Kinetic modelling of [¹¹C]PBR28 for 18 kDa translocator protein PET data: A validation study of vascular modelling in the brain using XBD173 and tissue analysis

Abstract

The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [C]PBR28 and [C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high-affinity binders, underwent two [C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter.

Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [18F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter

“…It is possible that this is a disease-specific difference, given that both the former studies were performed in healthy subjects; however, the sample size in our study was also small and the estimation of V ND may therefore be subject to some biological variability. Nevertheless, the proportion of non-specific binding for [ 18 F]GE-180 is comparable to or even lower than that of [ 11 C]PBR28 (V ND~5 5 vs.~69 %, respectively), although absolute V T s are lower [6,27]. This result further indicates that [ 18 F]GE-180 is able to identify specific TSPO signal in the MS brain, in spite of low brain penetration.…”

“…[ 11 C]PBR28 has been validated with blocking experiments prior to our study, both in healthy controls [6,26] and in a disease cohort [27]. [ 11 C]PBR28 is generally accepted as an effective TSPO tracer in vivo [28][29][30][31][32] although exhibits counterintuitively decreased V T in subjects with neuroinflammation [29].…”

PET imaging shows no changes in TSPO brain density after IFN-α immune challenge in healthy human volunteers

“…Quantification of [ 11 C]PBR28 tissue distribution was performed using both the standard 2TCM and the 2TCM-1K with total distribution volume (Vt) as main parameter of interest 41 . The two models were then used to assess Vt changes before and after IFN-α (%ΔVt), as done in a previous study 42 .…”

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

“…Given the lack of a true reference region, V T is the most suitable outcome for TSPO quantification under the assumption that nondisplaceable binding does not differ between groups. Apart from glial cells, TSPO is also expressed in perivascular and endothelial cells (55,70) and under certain conditions also neurons (71). Further research is needed to evaluate the contribution of these components to the observation of lower levels of V T in schizophrenia.…”