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 research areas
of high translational priority.