PET Imaging agents for a4b2 Nicotinic Receptors

项目摘要 尼古丁受体与许多病理生理学有关。在加州大学- 欧文大学（UCI）和威斯康星大学麦迪逊分校（UWM），我们有几个主要的项目，将获得 尼古丁受体的成像。这些包括：1）衰老和神经退行性疾病计划; 2） 与尼古丁依赖有关的研究方案; 3）肺癌早期检测方案，以及4） 学习和记忆的神经生物学。在过去的三年中，我们成功地 完成了[18 F]Nifene的初始人体PET研究（重测和辐射剂量测定）， 结果：1）[18F]Nifene需要40分钟动态扫描进行定量; 2）膀胱是关键 器官，每年可以进行4次5 mCi注射的PET研究; 3）Nifene测量104 × 102，103 × 102和104 × 102。 NIF 2受体亚型; 4）Nifene是部分激动剂; 5）[18 F]Nifene能够检测丘脑辐射（白色 物质束）; 6）女性比男性显示出更大的[18F]Nifene结合;以及7）对[18F]Nifene没有衰老影响 观察到结合。由于最初的研究仅包括8名受试者，因此需要更大的受试者组， 为了证实使用[18F]Nifene的男女差异和衰老的发现。在这3年的更新中 我们的目标是：1）使用32名健康受试者（16名男性，16名女性）确认男女差异， 通过将16名20多岁的人（8名男性，8名女性）和16名70多岁的人（8名男性，8名女性）分组，在所有大脑区域中检查衰老的影响。 2)在第二个目标中，为了寻求[18F]Nifene PET的翻译以研究人类神经变性，我们 建议研究阿尔茨海默病（AD）和帕金森病（PD）的死后大脑。两个大脑 根据以前的研究结果选择了这些区域，前扣带回（带体 胼胝体）和海马（含有CA 1/下托）。这些将在3中使用[18F]Nifene进行评价 组：对照组、AD组和PD组（每组32例受试者，16例男性，16例女性）。3)第三个目标是评估 使用敲除（KO）小鼠的[18F]Nifene与受体亚型的结合。将研究K12和K14 KO 使用[18 F]Nifene PET和放射自显影术，将在野生型中评估男性-女性和衰老效应 (WT)小鼠这一更新申请将有助于确定女性的[18F]Nifene水平更高 结合（更大的α 4 β 2* 受体的可用性），对[18 F]Nifene结合没有衰老效应， 在某些脑区域的神经变性中，β 4 β 2* 受体发生变化。此外，小鼠 使用[18F]Nifene的研究将提供有关受体选择性和与人类相似性的信息， 性别效应和衰老的影响。这些研究对于在中国开展翻译研究具有重要意义和必要性。 神经退行性变，小鼠模型和人类。

Project Summary Nicotinic 42* receptors have been implicated in a number of pathophysiologies. At University of California- Irvine (UCI) and University of Wisconsin-Madison (UWM), we have several major programs that would gain from imaging nicotinic receptors. These include: 1) Program in aging and neurodegenerative disorders; 2) Program on studies related to nicotine dependence; 3) Program in the early detection of lung cancer, and 4) Neurobiology of learning and memory. During the previous 3-year funding period we have successfully completed initial human PET studies (test-retest and radiation dosimetry) with [18F]Nifene with the following outcomes: 1) [18F]Nifene requires a 40 min dynamic scan for quantitation; 2) Urinary bladder is the critical organ, and 4 PET studies with 5 mCi injections can be done annually; 3) Nifene measures 42, 32 and 22 receptor subtypes; 4) Nifene is a partial agonist; 5) [18F]Nifene is able to detect thalamic radiations (white matter tracts); 6) Females show greater [18F]Nifene binding than males; and 7) No aging effect on [18F]Nifene binding was observed. Since the initial study included only 8 subjects, a larger group of subjects is required in order to confirm the findings of male-female differences and aging using [18F]Nifene. In this 3-year renewal application our goals are: 1) Confirm male-female differences using 32 healthy subjects (16M, 16F) and examine aging effects by grouping 16 (8M, 8F) in their 20’s and 16 (8M, 8F) in their 70’s in all brain regions. 2) In the second goal, in pursuit of translation of [18F]Nifene PET to study human neurodegeneration, we propose to study postmortem brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD). Two brain areas have been chosen based on previous findings of their significance, anterior cingulate (with corpus callosum) and hippocampus (containing CA1/subiculum). These will be evaluated using [18F]Nifene in 3 groups: controls, AD and PD (32 subjects in each group, 16M, 16F). 3) The third goal is to evaluate degree of binding of [18F]Nifene to the receptor subtypes using knock-out (KO) mice. Both 2 and 4 KO will be studied using [18F]Nifene PET and autoradiography and a male-female and aging effect will be evaluated in wild-type (WT) mice. This renewal application will help to ascertain that females have greater levels of [18F]Nifene binding (greater availability of 42* receptors), there is no aging effect on [18F]Nifene binding and whether there is a change in 42* receptors in neurodegeneration in certain brain regions. Additionally, the mice studies using [18F]Nifene will provide information on receptor selectivity and similarities with humans in terms of gender effects and aging. These studies will be important and necessary to carry translational studies in neurodegeneration, both mice models and humans.