Building a database for brain 18 kDa translocator protein imaged using [11C]PBR28 in healthy subjects

Abstract

Translocator protein 18 kDa (TSPO) has been widely imaged as a marker of neuroinflammation using several radioligands, including [11C]PBR28. In order to study the effects of age, sex, and obesity on TSPO binding and to determine whether this binding can be accurately assessed using fewer radio high-performance liquid chromatography (radio-HPLC) measurements of arterial blood samples, we created a database of 48 healthy subjects who had undergone [11C]PBR28 scans (23 high-affinity binders (HABs) and 25 mixed-affinity binders (MABs), 20 F/28 M, age: 40.6 ± 16.8 years). After analysis by Logan plot using 23 metabolite-corrected arterial samples, total distribution volume ( VT) was found to be 1.2-fold higher in HABs across all brain regions. Additionally, the polymorphism plot estimated nondisplaceable uptake ( VND) as 1.40 mL · cm-3, which generated a specific-to-nondisplaceable ratio ( BPND) of 1.6 ± 0.6 in HABs and 1.1 ± 0.6 in MABs. VT increased significantly with age in nearly all regions and was well estimated with radio-HPLC measurements from six arterial samples. However, VT did not correlate with body mass index and was not affected by sex. These results underscore which patient characteristics should be accounted for during [11C]PBR28 studies and suggest ways to perform such studies more easily and with fewer blood samples.

Trial registration: ClinicalTrials.gov NCT01547780 NCT00526916 NCT01322555 NCT01851356 NCT02233868 NCT00613119.

Keywords: Translocator protein; [C]PBR28; distribution volume; high-affinity binder; mixed-affinity binder.

Figures

Figure 1.

(a) Mean concentrations of radioactivity in whole brain for high-affinity binders (HABs) and mixed-affinity binders (MABs) as a function of time. (b) [11C]PBR28 concentrations in arterial plasma as a function of time. The timepoints shown with closed squares represent the six samples used to assess whether a smaller number of plasma samples can accurately measure distribution volume (VT). (c) The percentage of total radioactivity in plasma that represents parent radioligand separated from radiometabolites.

Figure 2.

Mean Logan parametric PET images of high-affinity binders (HABs) and mixed-affinity binders (MABs). Each pixel value representsVT and is indicated inVT color scale.

Figure 3.

Effect of (a) sex, (b) body mass index (BMI), and (c) age on distribution volume (VT) of [11C]PBR28. For clarity of presentation, panel A shows the high-affinity binder equivalent values ofVT for whole brain, calculated by multiplying the VT of mixed-affinity binders (MABs) by 1.2. Panels B and C show unstandardized residuals used in the partial correlations where genotype was used as a covariate.

Figure 4.

Correlation of whole brain distribution volume (VT) calculated from 23 plasma measurements with that calculated from six timepoints. The slope (1.10) implies that using six timepoints overestimatedVT by 10% compared toVT from all 23 time points.

Figure 5.

Polymorphism plot to estimate nondisplaceable uptake (VND) in an imaginary region with no specific binding (x-intercept). For 41 different brain regions, the distribution volume (VT) in mixed-affinity binders (MABs) was subtracted from that in high-affinity binders (HABs) and plotted against the distribution volume (VT) of HABs. The extrapolatedx-intercept marked with a circle shows that the estimated VND for this population was 1.4 mL · cm−3.