RADIOTRACER R & D IN NUCLEAR MEDICINE AND NEUROSCIENCES

描述(逐字摘自申请者的摘要)：人类令人兴奋的领域 正电子发射断层扫描(PET)的健康研发是其在 研究人类中枢和外周的药物作用。在.期间 在之前的赠款期间，有一个意想不到的惊人发现 吸烟者的大脑单胺氧化酶(MAO)比不吸烟者低， 前吸烟者，这种影响不是由尼古丁引起的。在这个发现的驱使下， 申请者扩大了对吸烟者大脑MAO的研究，并发起了 放射性示踪剂测量外周MAO方法的发展。外围MAO 吸烟者体内的水平是相关的，因为MAO是一种关键的酶 使食品或多种物质释放的血管活性胺解毒 包括尼古丁。放射性示踪化学研究进展 这项赠款26年的历史将与合并的能力一起被利用 它们具有人类PET成像的独特特征。吸烟是一种 这是一个巨大的全球公共卫生问题。然而，令人惊讶的是，人们对此知之甚少 关于烟雾对人体的药理作用，或者他们的 与吸烟流行病学的关系以及与证据的关系 包括尼古丁在内的烟草烟雾可能具有神经保护作用。以小说为基础 脑MAO的测定方法及其合成研究进展 测量大脑烟碱型乙酰胆碱受体(NAChR)的放射性示踪剂 烟草烟雾对人体内这两种重要物质影响的研究 提出了分子靶标的概念。在吸烟者身上显示出大脑MAO减少后， 吸烟对外周MAO的影响将利用氚进行研究。 [C-11]Clorgyline和[C-11]L-异丙烯基和氘的同位素效应 作为放射性示踪剂的取代衍生物(特定目标1)。为了检查 脑MAO B抑制的功能意义在于吸烟者、放射性示踪剂 用于研究苯乙胺(PEA)，一种内源性多巴胺和 将使用[N-13]PEA来跟踪PEA，以开发特定的MAO B底物 新陈代谢(特定目标2)。最后，一种安全的放射性示踪剂用于检查 吸烟对中枢nAChR(尼古丁的主要分子靶标)的影响 人类(具体目标3)将被开发出来。需要检验的假设是 吸烟者有：1)外周MAO减少；2)PEA代谢减少；3) 升高的nAChR。申请人实验室中的新研究和正在出现的 神经科学方面的知识支持拟议研究的可行性。 最主要的观点是，PET与复杂的放射性示踪剂相结合 方法和致力于翻译基本放射性示踪剂的成果 对人类神经科学的科学工具的研究，很有可能 描述使人上瘾、保护和 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.