RADIOTRACER R & D IN NUCLEAR MEDICINE AND NEUROSCIENCES

描述（来自申请人的摘要的逐字）： 正电子发射断层扫描（PET）的健康研发是其应用于 研究药物在人体中枢和外周的作用。期间 在上一个赠款期间，有一个意想不到的惊人发现， 吸烟者的脑单胺氧化酶（MAO）低于非吸烟者， 吸烟者，这不是尼古丁引起的。在这一发现的驱使下， 申请人已经扩大了吸烟者脑MAO的研究， 开发放射性示踪剂方法来测量外周MAO。外周MAO 吸烟者的水平是相关的，因为MAO是一种重要的酶， 解毒食物中的血管活性胺或许多物质释放的那些 包括尼古丁。放射性示踪剂化学的进展， 26-该补助金的一年历史将被利用沿着与合并的能力 它们具有人类PET成像的独特特征。吸烟是 一个全球性的大规模公共卫生问题。但令人惊讶的是， 关于烟对人体的药理学影响，或其 与吸烟流行病学的关系，以及 包括尼古丁的烟草烟雾可能具有神经保护作用。基于小说 测定脑单胺氧化酶的方法和合成单胺氧化酶的最新进展 用于测量大脑尼古丁乙酰胆碱受体（nAChR）的放射性示踪剂 研究烟草烟雾对人类这两个重要的 提出了分子靶点。吸烟者的大脑单胺氧化酶减少， 利用氘研究吸烟对外周MAO的影响 [C-11]氯吉林和[C-11] L-丙炔苯丙胺和氘同位素效应 取代的衍生物作为放射性示踪剂（具体目标1）。为了检查 脑MAO B抑制的功能意义是吸烟者、放射性示踪剂 用于研究苯乙胺（PEA），一种多巴胺的内源性神经调节剂， 将使用[N-13]PEA开发特定的MAO B衬底，以跟踪PEA 代谢（具体目标2）。最后，一种安全的放射性示踪剂， 吸烟对中枢nAChR（尼古丁的主要分子靶点）的影响 人类（具体目标3）将被开发。有待检验的假设是， 吸烟者具有：1）减少的外周MAO; 2）减少的PEA代谢;和3） nAChR升高申请人实验室的新研究和新出现的 神经科学知识支持拟议研究的可行性。 总体观点是，PET，加上先进的放射性示踪剂 方法和致力于将基本放射性示踪剂的成果 研究人类神经科学的科学工具，是很好的姿势， 表征成瘾性、保护性和 烟草烟雾的毒性作用。

DESCRIPTION (Verbatim from the Applicant's Abstract): An exciting area of human health R&D for positron emission tomography (PET) is its application to the study of drug actions in humans both centrally and peripherally. During the previous grant period, the unexpected and remarkable discovery was made that cigarette smokers have lower brain monoamine oxidase (MAO) than non-smokers and former smokers, an effect not caused by nicotine. Compelled by this discovery, the applicant has expanded studies of brain MAO in smokers and initiated the development of radiotracer methods to measure peripheral MAO. Peripheral MAO levels in smokers are of relevance because MAO is a crucial enzyme for detoxifying vasoactive amines in foods or those released by many substances including nicotine. Advances in radiotracer chemistry made over the previous 26-year history of this grant will be exploited along with the ability to merge them with the unique characteristics of human PET imaging. Cigarette smoking is a massive public health problem worldwide. Yet surprisingly little is known about the pharmacologic effects of smoke on the human body, or their relationships to smoking epidemiology and to evidence that components of tobacco smoke including nicotine may be neuroprotective. Building on novel approaches to measure brain MAO and recent progress in the synthesis of radiotracers to measure brain nicotinic acetylcholine receptors (nAChR), the study of the effects of tobacco smoke in humans on these two important molecular targets is proposed. Having shown reduced brain MAO in smokers, the effects of smoking on peripheral MAO will be studied exploiting the deuterium isotope effect with [C-11]clorgyline and [C-11]L-deprenyl and deuterium substituted derivatives as radiotracers (Specific Aim 1). In order to examine the functional significance of brain MAO B inhibition is smokers, radiotracers for studying phenethylamine (PEA), an endogenous neuromodulator of dopamine and a specific MAO B substrate will be developed using [N-13]PEA to track PEA metabolism (Specific Aim 2). Finally, a safe radiotracer for examining the effects of smoking on central nAChR (the major molecular target of nicotine) in humans (Specific Aim 3) will be developed. Hypotheses to be tested are that smokers have: 1) reduced peripheral MAO; 2) reduced metabolism of PEA; and 3) elevated nAChR. New studies in the applicant's laboratory and emerging knowledge in the neurosciences support the feasibility of the proposed studies. The overarching view is that that PET, coupled with sophisticated radiotracer methods and a commitment to translating the fruits of basic radiotracer research into scientific tools for human neuroscience, is well posed to characterize the molecular targets underlying the addictive, protective, and toxic effects of tobacco smoke.