PET Imaging of Abeta Plaques in Alzheimer?s Disease

阿尔茨海默病 Abeta 斑块的 PET 成像

• 批准号: 7577362
• 负责人: Hank F Kung
• 金额: $ 32.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577362
• 关键词: Acetylene; Affect; Affinity; Alkynes; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Autopsy; Autoradiography; Binding; Biodistribution; Biological Markers; Biopsy; Brain; Color; Data; Development; Diagnosis; Diagnostic Imaging; Diagnostic Procedure; Differential Diagnosis; Disease; Dose; Drug Kinetics; Early Diagnosis; Emission-Computed Tomography; Enzymes; Evaluation; Event; Funding; Goals; High Prevalence; Human; Image; Imaging Techniques; In Vitro; Injection of therapeutic agent; Label; Lead; Ligands; Maps; Measures; Medical; Metabolism; Microsomes; Mus; Naphthalene; Naphthalenes; Neurodegenerative Disorders; New Agents; Older Population; Papio; Pathogenesis; Patient Monitoring; Patients; Peptides; Pharmaceutical Preparations; Pittsburgh Compound-B; Play; Positron; Positron-Emission Tomography; Progress Reports; Property; Radiochemistry; Reporting; Risk Factors; Role; Senile Plaques; Series; Site; Social Problems; Staining method; Stains; Stilbenes; Testing; Tracer; brain tissue; diphenyl; disease diagnosis; imaging modality; in vitro testing; in vivo; metabolic abnormality assessment; mild neurocognitive impairment; nonhuman primate; novel; older patient; peptide A; small molecule; therapy design; uptake

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.

描述（由申请人提供）：我们建议开发针对 β-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 是一种常见的大脑神经退行性疾病，在老年人群中发病率很高。据信AD与大脑中可溶性A_肽和不溶性A_聚集物的过量产生和积累有关。 A_斑块在大脑中的积累被认为是这种疾病发病机制的关键危险因素。目前，还没有影像学方法来诊断AD。只有死后活检和对脑组织进行老年斑中 A_ 聚集体的彩色染色才能明确诊断该疾病。因此，开发A_斑块体内PET显像剂作为AD诊断和治疗的生物标志物极为重要。在过去的资助期间，我们开发了几种有效的 F-18 标记二苯乙烯衍生物，它们作为 PET 成像剂显示出理想的体外和体内特性。在下一个资助期内，我们建议测试额外的 F-18 标记的联苯乙炔和苯基萘衍生物。这些提出的新药物可能具有增强的体外和体内稳定性和更高的脑摄取以及A_斑块在脑中更好的选择性定位。为了实现这些目标，我们将： 1. 合成提议的新配体 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. 研究正常小鼠的生物分布（静脉注射后 2 分钟脑摄取 > 4%剂量/克）。 5.使用死后AD脑切片进行体外放射自显影研究（以显示高且选择性的A_斑块标记）。最终，优选的候选者将通过正电子发射计算机断层扫描（PET）成像在正常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，将选择一两个最终候选物作为PET显像剂用于人体测试，通过它们可以测量与AD病理状态相关的A_负荷。 A_ 斑块的 PET 成像可能对于 AD 患者老年斑的早期检测以及监测正在接受旨在逆转 A_ 斑块在大脑中积聚的药物治疗的患者至关重要。