Novel pro-drug imaging agents to detect neuroinflammation in Alzheimer's Disease

About This Grant

ABSTRACT: Alzheimer’s disease (AD) is the most common form of neurodegenerative disease, estimated to contribute to 60-70% of all cases of dementia worldwide. Pathological hallmarks of AD include amyloid-b (Ab) plaques and abnormal tau tangles; however, the detection of these biomarkers at quantifiable levels in the brain is late- stage in disease pathology. Thus, novel biomarkers of early AD are urgently needed to improve the understanding of central and targetable molecular pathways in AD pathology to better identify vulnerable neurons prior to cell death. Emerging evidence shows neuroinflammation, particularly innate immune activation, has a vital role in both the pathogenesis and progression of AD. The most widely studied approaches to quantify neuroinflammation in the brain, to-date, target the translocator protein (TSPO), a protein overexpressed at the mitochondrial surface of activated microglia, using Positron Emission Tomography (PET). While pioneering, TSPO PET is limited by low specificity, limited brain exposure, and a need to stratify patients by genotype; moreover, TSPO lacks biological specificity in the context of disease. Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) has a central role in the pro-inflammatory response as its phosphorylation/ubiquitination directly activates NF-kB signaling pathways, promoting inflammasome assembly and cytokine (IL-1b, IL-6, TNF-a) production. Pharmacologic and genetic inhibition of RIPK2 was also shown to be neuroprotective by inhibiting microglial activation in stroke, Parkinson’s disease, and AD. More recently, RIPK2/NF-kB were shown to drive neuronal tau spreading and toxicity, mediated by microglia, in the PS19 mouse model of AD, where these events far preceded neuronal loss and memory/learning deficits. We have identified a lead small molecule, [18F]SJ09, which shows preliminary evidence of increased accumulation in two mouse models of AD, J20 (amyloid-producing) and PS19 (tau-producing). Our study will commence by developing a streamlined radiosynthesis of [18F]SJ09, to improve reproducibility of the agent and promote access to the tracer for our team and the broader scientific community (Specific Aim 1). We will also develop a radiosynthesis of a novel lead compound, [18F]SJ16, which has high potency for RIPK2, but has more favorable pharmacokinetics and more seamless synthesis compared to [18F]SJ09. Upon validation of specificity and stability in vivo, we will investigate both agent’s ability to quantify changes in neuroinflammation over time in three different mouse models of AD (Specific Aim 2). These data will be crucial to understand the sensitivity of each agent toward changes in innate immune activation over time. In parallel, we will use postmortem human brain tissue to study temporal expression of RIPK2 in various stages of AD pathology to gauge the applicability of RIPK2 PET imaging in neurodegenerative disease.