PET Imaging of Abeta Plaques in Alzheimer?s Disease

描述（由申请人提供）：我们建议开发针对_-淀粉样蛋白（A_）聚集体的F-18标记药物，用于阿尔茨海默病（AD）患者的正电子发射断层扫描（PET）成像。阿尔茨海默病是一种常见的大脑神经退行性疾病，在老年人中发病率很高。人们认为AD与大脑中可溶性α多肽和不溶性α聚集体的过量产生和积累有关。大脑中A_斑块的积累被认为是该疾病发病的关键危险因素。目前，还没有影像学的方法来诊断AD。只有死后活检和脑组织中老年斑中A_聚集物的彩色染色才能明确诊断此病。因此，开发A_斑块的活体PET显像剂，作为AD诊断和治疗的生物标志物，具有十分重要的意义。在过去的资助期内，我们已经开发了几种有效的F-18标记的二苯乙烯衍生物，它们在体外和体内作为PET显像剂表现出理想的性能。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萘衍生物。这些提出的新药物可能增强了体外和体内稳定性，提高了脑吸收，并更好地选择性定位脑内A_斑块。为实现这些目标，我们将：合成新配体使用AD脑匀浆进行体外结合研究，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. 研究正常小鼠的生物分布（静脉注射后2分钟，脑摄取> 4%剂量/g）。5. 使用死后AD脑切片进行体外放射自显影研究（显示高选择性的A_斑块标记）。最终，首选候选者将通过正电子发射计算机断层扫描（PET）成像在正常的非人类灵长类动物中进行测试。从这一系列针对A_斑块的新型18F标记化合物中，将选择一到两种最终候选物作为PET显像剂进行人体测试，通过这些显像剂可以测量与AD病理状态相关的A_负担。A_斑块的PET成像可能对AD患者老年斑的早期检测和对正在接受药物治疗的患者的监测至关重要，这些药物旨在逆转大脑中A_斑块的积累。

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.