First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain

Abstract

Purpose: This study assessed whether the newly developed PET radioligand [11C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain.

Methods: Brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas.

Results: In the brain, [11C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11C]PS13 binding reflects actual COX-1 density in the human brain.

Conclusions: These results from the first-in-human evaluation of the ability of [11C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation.

Clinical trial registration: NCT03324646 at https://clinicaltrials.gov/ . Registered October 30, 2017. Retrospectively registered.

Keywords: Cyclooxygenase-1; Inflammation; Neuroimaging; Positron emission tomography; Test-retest reliability.

Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Fig. 1

Analysis of arterial plasma after intravenous injection of [11C]PS13 in 10 healthy human individuals. (A) Reversed phase radio high-performance liquid chromatography (HPLC) analysis of plasma at 60 min in a participant. At least six radiometabolites were detected; A = 10.5%; B = 14.5%; C = 5%; D = 12.1%; E = 0.4%; Parent = 57.4%; F = 0.1%. (B) Change of plasma parent fraction over time. (C) Plasma parent concentration during the earliest 3 min after injection. (D) Plasma parent concentration from 3 min post-injection. Data are mean ± SD in B and D, and mean in C, where the SD was not displayed for the sake of clarity. SUV, standardized uptake value

Fig. 2

Parametric total distribution volume (VT) images calculated by the Logan graphical analysis method. MRI is from a representative participant, and PET images are averaged from 20 scans in 10 participants. Arrows represent notable [11C]PS13 binding in the pericentral cortex, occipital cortex, and hippocampus

Fig. 3

Time-activity curves of representative brain regions in a participant fitted with the two-tissue compartment model (2TC) and one-tissue compartment model (1TC)

Fig. 4

Time-stability analysis. Total distribution volume (VT) results were calculated by the two-tissue compartment model and normalized to the values measured by 120 min duration scans (n = 20). Data are mean ± SD

Fig. 5

Correlation between in vivo brain total distribution volume (VT) of [11C]PS13 (n = 10) and ex vivo PTGS1 mRNA expression levels measured by probe A_24_P64167 provided in the Allen Human Brain Atlas (n = 6). Please note that, although [11C]PS13 binding is higher in pericentral cortices, the VT values of the parietal and frontal regions are not particularly high because they derive from a larger region encompassing the whole lobe