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

描述（由申请人提供）：5 -羟色胺5HT1A受体已被研究用于许多中枢神经系统疾病，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5HT1A受体成像应用于情绪障碍和AD的研究。目前正在努力改善5-HT1A药物、11种C-WAY-100635、18种F-MPPF和18种F-FCWAY在人体内的性能。我们已经确定并合成了F-Mefway，它在伯碳18上含有一个氟-18，使化合物在脱氟时更稳定。Mefway对5HT1A受体有很高的亲和力，体外啮齿动物脑切片显示F-mefway在海马、皮层和其他脑区选择性结合，在小脑区结合有限。初步的体外研究表明，血清素从不同脑区置换了18个f -通道，IC50在169-243 nM范围内。对恒河猴的PET研究表明，F- 18通道与颞叶皮质、海马、中缝等脑区结合，海马与小脑的比值为10。血浆分析显示大约有。30%的18f - meway未观察到除氟现象。在特定的大脑区域，如海马体中的高比率表明，F-mefway有潜力作为人类5HT1A受体的PET显像剂。因此，我们在本次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种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用于人体PET研究。为了将我们的发现扩展到人类研究，我们将在大鼠和猴子身上进行18F-mefway的剂量测定。药物诱导的血清素竞争研究将在啮齿类动物中使用PET成像研究来研究血清素的作用。为了评估f - meway在AD中的价值，UCI 18的两个重要专业领域聚集在一起，使用多学科方法解决具体假设，其中包括脑成像技术的专业知识，以及PET脑成像中心和脑衰老与痴呆研究所的一个研究小组，分别专注于脑衰老的动物模型。我们将对两种AD小鼠转基因模型Tg2576和3xTg小鼠进行体外研究，目的是通过f - meway将老年斑和神经原纤维缠结的形成与血清素5HT1A受体的丧失联系起来。由于18海马与小脑的高比率（约为10）和氟-18放射性标记的优点，18 F- meway可能在阿尔茨海默病的研究中具有潜在的用途。

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.