Sifting through the surfeit of neuroinflammation tracers

Abstract

The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.

A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo

“…Tracers for protein aggregation were excluded due to the singularities of protein aggregation, the challenge of dealing with undefined ratios of isoforms and post‐translational variants, and the presence of deposits in white matter complicating the discrimination between selective and nonspecific binding. Similarly, inflammation tracers such as [ 11 C]PK11195 were excluded from this analysis, as the signal resulting from cerebral TSPO binding depends on a diversity of cell types, complicating the interpretation of the PET signal specificity in acute inflammatory conditions …”

Widespread microglial activation in multiple system atrophy

“…Also, its binding affinity is not influenced by the TSPO polymorphism. However, [ 11 C] (R) ‐PK11195 has a lower specific‐to‐background signal ratio than newer microglial tracers, which might lead to underestimation of the extent of microglial activation …”

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…Further research is needed to evaluate the contribution of these components to the observation of lower levels of V T in schizophrenia. Finally, while there is as yet no published evidence showing an effect of the fraction of free radiotracer in plasma on brain V T for TSPO radioligands (72), it cannot be ruled out that potential patientcontrol differences in free radiotracer might contribute to the observed differences in V T . Of all the original studies included in this meta-analysis that measured free radiotracer (22)(23)(24), none found a significant difference between groups, suggesting that this factor did not have a major influence on the results.…”