素、去甲肾上腺素）的体外效力和 DAT 的体内占用情况。方法：在转染人 DAT 的 HEK-293 细胞中测定 DAT 亲和力。通过 DAT 探针 (11C)CFT ((11C)WIN 35,428) 和麻醉恒河猴的 PET 成像测量 DAT 占用率（结合电位的降低）。获得基线 DAT 水平后，施用测试化合物，并在一小时后第二次注射 (11C)CFT 进行 PET 成像。结果：新型吡咯戊酮类似物表现出高至中度的 DAT 效力 (3.1 - 216 nM) 和中度至高的 DAT:SERT 选择性。 所有化合物 (1 mg/kg) 占据纹状体中 59% 或更多的 DAT 位点。在 PET 会话的时间范围内，体外对 DAT 具有高亲和力的几种化合物显示出比亲和力较低的化合物更低的 DAT 占用率。 DAT 占有率与亲脂性（logP 值）相关，但与 DAT 亲和力无关。结论：对于吡咯戊酮类似物，亲脂性而非体外亲和力可以预测体内 DAT 占用。几种化合物表现出快速 DAT 起效，这些发现与治疗潜力或滥用倾向相关。