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。这个 阿尔茨海默病的临床痴呆与一种独特的病理相关联，表现为β-淀粉样斑块、神经原纤维缠结和 突触丢失。突触对认知功能是必不可少的，而它们的丧失是公认的主要 阿尔茨海默病认知损害的结构相关性。突触衰竭是AD发病机制中的早期事件 可在轻度认知障碍(MCI)的前驱阶段的个体中检测到。 正电子发射断层成像(PET)越来越多地应用于AD的研究。然而，直到 最近，还没有PET放射性示踪剂可以直接在体内成像突触密度，这将是 在AD的诊断以及监测治疗效果方面具有很高的价值。我们已经开发出11C-UCB-J 作为一种放射性示踪剂，用于对突触囊泡糖蛋白-2A(SV2A)进行PET成像和定量。在研究中 在健康受试者中，11C-UCB-J表现出良好的定量PET成像性能 人类的大脑。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患者的结果显示特定和明显的SV2A减少，最明显的是(30%-40%) 海马体，这是预期的，并与尸检结果一致，其中早期退行性变的 观察到内嗅皮层细胞向海马区的投射和海马区SV2a的减少。 因此，基于这些数据，11C-UCB-J似乎是用于SV2A定量成像的优秀放射性示踪剂 在人脑和11C-UCB-J中，PET可能是AD突触丢失的一个非常有用的体内生物标志物。 尽管11C-UCB-J被证明是突触密度成像的优秀示踪剂，但一个显著的缺点是 它的11C-放射性标记的半衰期很短(t1/2=20.4分钟)，这排除了它的中心生产和分配到 多个部位用于成像，从而限制了其在多中心临床试验或诊断中的广泛应用 诊所里的特工。尤其是对于AD来说，许多机构正在进行药物临床试验，因此需要 寿命更长的放射性示踪剂是显而易见的，标记有18F-放射性同位素(t1/2=109.8分钟)的将是 恰如其分。类似于11C-PIB及其FDA批准的18F标记的对应物的开发- 氟美他莫(维扎米)用于AD的β-淀粉样蛋白显像，在本应用中，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，并验证其作为人类神经成像生物标志物的用途 MCI/AD的突触丢失。其目标是提供一种“突触密度的神经成像生物标记物”，用于 阿尔茨海默病连续体的研究及AD早期、前驱期和早期AD的潜在诊断 监测疾病进展和新出现的阿尔茨海默病疗法的疗效。除AD外，还提供 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 涉及突触密度/可塑性异常的一系列神经精神疾病。