ABSTRACT Discovery of human radiotracers that serve as companion diagnostics and/or aid in understanding abnormal biological processes that underlie cognitive disorders, such as Alzheimer's disease (AD) and other brain disorders is an area of high translational priority towards key milestones tied to the implementation of the National Plan to Address Alzheimer's and Related Dementias and a specific requirement of PAR-20-038. Our study proposes the discovery and evaluation of a radiopharmaceutical agent for the positron emission tomography (PET) imaging of epichaperomes, emerging targets in AD. Epichaperomes, long-lived oligomeric protein scaffolding platforms, are among the earliest mediators of AD pathogenesis. They negatively impact the interactions of proteins important for neuronal function, such as synaptic plasticity, cell-to-cell communication, protein translation, cell cycle re-entry, axon guidance, metabolic processes and inflammation, leading to proteome-wide defects in protein-protein interaction networks, and in turn cell- and brain-network dysfunction and cognitive decline. We discovered both epichaperome drugs (eg. PU-AD) and companion diagnostics (eg. [124I]-PU-AD PET) and translated them to clinic. To image epichaperomes, we discovered [124I]-PU-AD, a [124I]- labeled epichaperome probe. In a pilot feasibility clinical study, [124I]-PU-AD provided proof-of-principle that epichaperomes are imageable and quantifiable in patients by PET. In preclinical models, it demonstrated that epichaperomes form in AD in a disease-relevant region- and age-dependent manner. The next step is to make epichaperome imaging probes practical for widespread clinical use. We posit replacing the 124I label with 18F will significantly improve sensitivity, spatial and temporal image quality, reduce radiation burden and imaging times, improve production costs and availability, thus increasing the clinical applicability of the probe. We here propose a plan for the discovery of the 18F epichaperome PET imaging agent with emphasis on steps such as synthesis, identification of lead candidates, tracer characterization, safety, dosing, preclinical validation and IND-enabling studies for a proposed future Exploratory Investigational New Drug Application. We assemble a multidisciplinary team with a history of successful collaborations (>40 papers, >20 PET tracers in clinic) and designed 3 Specific Aims to accomplish our goal: Aim 1. Identify F-containing epichaperome probes with favorable affinity, selectivity and BBB permeability; Aim 2. Investigate the probe's specificity and sensitivity in detecting epichaperome-mediated dysfunction in AD mouse models; and Aim 3. Perform IND-enabling studies for a proposed Exploratory Investigational New Drug Application. Outcomes of this work are novel PET probes for use as precision medicine tools to image in vivo early molecular dysfunction in the brain and as companion diagnostics for epichaperome targeted therapies, both resea...