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

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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.