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.

阿尔茨海默氏病（AD）是一种累积600万美国人的进行性神经退行性疾病。这 AD的临床痴呆与β-淀粉样斑块，神经原纤维缠结和 突触损失。突触对于认知功能至关重要，它们的损失已被确定为主要 AD认知障碍的结构相关。 AD发病机理的早期事件，突触失败是 在患有轻度认知障碍前驱阶段的个体中可检测到。 正电子发射断层扫描（PET）成像越来越多地用于AD研究。但是，直到 最近，没有宠物放射性示例可以直接在体内成像突触密度，这将是 广告诊断的价值高，以及监测治疗效率。我们已经开发了11C-UCB-J 作为用于PET成像和定量突触囊泡糖蛋白-2A（SV2A）的放射性示例。在研究中 在健康的人类受试者中，11C-UCB-J在SV2A中具有出色的特性 人脑。我们还验证了SV2A作为突触密度的体内生物标志物。初始成像 MCI/AD患者的结果表现出特定和独特的SV2A降低，最明显的（30-40％） 海马，这是预期的，并且与验尸研究一致，其中早期退化 已经观察到对海马和海马SV2A降低的内嗅皮质细胞投影。 基于这些数据，11C-UCB-J似乎是用于定量成像的极好的放射性示踪剂 在人脑和11C-UCB-J PET中，在AD中突触损失的体内生物标志物中可能非常有用。 尽管11C-UCB-J被证明是突触密度成像的绝佳示踪剂，但重要的缺点是 其11C-Radiolabel的短期半衰期（T1/2 = 20.4分钟），这排除了其中央生产和分布 用于成像使用的多个站点，因此限制了其在多中心临床试验中的广泛应用或作为诊断 诊所的特工。特别是对于广告，在许多机构正在进行药物临床试验的情况下，需要 寿命更长的放射性示意剂是证据，用18F-射射线异位素标记（T1/2 = 109.8分钟）将是 合适的。类似于11C-PIB的开发及其FDA批准的18F标签18F- 用于AD中的β-淀粉样蛋白成像的氟甲莫氨基酚（Vizamyl®），在此应用中，我们建议开发18F-SDM-8， UCB-J的扩散类似物，用于人类神经影像，并验证其用作成像生物标志物的使用 MCI/AD中的突触损失。目的是提供“突触密度的神经影像学生物标志物” AD连续元和AD的潜在诊断的研究最早的前驱阶段以及 监测新兴广告疗法的疾病进展和效率。除了广告外， 18F-SDM-8 PET作为一般成像的突触密度生物标志物将使投资能够宽阔 涉及突触密度/可塑性异常的神经精神疾病范围。