Development of new PET radiopharmaceuticals for imaging specific microglial phenotypes

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Neuroinflammation plays a crucial role in the pathology of neurological diseases. In an acute inflammatory event, microglia are activated and inflammatory processes are maintained until homeostasis is restored. Under chronic conditions, however, microglia may remain activated, so that their protective properties turn into chronic inflammatory processes. Microglia then adopt an altered phenotype depending on stimuli of their microenvironment and the duration of activation, thereby mediating opposite effects and losing their normal functionality. Dysregulation of the immune response in the CNS appears to be a central factor in the development of neurodegenerative diseases such as Alzheimer's disease or frontotemporal dementia. However, the heterogeneity of different microglial phenotypes does not allow clear conclusions on whether microglial activation promotes or counteracts the disease process. Positron emission tomography (PET) is a non-invasive technique that is particularly suitable for studying altered metabolic mechanisms in the CNS. PET can be used to longitudinally detect and quantify neuropathological biomarkers which are critical to the immune response in vivo, and thus to determine disease progression and effects of therapeutic treatment strategies. The current standard, TSPO PET, is not able to discriminate between opposing microglial polarizations, so that no direct statement on microglia function can be made.This research project therefore aims to develop new radiotracers to detect both disease-associated and homeostatic microglial phenotype. The studies will focus on radioligands of the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) immunoreceptor, which plays an important role in regulating microglial signature, and the purinergic P2Y12 receptor. Preliminary data suggest that TREM2 and P2Y12 map opposite microglia phenotypes. Specific radiolabeled TREM2 antibodies and P2Y12R ligands may provide key insights into the functional role of activated microglia in different stages of neuroinflammatory processes.