Radiotracer R and D in Nuclear Medicine and Neuroscience

描述（由申请人提供）： 在当前的资助期内，我们开发了新的方法来量化人类外周器官中的单胺氧化酶A和B，并进行了第一次研究，证明吸烟者外周器官中的单胺氧化酶显着减少。我们还为大脑烟碱受体（nAChR）开发了一种新的放射性示踪剂，并成功地将其从基础放射性示踪剂研究转化为人类神经科学的科学工具，以表征这一分子靶点，这是烟草烟雾成瘾，保护和毒性作用的基础。与此同时，我们的工作采取了一个新的方向与[11 C]甲基reboxylate和其他标记reboxylate衍生物的发展，作为第一个有前途的铅化合物的PET成像的脑去甲肾上腺素转运蛋白（NET）。NET参与ADHD、药物滥用和抑郁症的病理生理学和治疗，并且作为药物研发中的重要分子靶标，早已被认识到。然而，与多巴胺（DA）和血清素（SER）系统相比，存在许多适合人类的PF[放射性示踪剂]，NET的脑成像由于缺乏合适的：放射配体。基于我们在放射性示踪剂开发和翻译方面的长期记录，以及开发和应用新的放射性示踪剂来调查兴奋剂滥用和ADHD的迫切需要，我们现在建议开发一系列C- 11标记的reboxeratin衍生物和其他有前途的配体，并在狒狒中对其进行评估（具体目标1）。在体内绘制NET的能力将首次提供跟踪其在体内作用的机会，包括NET在兴奋剂药物中的作用。 我们还将测量可卡因和哌甲酯（MP）对狒狒NET的剂量依赖性阻断作用和作用持续时间（具体目标2）。我们将在狒狒模型中估计剂量测定，并在健康人类受试者中进行翻译和评价（具体目标4）之前，对IND申请进行毒理学研究（具体目标3）。我们还将测量健康人口服治疗剂量MP对NET的占用率（具体目标4）。这些研究的结果将提供有关NET在ADHD治疗中作用的相关临床信息。最后，我们将在可卡因滥用者中进行NET的第一次成像研究，以确定与正常对照相比，滥用者中的NET异常和可用性（具体目标5）。我们将测试的假设，在治疗剂量的MP占据了NET的显着部分，和NET是上调可卡因滥用者在死后的大脑中的研究协议。本研究将提供第一个合适的NET放射性配体，以首次研究NET在增强中的作用以及PET对人体刺激的治疗特性。此外，在我们的实验室的精神兴奋剂对多巴胺系统的影响的广泛的PET调查支持这种方法的价值，以促进我们的理解的过程中负责成瘾，毒性和治疗效果的兴奋剂。

DESCRIPTION (provided by applicant): During the current grant period, we developed new methods for quantification of MAO A and B in human peripheral organs and carried out the first studies demonstrating a significant reduction in MAO in peripheral organs of smokers. We also developed a new radiotracer for the brain nicotinic receptor (nAChR) and successfully translated it from basic radiotracer research into a scientific tool for human neuroscience to characterize this molecular target, which underlies the addictive, protective and toxic effects of tobacco smoke. In parallel, our work took a new direction with the development of [11C]methylreboxetine and other labeled reboxetine derivatives as the first promising lead compounds for PET imaging of the brain norepinephrine transporter (NET). The involvement of the NET in the pathophysiology and treatment of ADHD, substance abuse, and depression, and as an important molecular target in drug R&D, has long been recognized However, in contrast to the dopamine (DA) and serotonin (SER) systems for which there are a number of suitable PF[ radiotracers for humans, brain imaging of NET has been hampered for over 20 years due to the lack of suitable: adioligands. Building on our long-standing track record in radiotracer development and translation, and the urgent need to develop and apply new radiotracers to investigate stimulant abuse and ADHD, we now propose to develop a series of C- 11 labeled reboxetine derivatives and other promising ligands, and to evaluate them in baboons (Specific Aim 1). The ability to map NET in vivo will provide the first opportunity to track its role in vivo, including the role of NET in stimulant drugs. We will also measure the dose-dependent blocking effects and duration of action on NET by cocaine and methylphenidate (MP) in baboons (Specific Aim 2). We will estimate dosimetry in the baboon model and carry out a toxicology study for IND application (Specific Aim 3) prior to translation and evaluation in healthy human subjects (Specific Aim 4). We will also measure the occupancy of the NET by oral MP at therapeutic doses in healthy humans (Specific Aim 4). Results from these studies will provide relevant clinical information regarding the role of NET in ADHD treatment. Finally, we will perform the first imaging studies of NET in cocaine abusers to determine NET abnormality and availability in abusers as compared to normal controls (Specific Aim 5). We will test the hypotheses that MP at therapeutic doses occupies a significant fraction of NET, and that NET is upregulated in cocaine abusers in agreement with studies in post-mortem brain. _This study will provide the first suitable NET radioligand to investigate, for the first time, the role of NET in the reinforcing as well as the therapeutic properties of stimulants in humans with PET. Moreover, extensive PET investigations in our laboratory of the psychostimulant effects on the dopamine system support the value of this approach to advance our understanding of the processes responsible for addictive, toxic and therapeutic effects of stimulants.