11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-( R)-PK11195

Abstract

Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the "signal to background" ratio (assessed as binding potential ( BPND)) of 11C-( R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-( R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30-90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-( R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-( R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-( R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.

Trial registration: ClinicalTrials.gov NCT02147392.

Keywords: 18 kDa (TSPO); XBD173; metabolite-corrected arterial input; positron emission tomography; rs6971 polymorphism.

Figures

Figure 1.

Mean brain radioactivity concentrations of 11C-DPA713 (a) and 11C-(R)-PK11195 (b) in each binder group. HABs: high-affinity binders; MABs: mixed-affinity binders; LABs: low-affinity binders. Error bars denote SD.

Figure 2.

Time–stability analysis for kinetic analysis of 11C-DPA713 (a) and 11C-(R)-PK11195 (b). Total distribution volume (VT) obtained from baseline scans for HABs, MABs, and LABs are plotted as a function of duration of image acquisition. VT was calculated for whole brain using a Logan plot. VT values are normalized as a percentage of terminal value attained from 90 min of imaging. The data represent mean ± SD of all three subjects. HABs: high-affinity binders; MABs: mixed-affinity binders; LABs: low-affinity binders.

Figure 3.

Data from a representative 11C-DPA713 subject in whole brain (a) and arterial plasma (b) at baseline (○) and after blockade (•). Data from a representative 11C-(R)-PK11195 subject in brain (c) and arterial plasma (d) at baseline (○) and after blockade (•). Blockade was done with 90 mg XBD173. Time courses of parent concentrations in arterial plasma were triexponentially fitted.

Figure 4.

Lassen occupancy plot to determine non-displaceable uptake (VND) of 11C-DPA713 in HABs (n = 6; a) and that of 11C-(R)-PK11195 in HABs (n = 5; b) and MABs (n = 8; c). Each point represents a brain region in an individual subject. HABs: high-affinity binders; MABs: mixed-affinity binders.

Figure 5.

Polymorphism plot to determine a population average of non-displaceable uptake (VND) of 11C-DPA713 in 14 HABs, five MABs, and three LABs. The plots were performed for three different combinations of the affinity types, HABs and MABs (a), HABs and LABs (b), and MABs and LABs (c). The plots were performed using average VT values in each volume of interest (VOI) of the same affinity type.