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

描述(申请人提供)：5-羟色胺5HT1A受体已被研究在许多中枢神经系统疾病中，包括抑郁、焦虑、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阿尔茨海默病的研究。目前正在努力改善目前人类使用的5-HT1A剂、11 C-Way-100635、18 F-MPPF和18 F-FCWAY的体内性质。我们鉴定并合成了F-Mefway，它在伯碳18上含有一个氟-18，使化合物对脱氟更稳定。Mefway对5HT1a受体有很高的亲和力，在体外，啮齿类动物脑片在海马区、皮质和其他脑区显示F-Mefway的选择性结合，在小脑有18个有限的结合。初步的体外研究表明，5-羟色胺使18F-半衰期从不同的脑区移位，其IC50范围为169-243 NM。对恒河猴的PET研究表明，F-18与颞叶皮质、海马体、中缝和其他脑区有中途结合，海马体与小脑的比例为10。血浆分析表明，F-18与大脑皮质、海马体、中缝和小脑的比例约为10。30%的18F-Mefway，未观察到除氟。F-mefway在特定大脑区域如海马区的高比率表明，F-mefway有潜力成为人类5HT1A受体的PET显像剂。因此，我们在这项应用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性，并研究18F-氟标记类似物的PET成像特征，以确定哪些异构体更适合于人类PET研究。为了将我们的发现扩展到人类研究，将在大鼠和猴子身上测量18F-Mefway的剂量学。药物诱导的5-羟色胺竞争研究将在啮齿类动物中使用PET成像研究，以研究5-羟色胺的影响。为了评估F-Mefway在AD中的价值，UCI 18的两个重要专业领域在这一应用中结合在一起，使用多学科方法解决特定假设，其中包括脑成像技术的专业知识，以及分别在PET脑成像中心和脑老化与痴呆研究所专注于脑老化动物模型的研究小组。将在两个AD转基因模型Tg2576和3xTg小鼠上进行体外研究，以利用F-mefway将衰老斑块和神经纤维缠结形成与5-羟色胺5HT1a受体丢失联系起来。由于18F-Mefway的高海马区/小脑比值(约10)和18F-放射性标记的优点，18F-Mefway可能在AD的研究中有潜在的应用。 研究5-羟色胺在大脑中的作用的成像方法将有助于了解情绪障碍，而研究转基因小鼠模型中5-羟色胺受体异常变化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、治疗计划和治疗发展具有重要意义。

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.