Katharine Henry

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 (V_T) were assessed. Correlation analyses were conducted between brain regional V_T 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. V_T values showed excellent test-retest variability (range 6.0–8.5%) and good reliability (intraclass correlation coefficient range 0.74–0.87). V_T 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 V_T. Significant correlation was observed between V_T 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.

This study assessed whether the newly developed PET radioligands ¹¹C-PS13 and ¹¹C-MC1 could image constitutive levels of cyclooxygenase-1 (COX-1) and COX-2, respectively, in rhesus monkeys. Methods: After intravenous injection of either radioligand, 24 whole-body PET scans were performed. To measure enzyme-specific uptake, scans of the two radioligands were also performed after administration of a non-radioactive drug preferential for either COX-1 or COX-2. Concurrent venous samples were obtained to measure parent radioligand concentrations. Standardized uptake values were calculated from 10-90 minutes. Results: ¹¹C-PS13 showed specific uptake in most organs including spleen, gastrointestinal tract, kidneys, and brain, which was blocked by COX-1, but not COX-2, preferential inhibitors. Specific uptake of ¹¹C-MC1 was not observed in any organ except the ovaries and possibly kidneys. Conclusion: The findings suggest that ¹¹C-PS13 has adequate signal in monkeys to justify its extension to human subjects. In contrast, ¹¹C-MC1 is unlikely to show significant signal in healthy humans, though it may be able to do so in inflammatory conditions.

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 ( V_T) was found to be 1.2-fold higher in HABs across all brain regions. Additionally, the polymorphism plot estimated nondisplaceable uptake ( V_ND) as 1.40 mL · cm⁻³, which generated a specific-to-nondisplaceable ratio ( BP_ND) of 1.6 ± 0.6 in HABs and 1.1 ± 0.6 in MABs. V_T increased significantly with age in nearly all regions and was well estimated with radio-HPLC measurements from six arterial samples. However, V_T 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.