18F-Mefway PET for Human Aging and Alzheimer's Disease

描述(申请人提供)：5-羟色胺异常与困扰大量人的大脑疾病有关，包括影响1800多万人的抑郁障碍和影响500多万美国人口的阿尔茨海默病(AD)。5-羟色胺5HT1A受体与这些疾病有关，目前正在进行深入的研究。我们的长期目标是开发正电子发射断层扫描(PET)的非侵入性成像方法，这将有助于这些疾病的早期诊断，因此可能对治疗计划有用。使用11C-Way-100635、18F-MPPF和18F-FCWAY对5-HT1a受体的人体研究正在进行中。虽然这些显像剂提供了对几种人类状况的极好洞察，但由于生产困难、半衰期短、代谢不稳定和适中的信噪比，应用受到限制。在NIH R21拨款申请的支持下，我们开发并评估了一种新的显像剂18F-Mefway，它在伯碳上含有一个氟-18，使该化合物对脱氟更稳定。Mefway对5HT1A受体有很高的亲和力，在啮齿类动物的脑成像研究中发现，在海马区和皮质有选择性结合，在小脑有有限的结合。对恒河猴的PET研究表明，18F-Mefway与大脑皮质、海马体、中缝及其他脑区结合，海马区与小脑区的比值为10。血浆分析表明，18F-Mefway的存在与大脑皮质、海马区、中缝区及其他脑区有关。20-30%的18F-Mefway，未观察到除氟。大脑特定区域如海马区的高比率表明，18F-Mefway作为人类5HT1A受体的PET显像剂具有良好的潜力。Mefway的毒性结果表明，18F-Mefway的放射性示踪剂注射适合人体使用。因此，我们在NIH R33应用中的总体目标是使用18F-Mefway进行第一次人体研究。最初的人体辐射剂量研究将使用PET/CT扫描仪对6名受试者进行。毒性数据、辐射剂量测定和化学标准操作程序都将通过NIMH/SNIDD示踪器数据库提供，供其他机构的研究人员使用18F-Mefway进行应用。18F-Mefway在正常志愿者中的脑分布将以重测范式进行评估，以建立用于定量分析的重复性和成像方法学。为了评估18F-Mefway对衰老和轻度认知损害(MCI)和AD的诊断价值，UCI的两个重要专业领域在这一应用中结合在一起。具体的假设将使用多学科方法进行测试，其中包括脑成像技术的专业知识和精神障碍和神经疾病研究所(Mind)的阿尔茨海默病研究中心(ADRC)。18F-Mefway将在具有良好特征的对照组、MCI和AD受试者中进行评估，结果将与18F-FDG、MRI和神经心理测试的临床结果相关。 与公共健康相关：人类5-羟色胺受体成像方法的发展将有助于了解几种大脑疾病，包括焦虑、抑郁、癫痫和阿尔茨海默病。这项赠款申请将特别对阿尔茨海默病的潜在诊断、治疗计划和治疗发展产生影响。

DESCRIPTION (provided by applicant): Serotonin abnormalities have been related to brain disorders which afflict a large number of people and include depressive disorders which affect over 18 million and Alzheimer's disease (AD) which affects over 5 million of the American population. Serotonin 5HT1A receptors have been implicated in these disorders and are being intensively studied. Our long-term goal is to develop noninvasive imaging methods of positron emission tomography (PET) that will aid in the early diagnosis of these disorders and may therefore be useful in treatment planning. Human studies of 5-HT1A receptor have been underway using 11C-WAY-100635, 18F- MPPF and 18F-FCWAY. Although these imaging agents have provided excellent insights into several human conditions, applications have been limited due to difficulty in production, short half-life, metabolic instability and moderate signal-to-noise ratios. With the support of an NIH R21 grant application, we have developed and evaluated a new imaging agent, 18F-Mefway which contains a fluorine-18 on a primary carbon to make the compound more stable to defluorination. Mefway has high affinity for 5HT1A receptors and in rodent brain imaging studies exhibited selective binding in hippocampus and cortex with limited binding in the cerebellum. PET studies in rhesus monkeys showed 18F-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. 20-30% of 18F-Mefway and no observed defluorination. The high ratios in specific brain regions such as the hippocampus suggest that 18F-Mefway has good potential as a PET imaging agent for 5HT1A receptors in humans. Our toxicity results of Mefway suggest that a radiotracer injection of 18F-Mefway is suitable for human use. Therefore, our overall goal in this NIH R33 application is to carry out first human studies with 18F- Mefway. Initial human radiation dosimetry studies will be carried out using a PET/CT scanner on 6 subjects. The toxicity data, radiation dosimetry and chemistry standard operating procedures will all be made available through the NIMH/SNIDD Tracer database for investigators at other institutions to use 18F-Mefway for their applications. Brain distribution of 18F-Mefway will be evaluated in normal volunteers in a test-retest paradigm to establish reproducibility and imaging methodology for quantitative analysis. In order to assess the diagnostic value of 18F-Mefway in aging and mild cognitive impairment (MCI) and AD, two important areas of expertise at UCI have come together in this application. Specific hypotheses will be tested using multidisciplinary approaches that include expertise in brain imaging techniques and the Alzheimer's Disease Research Center (ADRC) at the institute for Mental Impairments and Neurological Disorders (MIND). 18F-Mefway will be evaluated in well-characterized groups of control, MCI and AD subjects and results will be correlated with clinical outcome measures of 18F-FDG, MRI and neuropsychological tests. PUBLIC HEALTH RELEVANCE: Development of human imaging methods for serotonin receptors will help understand several brain disorders, including anxiety, depression, epilepsy and Alzheimer's disease. This grant application will specifically have implications in the potential diagnosis, treatment planning and therapeutics development for Alzheimer's disease.