Development of brain PET imaging agents: Strategies for imaging neuroinflammation in Alzheimer's disease.

Neuroinflammation is thought to play a key role in the development and progression of neurodegenerative diseases such as Alzheimer's disease. Positron emission tomography (PET) is an in vivo imaging technique capable of studying the biochemical processes which provide the molecular basis of disease. PET imaging of neuroinflammation, which is characterized by the activation of glial cells in the central nervous system (CNS), has been traditionally studied using radiotracers targeting the translocator protein 18kDa (TSPO). However, limitations in the properties of PET radiotracers for imaging the TSPO has led to the search for alternative strategies for imaging neuroinflammation. The current review presents the current status of PET radiotracers for imaging the TSPO, and describes alternative biological targets that have gained interest for imaging of microglial activation over recent years. These include cannabinoid receptor type-2, cyclooxygenase-2, the P2X7 receptor, CSF1R and reactive oxygen species and some promising radiotracers for these targets. Although a lot of advances have been made in the field of imaging neuroinflammation, current radiotracers all target the pro-inflammatory (M1) phenotype of activated microglia, since the number of known biological targets specific for the anti-inflammatory (M2) phenotype, is still limited. In spite of these limitations, PET imaging studies comparing the temporal relationship between Aβ plaque formation, microglial activation, and the formation of tau-based neurofibrillary tangles would provide valuable information on the "neuroinflammatory hypothesis" of neurodegeneration. The development of a suitable radiotracer for imaging the anti-inflammatory, M2 microglia would represent a great advance in imaging neuroinflammation since this would allow for imaging of the dynamics of microglial activation in different diseases.