The peripheral benzodiazepine binding site in the brain in multiple sclerosis

Abstract

This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.

Assessment of Neuroinflammation in Transferred EAE Via a Translocator Protein Ligand

“…This study extends earlier observations using [ 3 H](R)-PK11195 (Banati et al, 2000) in which increased binding in the spinal cords from rats with tEAE, at peak of clinical disease was documented.…”

“…A study on the same model (Banati et al, 2000) also found normal autoradiography up to day 4 with [3H]-PK11195. One should point out that we used two appropriate controls (not only naive rats).…”

Development of Ligands for the Peripheral Benzodiazepine Receptor

“…The synthesis of selective ligands for the PBR is therefore invaluable not only in characterising the receptor but also since the PBR could itself be a worthwhile target for therapeutic intervention. PK 11195 has been used in countless activated microglia studies and has provided a number of novel insights on the cellular pathology involved in certain disease states including MS [52] and AD [53]. Consequently, PK 11195 has been tagged the gold standard of PBR ligands.…”

Microglial positron emission tomography (PET) imaging in epilepsy: Applications, opportunities and pitfalls

“…Increased levels of TSPO in the CNS was originally considered to be specific for activated microglia as well as infiltrating macrophages, representing a neuroinflammatory biomarker, although it has since been established that TSPO expression is also increased in reactive astrocytes [22]. increased TSPO expression in a range of neuroinflammatory and neurodegenerative conditions, including Rasmussen's encephalitis [18], herpes encephalitis [19], multiple sclerosis [20], TBI [21], stroke [22] and Alzheimer's disease [23] (for detailed reviews see [7,13]). In the healthy human brain, [ 11 C]PK11195 uptake is low, with relatively high binding in subcortical structures, including midbrain, thalamus and basal ganglia, with overall brain uptake increasing with age [24].…”