Toward translation of a novel PET probe for imaging innate immune function in Alzheimer's Disease

SUMMARY Alzheimer’s Disease (AD) is the most common dementia, affecting 1 in 10 adults age 65+ in the US. No disease-modifying treatments currently exist, and definitive diagnosis is only possible through postmortem. To enable earlier diagnosis, we need a better understanding of the molecular processes involved in AD followed

by effective ways to visualize and monitor these processes in vivo. Genome wide association studies have shown that a loss of healthy innate immune function is significantly involved in disease pathogenesis. Thus, there is a great need to evaluate innate immune activation in vivo throughout disease progression. Here, I

propose to use Positron Emission Tomography (PET) to image activated microglia and macrophages with a novel highly sensitive and specific tracer in a mouse model of AD. PET is an extremely sensitive imaging modality that is well-suited for non-invasive and longitudinal interrogation of molecular processes in vivo.

Current neuroinflammation PET tracers are not suitable for addressing this great need since they target proteins that are not specific to innate immune cells and/or whose functional role in AD is ill-defined. In collaboration with Ashvattha Therapeutics, I have developed a new, non-toxic hydroxyl dendrimer-based PET

imaging agent that crosses the blood brain barrier and is selectively taken up by activated macrophages and microglia. I synthesized this tracer via a two-step azide fluorination and copper click reaction, under the mentorship of Drs. Michelle James and Bin Shen, and observed significant tracer uptake in regions containing

inflammation in the body and brain of septic mice injected with 10 mg/kg lipopolysaccharide (LPS), a well- established model of inflammation. I found that brain uptake of [18F]-OP-801 was significantly correlated with the sepsis score of each animal. In Aim 1, I will optimize the radiolabeling of [18F]OP-801 for routine clinical

production and conduct dosimetry studies in male and female mice, which will move this project towards our long-term goal of translation for human use. In Aim 2, I will evaluate the sensitivity and specificity of [18F]OP- 801 in the 5XFAD mouse model of AD and compare tracer uptake with quantitative susceptibility mapping

(QSM) to investigate how immune dysfunction corresponds with other AD-related changes in the brain, including iron accumulation and changes in oxidation state of brain metals. This analysis will be accompanied alongside assessment of other pathologic hallmarks of AD, amyloid and tau protein accumulation. Completing

these aims and working in collaboration with Ashvattha Therapeutics and GE Healthcare will allow me to develop a critical skillset to pursue a future career as an industry researcher and instructor. I will carry out this work under the mentorship of Dr. James, a world leader in neuroinflammation PET, and Dr. Zeineh, an expert

physician-scientist in advanced MRI (including QSM). The support of my mentors, along with the world- renowned training environment and excellent resources available to me as a bioengineering PhD student at Stanford University, are highly conducive to successful completion of this work.