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.

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 并且子项目的主要研究者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：兴奋剂莫达非尼及其活性异构体 r-莫达非尼 (armodafinil) 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。 Armodafinil 更有效，作用持续时间更长，并且不含非活性成分。由于其作用机制未知，两者都被指定为非典型。在一项针对非人类灵长类动物的 PET 成像研究中，我们报道了临床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) 转运蛋白，可以想象，提高了大脑中细胞外儿茶酚胺的水平，并消除了其“非典型”称号。我们现在报告这些在灵长类动物中的发现是否可以通过阿莫达非尼延伸到人类大脑。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(11C)阿托烷检测体内阿莫达非尼在纹状体中DAT的占据情况。通过间接置换人类受试者中的 D2 多巴胺受体激动剂 (11C)雷氯必利来检测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 小时，n=6；250 mg：60%-%，1-2.5 小时；n=6）。两种剂量的阿莫达非尼均导致细胞外多巴胺水平适度增加。结论：阿莫达非尼体内 DAT 的占据和细胞外多巴胺的升高进一步表明 DAT 作为治疗作用位点。这些发现验证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的评估，例如注意力缺陷多动障碍，强调了低亲和力 DAT 抑制剂的治疗潜力，以及这种先前指定的“非典型”药物类别可能的滥用倾向。