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标记试剂，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是一种常见的脑部神经退行性疾病，在老年人群中发病率较高。目前认为阿尔茨海默病与脑内可溶性A_肽和不溶性A_聚集体的过度生成和积聚有关。脑内A_2斑块的积聚被认为是该病发病的关键危险因素。目前，尚无影像诊断AD的方法。只有尸检和老年斑块中A_聚集体的彩色染色才能明确诊断本病。因此，开发可作为AD诊断和治疗生物标志物的A_1斑块活体PET显像剂具有重要意义。在过去的资助期间，我们已经开发了几个有效的F-18标记的二苯乙烯类衍生物，它们作为PET显像剂在体外和体内都显示出良好的性能。在下一个资助期，我们建议测试更多标有F-18标签的联苯乙炔和苯基萘的衍生物。这些建议的新药物可能增强了体外和体内的稳定性和更高的脑摄取，以及更好的A_1斑块在脑内的选择性定位。为了实现这些目标，我们将：1.合成新的配体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的配体(Ki&lt；10 nM)。3.进行18F标记研究和体外稳定性试验。4.研究其在正常小鼠体内的生物分布(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(以显示高选择性的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成像(PET)在正常的非人类灵长类动物身上进行测试。从这一系列针对A_斑块的新型18F标记化合物中，将选择一到两个最终候选作为PET显像剂用于人体测试，通过这些显像剂可以测量与AD病理状态相关的A_Burden。A_1斑块的PET成像对早期发现AD患者的老年斑块和监测正在接受药物治疗的患者有重要意义。

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.