PET Imaging of Abeta Plaques in Alzheimer?s Disease

描述（由申请人提供）：我们建议开发F-18标记的药物，靶向淀粉样蛋白（A_）聚集体，用于阿尔茨海默病（AD）患者的正电子发射断层扫描（PET）成像。AD是一种常见的脑神经退行性疾病，在老年人群中患病率较高。据认为，AD与脑内可溶性A_肽和不溶性A_聚集体的过度产生和积聚有关。A_斑块在脑内的积聚被认为是该疾病发病的关键危险因素。目前，还没有诊断AD的影像学方法。只有死后脑组织活检及老年斑A聚集体染色才能明确诊断。因此，开发能够作为AD诊断和治疗的生物标志物的A_斑块体内PET显像剂是非常重要的。在过去的资助期间，我们已经开发了几种有效的F-18标记的芪衍生物，这些衍生物在体外和体内显示出理想的PET成像剂特性。在下一个资助期内，我们建议测试更多的F-18标记的联苯乙炔和苯基萘衍生物。这些新药物可能具有增强的体内外稳定性和更高的脑摄取以及更好的脑内A_斑块的选择性定位。为了实现这些目标，我们将：1。合成所提出的新配体2.使用AD脑匀浆进行体外结合研究以选择具有良好结合亲和力（Ki < 10 nM）的配体。3.进行18F标记研究并测试体外稳定性。4.研究在正常小鼠中的生物分布（脑摄取> 4%剂量/g，静脉注射后2分钟）。5.使用死后AD脑切片进行体外放射自显影研究（以显示高选择性A_空斑标记）。最终，优选的候选物将通过正电子发射计算机断层扫描（PET）成像在正常的非人灵长类动物中进行测试。从这一系列靶向A_斑块的新型18F标记化合物中，将选择一种或两种最终候选物作为PET成像剂用于人体测试，通过其可以测量与AD病理状态相关的A_负荷。A_斑块的PET显像对AD患者老年斑的早期发现和对正在接受旨在逆转脑内A_斑块积聚的药物治疗的患者的监测可能是至关重要的。

DESCRIPTION (provided by applicant): We propose to develop F-18 labeled agents targeting _-amyloid (A_) aggregates for positron emission tomography (PET) imaging of patients with Alzheimer's disease (AD). AD is a common neurodegenerative disease of the brain with a high prevalence in the older population. It is believed that AD is associated with the overproduction and buildup of soluble A_ peptides and insoluble A_ aggregates in the brain. The accumulation of A_ plaques in the brain is thought to be a key risk factor for the pathogenesis of this disease. Currently, there is no imaging method to diagnose AD. Only postmortem biopsy and color staining of the brain tissues for A_ aggregates in senile plaques can definitively diagnose the disease. Therefore, it is extremely important to develop in vivo PET imaging agents for A_ plaques which can be used as biomarkers in the diagnosis and treatment of AD. In the past funding period, we have developed several potent F-18 labeled stilbene derivatives, which show desirable in vitro and in vivo properties as PET imaging agents. In the next funding period, we propose to test additional F-18 labeled biphenyl acetylene and phenyl-naphthalene derivatives. These proposed new agents may have enhanced in vitro and in vivo stability and higher brain uptake as well as better selective localization of A_ plaques in the brain. To accomplish these objectives we will: 1. synthesize the proposed new ligands 2. perform in vitro binding studies using AD brain homogenates to select ligands with good binding affinity (Ki < 10 nM). 3. perform 18F labeling studies and test the in vitro stability. 4. study the biodistribution in normal mice (brain uptake > 4 %dose/g, at 2 minutes after an iv injection). 5. perform in vitro autoradiography studies using postmortem AD brain sections (to show high and selective A_ plaque-labeling). Ultimately, preferred candidates will be tested in normal non-human primates by positron emission computed tomography (PET) imaging. From this series of novel 18F labeled compounds targeting A_ plaques, one or two final candidates will be selected as PET imaging agents for testing in humans, through which the A_ burden relating to pathological states of AD may be measured. The PET imaging of A_ plaques may be critically useful for the early detection of senile plaques in patients with AD and the monitoring of patients undergoing drug treatment designed to reverse the buildup of A_ plaques in the brain.