18F-Mefway for Imaging Mood Disorders and Alzheimer's Disease

描述（由申请人提供）：已经在许多CNS疾病中研究了5-羟色胺5 HT 1A受体，包括抑郁症、焦虑症、睡眠障碍、癫痫、帕金森病（PD）和阿尔茨海默病（AD）。我们特别感兴趣的是将5 HT 1A受体成像应用于情绪障碍和AD的研究。正在努力改善目前在人类中使用的5-HT 1A剂、11 C-WAY-100635、18 F-MPPF和18 F-FCWAY的体内性质。我们已经鉴定并合成了F-Mefway，它在伯碳18上含有氟-18，使化合物对去氢更稳定。Mefway对5 HT 1A受体具有高亲和力，并且在体外啮齿动物脑切片中表现出F-mefway在海马、皮质和其他脑区域中的选择性结合，18在小脑中具有有限的结合。初步的体外研究显示，5-羟色胺从不同的大脑区域取代18 F-甲基，IC 50在169-243 nM范围内。在恒河猴中的PET研究显示F- 18与颞叶皮质、海马、中缝和其他脑区域结合，其中海马与小脑的比率= 10。血浆分析表明存在约。30%的18 F-mefway，未观察到脱钙。在特定脑区域如海马体中的高比率表明F-mefway具有作为人类5 HT 1A受体的PET成像剂的潜力。因此，我们在本申请中的总体目标是合成和表征Mefway的纯顺式和反式异构体，研究异构体的药理学特征，并研究18 F-氟放射性标记类似物的PET成像特征，以确定哪种异构体更适合于人体PET研究。为了将我们的发现扩展到人类研究，将在大鼠和猴中测量18F-mefway的剂量。药物诱导的5-羟色胺竞争研究将使用啮齿动物的PET成像研究进行，以研究5-羟色胺的作用。为了评估F-mefway在AD中的价值，UCI 18的两个重要专业领域在此应用中结合在一起，使用多学科方法解决特定假设，包括脑成像技术的专业知识和PET脑成像中心和脑老化和痴呆研究所分别专注于脑老化动物模型的研究小组。将在AD的两种小鼠转基因模型Tg 2576和3xTg小鼠上进行体外研究，以使用F-mefway将老年斑和神经纤维缠结形成与5-羟色胺5 HT 1A受体的损失相关联。由于18海马与小脑的高比率（约10）和氟-18放射性标记的优点，18F-mefway可能在AD的研究中有潜在的用途。 开发用于理解脑中5-羟色胺效应的成像方法将有助于理解情绪障碍，并且研究转基因小鼠模型中5-羟色胺受体异常改变的方法将对阿尔茨海默病和其他中枢神经系统疾病的诊断、治疗计划和治疗开发具有意义。

DESCRIPTION (provided by applicant): Serotonin 5HT1A receptors have been investigated in a number of CNS disorders, including depression, anxiety, sleep disorders, epilepsy, Parkinson's disease (PD) and Alzheimer's disease (AD). Our particular interest is to apply 5HT1A receptor imaging for the study of mood disorders and AD. Efforts are underway to improve in vivo properties of 5-HT1A agents, 11 C-WAY-100635, 18 F-MPPF and 18 F-FCWAY currently in human use. We have identified and synthesized F-Mefway, which contains a fluorine-18 on a primary carbon 18 to make the compound more stable to defluorination. Mefway has high affinity for 5HT1A receptors and in vitro rodent brain slices exhibited selective binding of F-mefway in hippocampus, cortex and other brain regions, 18 with limited binding in the cerebellum. Preliminary in vitro studies showed serotonin displaced 18 F-mefway from various brain regions with IC50 in the range of 169-243 nM. PET studies in a rhesus monkey showed F- 18 mefway binding to temporal cortex, hippocampus, raphe and other brain regions with ratios of hippocampus to cerebellum = 10. Plasma analysis indicated the presence of approx. 30% of 18 F-mefway and no observed defluorination. The high ratios in specific brain regions such as the hippocampus suggest that F-mefway has 18 potential as a PET imaging agent for 5HT1A receptors in humans. Therefore, our overall goals in this application are to synthesize and characterize pure cis- and trans-isomers of Mefway, study pharmacological characteristics of the isomers and investigate PET imaging characteristics of the 18 F-fluorine radiolabeled analogs in order to identify which of the isomers will be more suitable for human PET studies. In order to extend our findings to human studies, dosimetry of 18F-mefway will be measured in rats and monkeys. Drug- induced serotonin competition studies will be carried out using PET imaging studies in rodents to study serotonin effects. In order to assess the value of F-mefway in AD, two important areas of expertise at UCI 18 have come together in this application to address specific hypotheses using multidisciplinary approaches that include expertise in brain imaging techniques and a research group focusing on animal models of brain aging at the PET Brain Imaging Center and the Institute for Brain Aging and Dementia, respectively. In vitro studies will be carried out on two mice transgenic models of AD, the Tg2576 and 3xTg mice in order to correlate senile plaque and neurofibrillary tangle formation with the loss of serotonin 5HT1A receptors using F-mefway. Due 18 to the high hippocampus to cerebellum ratio (approx 10) and advantages of the fluorine-18 radiolabel, 18 F- mefway may have potential use in the study of AD. Development of imaging methods for understanding serotonin effects in the brain will help understand mood disorders and methods to study alterations of the serotonin receptor abnormailites in transgenic mice models will have implications in diagnosis, treatment planning and therapeutics development of Alzheimer's disease and other disorders of the central nervous system.