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：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，并正在接受治疗其他神经精神疾病的评估。阿莫达非尼的药效更强，作用时间更长，不含非活性成分。两者都被指定为非典型，因为它们的作用机制尚不清楚。在一项对非人类灵长类动物的PET成像研究中，我们报道了临床上相关剂量的莫达非尼占据了活体大脑中的多巴胺(DAT)和去甲肾上腺素(NET)转运体，可以想见地提高了脑细胞外儿茶酚胺的水平，并使其“非典型”名称无效。我们现在报告这些发现是否在使用阿莫达非尼的灵长类动物中延伸到人脑。方法：12名受试者入选。测定血浆阿莫达非尼浓度，并用~(11)C阿托品检测体内纹状体DAT的阿莫达非尼占有率。通过间接置换D2多巴胺受体激动剂(11C)雷氯普利，检测受试者细胞外多巴胺的变化。结果：阿莫达非尼占用纹状体DAT(100 mg PO：34%~40%，1~2.5小时，n=6；250 mg：60%，1~2.5小时；n=6)。在两种剂量下，阿莫达非尼导致细胞外多巴胺水平略有增加。结论：体内阿莫达非尼对DAT的清除和细胞外多巴胺的升高进一步表明DAT是一种治疗作用部位。这些发现证实了我们之前在非人类灵长类动物中的发现，支持对阿莫达非尼治疗多巴胺相关疾病(如注意力缺陷多动障碍)的评估，强调了低亲和力DAT抑制剂的治疗潜力，以及可能是这类先前指定的“非典型”药物的滥用倾向。