Clinical translation of novel PET radiotracers for mapping innate immune activation in CNS diseases (Renewal)

Neuroinflammation and innate immune activation are key pathological features of many central nervous system (CNS) diseases. Therefore, our ability to quantify and track immune responses non-invasively using functionally relevant biomarkers is of great importance, both for disease staging and monitoring of new immunomodulatory therapies.  

Unfortunately, there is currently a lack of biomarkers enabling specific, sensitive, spatial detection of innate immune responses in the CNS. To address this unmet need, we identified GPR84—a sensitive and specific biomarker of innate immune activation and developed the first 18F-labeled positron emission tomography (PET) radiotracer that specifically binds to this biomarker. 

In the initial round of funding for this Wu Tsai Translate project we made significant progress optimizing the synthesis of this tracer for clinical production (meeting criteria for patient administration), proved it can sensitively detect pro-inflammatory innate immune activation in vitro in human cells and tissues, and showed that it can track activated microglia and macrophages in vivo in a mouse model of multiple sclerosis.   

In this renewal proposal, we will be developing a second-generation GPR84 radiotracer with higher affinity than our first lead to enhance our chance of clinical success, and broaden our focus from multiple sclerosis to all CNS diseases with underlying neuroinflammation, including Alzheimer’s disease.