Development of a Novel Biomarker and PET Radiotracer for Specific Imaging of Microglial Responses

Project Summary/Abstract Chronic microglial activation is an early and critical driver of neurodegenerative diseases. Hence, there is an urgent need to measure microglial responses in vivo. Positron emission tomography (PET) provides a non- invasive means to track and quantify microglial responses. However, current approaches are limited by the lack of microglial-specific imaging biomarkers. To address this gap, we propose the development of the first Tandem pore domain halothane-inhibited K+ channel 1 (THIK-1)-targeted PET radioligands. THIK-1 is a K+ channel which exhibits high microglial specificity. Moreover, THIK-1 was recently associated with microglial functions such as proinflammatory IL-1b release and phagocytosis and identified as a therapeutic target for neurodegenerative diseases. We have identified two lead small molecule candidates as the first THIK-1-targeted PET probes, exhibiting THIK-1 specificity and high potential to cross the blood brain barrier. First, we will 3H-radiolabel these lead compounds and evaluate their specificity and concordance with neuroinflammatory markers in vitro. We will subsequently develop 18F-radiolabeled ligands and assess their in vivo biodistribution and brain penetrance in healthy C57/bl6 mice. The ability of these THIK-1 radiotracers to detect changes in microglial responses within disease will be assessed in vitro and in vivo using animal models of Alzheimer’s disease and multiple sclerosis. The specificity and sensitivity of these THIK-1 PET ligands for imaging microglia will be further assessed through blocking and microglial depletion studies. The innovation of this multi-disciplinary proposal lies in the development of the novel targeting of THIK-1 for highly specific and functionally relevant imaging of microglia. This will be the first report of THIK-1-PET approaches. Additionally, PET imaging of THIK-1 will provide critical information on the metabolism, efficacy, and safety of THIK-1 therapeutics. The novel approach proposed here has high potential for significant impact in both fields of neuroinflammation and neurodegeneration research. Enhancing understanding of the in vivo dynamics of microglia in neurological disease will improve disease monitoring, screening of potential disease-modifying therapeutics, and development of effective strategies to reduce risk of disease development.