Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease

验证氟 18 放射性配体对阿尔茨海默病突触密度 PET 成像的效果

• 批准号: 10319957
• 负责人: YIYUN HENRY HUANG
• 金额: $ 75.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319957
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; American; Amyloid beta-Protein; Autopsy; Binding; Biological Markers; Blood Glucose; Brain; Brain Diseases; Cells; Clinic; Clinical; Clinical Trials; Communities; Coupled; Data; Dementia; Development; Diagnostic; Disease; Disease Progression; Event; FDA approved; Fasting; Female; Fluorine; Frontotemporal Dementia; Glycoproteins; Goals; Half-Life; Hippocampus (Brain); Human; Image; Impaired cognition; In Vitro; Individual; Institution; Investigation; Keppra; Kinetics; Label; Levetiracetam; Limbic System; Measures; Medical Imaging; Membrane Proteins; Methods; Molecular Target; Monitor; Multi-Institutional Clinical Trial; Multicenter Trials; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathology; Patients; Persons; Pharmaceutical Preparations; Positron-Emission Tomography; Preventive; Production; Property; Protein Isoforms; Proteins; Protocols documentation; Radioisotopes; Regulation; Reproducibility; Research; Resolution; Scanning; Senile Plaques; Signal Transduction; Site; Synapses; Synaptic Vesicles; Synaptophysin; Testing; Tracer; Treatment Efficacy; Treatment Protocols; Treatment outcome; Validation; Vesicle; abeta oligomer; amyloid imaging; analog; base; cognitive function; density; fluorodeoxyglucose; glucose metabolism; human subject; imaging agent; imaging biomarker; imaging properties; in vivo; in vivo imaging; kinetic model; male; mild cognitive impairment; nervous system disorder; neuroimaging; neuroimaging marker; neuropsychiatric disorder; pre-clinical; presynaptic; quantitative imaging; radioligand; radiotracer; synaptic failure; tomography; tool; trafficking; uptake; virtual; white matter

Alzheimer's disease (AD) is a progressive neurodegenerative disorder afflicting 6 million Americans. The clinical dementia of AD is coupled to a distinct pathology, with β-amyloid plaques, neurofibrillary tangles, and synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is detectable in individuals with the prodromal stage of mild cognitive impairment (MCI). Positron Emission Tomography (PET) imaging is increasingly employed in the study of AD. However, until recently there have been no PET radiotracers that can directly image synaptic density in vivo, which would be of high value in AD diagnosis, as well as in monitoring efficacy of treatments. We have developed 11C-UCB-J as a radiotracer for PET imaging and quantification of the synaptic vesicle glycoprotein-2A (SV2A). In studies in healthy human subjects, 11C-UCB-J displayed excellent properties for quantitative PET imaging of SV2A in the human brain. We have also validated SV2A as an in vivo biomarker for synaptic density. Initial imaging results in MCI/AD patients show specific and distinct SV2A reductions, most pronounced (30-40%) in the hippocampus, which is expected and consistent with postmortem studies, where early degeneration of the entorhinal cortical cell projection to hippocampus and hippocampal SV2A reductions have been observed. Thus, based on these data, 11C-UCB-J appears to be an excellent radiotracer for quantitative imaging of SV2A in the human brain and 11C-UCB-J PET can be an extremely useful in vivo biomarker of synaptic loss in AD. Although 11C-UCB-J proves to be an excellent tracer for synaptic density imaging, a significant drawback is the short half-life (t1/2 = 20.4 min) of its 11C-radiolabel, which precludes its central production and distribution to multiple sites for imaging use, and thus limits its wide application in multi-center clinical trials or as diagnostic agent in clinics. For AD in particular, where drug clinical trials at many institutions are ongoing, the need for a longer-lived radiotracer is evident and one labeled with the 18F-radioisotope (t1/2 = 109.8 min) will be appropriate. Analogous to the development of 11C-PIB and its FDA-approved 18F-labeled counterpart 18F- flutemetamol (Vizamyl®) for β-amyloid imaging in AD, in this application we propose to develop18F-SDM-8, the difluorinated analog of UCB-J, for human neuroimaging, and to validate its use as a imaging biomarker of synaptic loss in MCI/AD. The goal is to provide a “neuroimaging biomarker of synaptic density” for use in the study of the AD continuum and potential diagnosis of AD in its earliest, prodromal stage, as well as in the monitoring of disease progression and efficacy of emerging AD therapies. In addition to AD, the availability of 18F-SDM-8 PET as a general imaging biomarker of synaptic density will enable the investigation of a wide range of neuropsychiatric diseases where abnormalities in synaptic density/plasticity are implicated.

阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，困扰着 600 万美国人。 AD 的临床痴呆与独特的病理学相关，包括 β-淀粉样斑块、神经原纤维缠结和 突触损失对于认知功能至关重要，并且其损失已被确定为主要因素。 AD 认知障碍的结构相关性是 AD 发病机制的一个早期事件，突触衰竭是 在轻度认知障碍 (MCI) 前驱阶段的个体中可检测到。 然而，正电子发射断层扫描 (PET) 成像越来越多地应用于 AD 研究。 最近还没有可以直接成像体内突触密度的 PET 放射性示踪剂，这将是 在 AD 诊断以及监测治疗效果方面具有很高的价值。我们开发了 11C-UCB-J。 在研究中作为突触小泡糖蛋白 2A (SV2A) 的 PET 成像和定量的放射性示踪剂。 在健康人类受试者中，11C-UCB-J 在 SV2A 定量 PET 成像方面表现出优异的特性 我们还验证了 SV2A 作为突触密度的体内生物标志物。 MCI/AD 患者的结果显示出特定且明显的 SV2A 降低，在 海马体，这是预期的并且与尸检研究一致，其中海马体的早期退化 观察到内嗅皮质细胞向海马投射和海马 SV2A 减少。 因此，根据这些数据，11C-UCB-J 似乎是一种用于 SV2A 定量成像的出色放射性示踪剂 11C-UCB-J PET 可以作为 AD 突触丧失的体内极其有用的生物标志物。 尽管 11C-UCB-J 被证明是突触密度成像的优秀示踪剂，但一个显着的问题是 其 11C 放射性标记的半衰期短（t1/2 = 20.4 分钟），这妨碍了其集中生产和分配 多个部位进行成像，从而限制了其在多中心临床试验或诊断中的广泛应用 特别是对于 AD，许多机构正在进行药物临床试验，因此需要一种药物。 寿命较长的放射性示踪剂是显而易见的，并且用 18F-放射性同位素（t1/2 = 109.8 分钟）标记的放射性示踪剂将是 类似于 11C-PIB 及其 FDA 批准的 18F 标记对应物 18F- 的开发。 Flutemetamol (Vizamyl®) 用于 AD 中的 β-淀粉样蛋白成像，在此应用中，我们建议开发 18F-SDM-8， UCB-J 的二氟化类似物，用于人类神经成像，并验证其作为成像生物标志物的用途 MCI/AD 中的突触丢失目标是提供“突触密度的神经影像生物标志物”以用于 AD 连续体的研究以及 AD 早期、前驱阶段以及早期阶段的潜在诊断 监测疾病进展和新兴 AD 疗法的疗效。 18F-SDM-8 PET 作为突触密度的通用成像生物标志物将使广泛的研究成为可能 涉及突触密度/可塑性异常的一系列神经精神疾病。