PET imaging of ionotropic glutamate receptor signaling in Alzheimer's disease

阿尔茨海默病中离子型谷氨酸受体信号传导的 PET 成像

• 批准号: 10574694
• 负责人: Steven H Liang
• 金额: $ 23.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574694
• 关键词: AD transgenic mice; APP-PS1; Affinity; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Animals; Applications Grants; Astrocytes; Binding; Biological Process; Brain; Brain region; CSF1R gene; Characteristics; Chronic; Clinical Research; Clinical Trials; Correlation Studies; Development; Disease; Disease Progression; Disease model; Economic Burden; Foundations; Functional disorder; Glutamate Receptor; Glutamates; Goals; Human; Image; Imaging Device; Incidence; Inflammatory; Kinetics; Knowledge; Life Expectancy; Ligands; Maps; Measurement; Mediating; Medical; Memantine; Microglia; Monitor; Mus; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neuroimmune; Observational Study; Outcome; Pathogenesis; Pathologic; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Societies; Symptoms; Synapses; Testing; Time; Tracer; Transgenic Organisms; Treatment Efficacy; United States; Work; cohort; cytokine; design; disease phenotype; drug development; drug discovery; efficacious treatment; excitotoxicity; healthy volunteer; imaging study; inhibitor; longitudinal positron emission tomography; molecular imaging; mouse model; neuroinflammation; neuron loss; neurotoxicity; non-invasive imaging; novel; outcome prediction; pre-clinical; tool; treatment response

Project Summary. There are no efficacious therapies available to halt or reverse AD progression, which is attributed, at least in part, to the lack of translational molecular imaging tools suitable for both preclinical disease models and humans to facilitate drug discovery and development. Therefore, the development of such tools for non-invasive assessment of AD progression and therapeutic efficacy hold promises to fill the gap of this urgent and unmet medical need. Chronic neuroinflammation has demonstrated a key role in the pathogenesis of AD. As such, activated microglia release high levels of pro-inflammatory cytokines that prompt the release of excessive glutamate from adjacent astrocytes. The resulting glutamate spillover activates extrasynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs), thereby leading to the loss of synaptic integrity and neuronal cell death. As a primary contributor to this process, the GluN2B subunit is enriched in detrimental extrasynaptic NMDARs, which represents a promising target for monitoring glutamate-triggered neurotoxicity in AD. Our strategy involves the use of a specific positron emission tomography (PET) tracer, [11C]Me-NB1, that targets GluN2B-carrying NMDARs. To date, [11C]Me-NB1 is the only GluN2B PET tracer that has been successfully validated in small animals and healthy humans. Preliminary studies have shown that [11C]Me-NB1-PET is highly suited for non- invasive mapping of the GluN2B subunit, with excellent target affinity and selectivity across different species. However, non-invasive assessment of the distribution and expression of GluN2B has not yet been conducted in AD and the availability of [11C]Me-NB1 now provides new opportunity to fill this fundamental knowledge gap. Accordingly, our proposed study will lay the foundation for an appropriately designed clinical study with AD patients and age-matched healthy volunteers using [11C]Me-NB1-PET in the subsequent R01 application. As our specific objectives, utilizing non-invasive [11C]Me-NB1-PET, we propose to directly monitor GluN2B changes in AD models and evaluate treatment response for novel microglia-modulating therapy in transgenic APP/PS1 mouse models. Following this, our long-term goal is to assess the utility of [11C]Me-NB1-PET as a translational molecular imaging tool to provide new information (neuroimmune function and NMDAR-mediated neurotoxicity) of AD pathophysiology, and to enable target engagement and evaluate treatment response in clinical trials of novel AD drugs.

项目总结。目前还没有有效的治疗方法来阻止或逆转阿尔茨海默病的进展