PET Imaging agents for a4b2 Nicotinic Receptors

项目摘要 烟碱型-4--2*受体参与了多种病理生理过程。在加州大学- 欧文(UCI)和威斯康星大学麦迪逊分校(UWM)，我们有几个主要项目将获得 通过对尼古丁受体进行成像。其中包括：1)老龄化和神经退行性疾病计划；2) 尼古丁依赖相关研究计划；3)肺癌早期检测计划；4) 学习和记忆的神经生物学。在之前的3年资助期内，我们成功地 完成了使用[18F]Nifene的初步人体PET研究(测试-再测试和辐射剂量测定)，其中包括以下内容 结果：1)[18F]尼芬需要40分钟的动态扫描进行定量；2)膀胱是关键 每年可以进行4次正电子发射计算机断层扫描研究，注射5次微循环；3)尼芬测量42，32和 -2--2受体亚型；4)尼芬是部分激动剂；5)[18F]尼芬能够检测丘脑辐射(白色 物质束)；6)女性比男性表现出更强的[18F]Nifene结合力；以及7)对[18F]Nifene没有老化影响 观察到结合情况。由于最初的研究只包括8名受试者，因此需要更多的受试者。 为了证实使用[18F]尼芬的男女差异和衰老的研究结果。在这份为期3年的续约中 应用我们的目标是：1)使用32名健康受试者(男性16岁，女性16岁)和 通过将16名(8米，8女)20岁的S和16名(8米，8岁)70岁的S分组，对所有脑区的衰老效应进行了研究。 2)在第二个目标中，为了追求翻译[18F]Nifene PET来研究人类神经退行性变，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 根据先前对其重要性的发现，选择了前扣带回(与体部) 和海马区(含CA1/下丘)。这些药物将在3中使用[18F]Nifene进行评估 对照组、AD组和PD组，每组32例，男性16例，女性16例。3)第三个目标是评估 用基因敲除(KO)小鼠将[18F]尼芬与受体亚型结合。将研究2和4 KO 使用[18F]Nifene PET和放射自显影，并在野生型中评估男女和衰老的影响 (WT)小鼠。这一续期申请将有助于确定女性体内的[18F]尼芬水平更高 结合(42*受体的更大可用性)，对[18F]尼芬结合没有老化影响，以及是否 在某些脑区的神经退行性变过程中，42*受体发生了变化。此外，这些老鼠 使用[18F]Nifene的研究将提供受体选择性的信息以及在以下方面与人类的相似之处 性别影响和老龄化。这些研究对开展翻译研究将是重要和必要的。 神经退化，无论是小鼠模型还是人类。

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.