Determination of [¹¹C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

Abstract

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BP ND ). Here, we used blockade of the TSPO radioligand [ 11 C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V ND ), and hence estimate the BP ND . A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [ 11 C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V ND was estimated via the occupancy plot. Values of BP ND for all subjects were calculated using this V ND estimate. Total volume of distribution (V T ) of MABs (2.94±0.31) was lower than V T of HABs (4.33±0.29) (Po0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 ¼ 0.34±0.13 mg/kg). The occupancy plot provided a V ND estimate of 1.98 (1.69, 2.26). Based on these V ND estimates, BP ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [ 11 C]PBR28 V ND and hence BP ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V ND for TSPO targeting radioligands.

[11C]PBR28 PET Imaging is Sensitive to Neuroinflammation in the Aged Rat

“…The in vivo specificity for this tracer has also been shown by others in the rat, 12 monkey, 4,33 and human. 34 The increase in PBR28 uptake with age is in agreement with the expectations for a TSPO ligand designed to quantify microglial activation. Aging is known to lead to changes in the microglial phenotype with a shift toward a more activated state; the microglia tend to become larger and more complex, with several changes in antigen expression.…”

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…TSPO is also expressed in astrocytes; however, immunohistochemistry performed in a nonhuman primate brain after LPS administration confirmed that TSPO expression occurred mainly in activated microglia (32). To estimate the nonspecific binding contribution to [ 11 C]PBR28 V T , a blocking study with TSPO agonist XBD173 in humans confirmed that [ 11 C]PBR28 V T largely constitutes specific binding to TSPO (44). Thus, with the current imaging paradigm, the neuroimmune response to LPS can be quantitatively measured in vivo with [ 11 C]PBR28 and PET, in association with peripheral inflammation and sickness symptoms.…”

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

“…Because there is no brain region devoid of TSPO expression (65,66), metabolite-corrected arterial plasma measurements of radioligand concentration are necessary for accurate in vivo quantification of binding. To overcome variability that may be associated with the arterial measurements (27,67), relative measures of binding, such as distribution volume ratios (DVRs), have been proposed (22).…”