PET Imaging of Microglial Activation—Beyond Targeting TSPO

Abstract

Neuroinflammation, which involves microglial activation, is thought to play a key role in the development and progression of neurodegenerative diseases and other brain pathologies. Positron emission tomography is an ideal imaging technique for studying biochemical processes in vivo, and particularly for studying the living brain. Neuroinflammation has been traditionally studied using radiotracers targeting the translocator protein 18 kDa, but this comes with certain limitations. The current review describes alternative biological targets that have gained interest for the imaging of microglial activation over recent years, such as the cannabinoid receptor type 2, cyclooxygenase-2, the P2X7 receptor and reactive oxygen species, and some promising radiotracers for these targets. Although many advances have been made in the field of neuroinflammation imaging, 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 that are also suited as a target for radiotracer development is still limited. Next to proceeding the currently available tracers for M1 microglia into the clinic, the development of a suitable radiotracer for M2 microglia would mean a great advance in the field, as this would allow for imaging of the dynamics of microglial activation in different diseases.

Widespread microglial activation in multiple system atrophy

“…23,24 To further elucidate the complex interaction between microglial activation and clinical phenotype and progression in MSA and other neurodegenerative disorders, longitudinal combined clinical and imaging studies are needed that also investigate other aspects of microglial activation apart from TSPO expression. 25 When interpreting our results, it is important to realize that TSPO expression is only one part of the much more complex phenomenon of microglial activation. We currently do not have in vivo imaging methods available that allow distinguishing between different types of activated micro-and astroglia.…”

“…To further elucidate the complex interaction between microglial activation and clinical phenotype and progression in MSA and other neurodegenerative disorders, longitudinal combined clinical and imaging studies are needed that also investigate other aspects of microglial activation apart from TSPO expression …”

In vivo molecular imaging of neuroinflammation in Alzheimer's disease

“…Other targets, such as monoamine oxidase, adenosine receptors, P2X7 receptors or metalloprotease are currently being considered and have been recently and comprehensively reviewed by Janssen et al . (, ).…”

“…Amongst them, the cannabinoid type 2 receptor holds promises, but the first reports using cannabinoid type 2 receptor tracers suggest that both biomarkers and tracers might not be suitable to monitor neuroinflammation in vivo (Vandeputte et al 2012;Ahmad et al 2013). Other targets, such as monoamine oxidase, adenosine receptors, P2X7 receptors or metalloprotease are currently being considered and have been recently and comprehensively reviewed by Janssen et al (2016Janssen et al ( , 2018.…”

Radiosynthesis of a Novel 11C‐Labeled Derivative of 4’‐O‐Methylhonokiol and Its Preliminary Evaluation in an LPS Rat Model of Neuroinflammation

“…Positron emission tomography (PET) based on operation of biologically active compounds labeled with short‐lived isotopes 11 C (T 1/2 =20.4 min) and 18 F (T 1/2 =109.8 min) provides a non‐invasive and direct method for assessing neuroinflammatory changes in the brain . Recently, significant progress was achieved in the development of PET radiotracers for inflammatory protein targets, including enzymes (translocator protein 18 kDa, glycogen synthase kinase 3, monoamine oxidase‐B, cyclooxygenase), cannabinoid (CB2) and purine (P2X7) receptors . Cyclooxygenase type 2 (COX‐2) is an inducible enzyme involved in the prostaglandin biosynthesis, it is minimally expressed at baseline in several peripheral tissues and brain, and overexpressed at sites of inflammation.…”