The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: From pathology to imaging

Abstract

Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using Positron Emission Tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders.

Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

“…Inflammation can be associated with several fold increased densities of PBRs (Venneti et al, 2006). We performed Monte Carlo simulations to investigate if such large increases in receptor binding could be measured accurately in vivo with [ 11 C]PBR28.…”

“…An area with high density of glia or significant inflammation may have several fold increased density of PBRs (Venneti et al, 2006). Therefore, in addition to measuring low density of receptors found in healthy human brain, a useful PET radioligand must also be able to measure areas of increased binding.…”

“…Both in vitro and in vivo imaging of PBRs can localize and quantify inflammation in tissues (Venneti et al, 2006). For the past two decades, [ 3 H]PK 11195 has been used for in vitro studies (e.g., binding to homogenates or sections of tissues), and the PET radioligand [ 11 C]PK 11195 has been used for in vivo imaging (Venneti et al, 2006). [ 3 H]PK 11195 is useful as an in vitro radioligand and has a high ratio of specific to nonspecific binding, in part because much of the nonspecific binding can be washed away from tissue homogenates or sections.…”

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…TSPO is present on the outer mitochondrial membrane of microglia, and one established function of TSPO is to transport cholesterol to the inner mitochondrial membrane for the production of steroids, with possible additional functions in regulating cell death, cytokine production, and microglial proliferation (20). Recent studies have also found that TSPO itself has a role in regulating microglial immune function, as antagonists of TSPO reduce the activation of microglia (21).…”

MRI Assessment of Post-Ischemic Neuroinflammation in Stroke: Experimental and Clinical Studies

“…Nearly 30 years ago, radiolabeling of the prototypic PBR/TSPO ligand PK11195 with carbon-11 enabled in vivo imaging of microglial activation using Positron Emission Tomography (PET scan) (Camsonne et al, 1984), and paved the road for neuroinflammation imaging. However, [ 11 C]PK11195 has shown limitations that until now slowed clinical application of neuroinflammation imaging by PET (Venneti et al, 2006). Although the field is still very active, as seen from the plethora of radioligands for PBR/TSPO that have been radiolabeled these last few years (Chauveau et al, 2008), large-scale clinical PET studies are difficult to set up in the context of emergency stroke management.…”