Determination of [(11)C]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 (BPND). Here, we used blockade of the TSPO radioligand [(11)C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (VND), and hence estimate the BPND. 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, VND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this VND estimate. Total volume of distribution (VT) of MABs (2.94±0.31) was lower than VT of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13 mg/kg). The occupancy plot provided a VND estimate of 1.98 (1.69, 2.26). Based on these VND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [(11)C]PBR28 VND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating VND for TSPO targeting radioligands.

Figure 1

Effect of genotype on ¹¹C-PBR28 total volume of distribution in high-affinity binders (HABs) (n=16) and mixed affinity binders (MABs) (n=10).

Figure 2

Integral images (0 to 90 minutes) of [¹¹C]PBR28 in a high-affinity binders (subject 11) before and after blockade. (A) Baseline. (B) Blockade with 90 mg XBD713.

Figure 3

Time-activity curves of [¹¹C]PBR28 in a high-affinity binders (subject 11) before and after blockade 90 mg XBD713 in brainstem, thalamus, and cerebellum.

Figure 4

(A) Polymorphism plot to determine ¹¹C-PBR28 V_ND. Each point represents the group mean for a specific region of interest (ROI). (B) Occupancy plot to determine group mean ¹¹C-PBR28 V_ND. Each point represents an individual subject ROI value. (C) Occupancy plot to determine ¹¹C-PBR28 V_ND without V_ND constraint. Each point represents an individual subject ROI value.

Figure 5

Dose translocator protein-occupancy curve for single oral administration of XBD173 (10 to 90 mg), based on each individual occupancy plot.