A PET STUDY OF DOPAMINERGIC ACTIVITY WITH ARMODAFINIL

阿莫达非尼多巴胺能活性的宠物研究

• 批准号: 8357964
• 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/8357964
• 关键词: Affinity; Altropane; Attention deficit hyperactivity disorder; Brain; Catecholamines; Corpus striatum structure; Disease; Dopamine; Dopamine Agonists; Dose; Enrollment; Evaluation; Funding; Grant; Human; Isomerism; Life; Modafinil; Narcolepsy; National Center for Research Resources; New England; Norepinephrine; Pharmaceutical Preparations; Plasma; Positron-Emission Tomography; Primates; Principal Investigator; Raclopride; Reporting; Research; Research Infrastructure; Resources; Site; Source; Therapeutic; United States National Institutes of Health; base; clinically relevant; cost; extracellular; human subject; in vivo; inhibitor/antagonist; neuropsychiatry; nonhuman primate

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: The stimulant modafinil and its active isomer r-modafinil (armodafinil) are approved for the treatment of narcolepsy and undergoing assessment to treat other neuropsychiatric disorders. Armodafinil is more potent, has a longer duration of action, and contains no inactive components. Both were designated atypical because of their unknown mechanism of action. In a PET imaging study in nonhuman primates, we reported that clinically relevant doses of modafinil occupied the dopamine (DAT) and norepinephrine (NET) transporters in living brain, conceivably elevating extracellular catecholamine levels in brain and nullifying its "atypical" designation. We now report whether these findings in primates extend to human brain with armodafinil. METHODS: Twelve human subjects were enrolled. Plasma armodafinil levels were obtained and in vivo armodafinil occupancy of the DAT in striatum was detected by (11C)altropane. Changes in extracellular dopamine were detected by indirect displacement of the D2 dopamine receptor agonist (11C)raclopride in human subjects. RESULTS: Armodafinil occupied striatal DAT (100 mg PO: 34 percent-40 percent, 1- 2.5 hrs, n=6; 250 mg: 60 percent-percent, 1-2.5 hrs; n=6). Armodafinil resulted in modest increases in extracellular dopamine levels, at both doses. CONCLUSIONS: Armodafinil cccupancy of the DAT and elevation of extracellular dopamine in vivo further implicate the DAT as a therapeutic site of action. These findings validate our previous discovery in nonhuman primates, support evaluation of armodafinil for dopamine-related disorders, e.g. attention deficit hyperactivity disorder, highlight the therapeutic potential of low affinity DAT inhibitors, and possibly the abuse liability of this previously designated class of "atypical" drugs.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目标：兴奋剂莫达非尼及其活性异构体r-莫达非尼（阿莫达非尼）被批准用于治疗发作性睡病，并正在接受评估以治疗其他神经精神疾病。阿莫达非尼更有效，作用持续时间更长，不含非活性成分。由于其作用机制未知，两者均被指定为非典型。在非人灵长类动物的PET成像研究中，我们报告了临床相关剂量的莫达非尼占据了活体脑中的多巴胺（DAT）和去甲肾上腺素（NET）转运蛋白，可以想象地提高了脑中细胞外儿茶酚胺水平，并取消了其“非典型”名称。我们现在报告这些在灵长类动物中的发现是否会扩展到人类大脑。方法：招募了12名人类受试者。获得血浆阿莫达非尼水平，并通过（11 C）阿托烷检测纹状体中DAT的体内阿莫达非尼占有率。通过间接置换D2多巴胺受体激动剂（11 C）雷氯必利检测人类受试者细胞外多巴胺的变化。结果：阿莫达非尼占据纹状体DAT（100 mg PO：34%-40%，1- 2.5 h，n=6; 250 mg：60%，1-2.5 h; n=6）。在两种剂量下，阿莫达非尼均导致细胞外多巴胺水平适度增加。结论：阿莫达非尼对DAT的抑制和体内细胞外多巴胺的升高进一步暗示DAT是治疗作用部位。这些发现验证了我们先前在非人灵长类动物中的发现，支持对阿莫达非尼用于多巴胺相关疾病（例如注意缺陷多动障碍）的评价，突出了低亲和力DAT抑制剂的治疗潜力，以及这种先前指定的“非典型”药物类别的可能滥用倾向。