DOPAMINE TRANSPORTER OCCUPANCY BY NOVEL PYROVALERONE ANALOGS, A PET STUDY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：影响多巴胺转运体(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。它们也有滥用的潜力，这取决于结构、效力、剂量、药代动力学特性和给药途径。兴奋剂吡咯烷酮是一种亲和力相对较高的DAT抑制剂，由于滥用倾向，其治疗用途有限。为了开发减少滥用倾向的药物，我们设计了吡喃丙酮类似物，并在体外评估了单胺转运体(多巴胺、5-羟色胺、去甲肾上腺素)的效力和体内DAT的占有率。方法：检测转染人DAT的HEK-293细胞的DAT亲和力。DAT探针(11C)CFT((11C)Win 35,428)和麻醉恒河猴的PET成像测量DAT占有率(结合电位降低)。在获得基线DAT水平后，给予测试化合物，并在一小时后进行第二次注射(11C)CFT的PET成像。结果：新的吡咯烷酮类似物表现出高到中等的DAT效价(3.1-216 nm)和中等到高的DAT：SERT选择性。所有化合物(1 mg/kg)占据纹状体DAT部位的59%或更多。在PET会议的时间范围内，几个在体外对DAT具有高亲和力的化合物显示出比低亲和力化合物更低的DAT占有率。DAT占有率与亲脂性(logP值)相关，与DAT亲和力无关。结论：对于吡咯烷酮类似物，亲脂性，而不是体外亲和力，可以预测体内DAT的占有率，几种化合物显示出快速的DAT发病，这一发现与治疗潜力或滥用倾向都相关。

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.