Min-Jeong Kim

Cyclooxygenase-1 (COX-1), an essential enzyme in the synthesis of pro-inflammatory prostanoids from arachidonic acid, is widely expressed in the brain, primarily in microglia. Previous studies from our laboratory found that the novel positron emission tomography (PET) radioligand [ ¹¹ C]PS13 has excellent in vivo selectivity for constitutively expressed COX-1 in human brain. This study sought to further evaluate the effects of age and sex on levels of constitutive COX-1 expression in the brains of 56 healthy volunteers. COX-1 density in the brain measured by [ ¹¹ C]PS13 PET showed a significant positive correlation with age in the whole brain, as well as in regions with the highest COX-1 expression, such as the hippocampus, lateral occipital cortex, and pericentral cortex. No significant sex differences were observed in any regions. Consistent findings were observed regardless of partial volume correction (PVC), while overall statistical significance was enhanced with PVC. In conclusion, the present study found that constitutive COX-1 binding in the brain, which is associated with microglial density, increased with age with no significant sex differences. The physiological roles of COX-1 in these regions and its potential contributions to the aging process remain largely unknown, and further investigation is warranted. Clinical trial registration information: NCT03324646; NCT04396873 in ClinicalTrials.gov.

Purpose (2S,4R)-4-[¹⁸F]fluoroglutamine ([¹⁸F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [¹⁸F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA). Procedures The CIPE model (n = 4) was generated by injecting 200 µL of 3% carrageenan solution into the left hind paw three hours before the PET. The CIA model (n = 4) was generated by injecting 200 µg of collagen emulsion subcutaneously at the tail base 3–4 weeks before the PET. A qualitative scoring system was used to assess the severity of paw inflammation. After a CT scan, 15.7 ± 4.9 MBq of [¹⁸F]FGln was injected via the tail vein, followed by a dynamic micro-PET scan for 90 min under anesthesia with isoflurane. The standard uptake value of [¹⁸F]FGln was measured by placing a volume of interest in each paw. The non-injected right hind paws of the CIPE model rats served as controls for both models. The paws with CIA were pathologically examined after PET. Results The CIPE models showed a trend toward higher uptake in the injected paw compared to the non-injected paw (P = 0.068). In CIA models, uptake in the paws with severe inflammation was significantly higher than the controls (P = 0.011), while that with mild and no inflammation was slightly higher (33%) and lower (-7%), respectively. Combined overall, the [¹⁸F]FGln uptake in CIA showed a significant positive correlation with inflammation severity (r = 0.88, P = 0.009). The pathological findings confirmed profound inflammation in CIA. Conclusions [¹⁸F]FGln uptake was increased in both acute and chronic inflammation, and the uptake level was significantly correlated with the severity, suggesting its potential utility as a novel metabolic imaging marker for inflammation.

Purpose (2S,4R)-4-[¹⁸F]fluoroglutamine ([¹⁸F]FGln) is a promising metabolic imaging marker in cancer. Based on the fact that major inflammatory cells are heavily dependent on glutamine metabolism like cancer cells, we explored the potential utility of [¹⁸F]FGln as a metabolic imaging marker for inflammation in two rat models: carrageenan-induced paw edema (CIPE) and collagen-induced arthritis (CIA). Procedures: The CIPE model (n = 4) was generated by injecting 200 µL of 3% carrageenan solution into the left hind paw three hours before the PET. The CIA model (n = 4) was generated by injecting 200 µg of collagen emulsion subcutaneously at the tail base 3–4 weeks before the PET. A qualitative scoring system was used to assess the severity of paw inflammation. After a CT scan, 15.7 ± 4.9 MBq of [¹⁸F]FGln was injected via the tail vein, followed by a dynamic micro-PET scan for 90 minutes under anesthesia with isoflurane. The standard uptake value of [¹⁸F]FGln was measured by placing a volume of interest in each paw. The non-injected right hind paws of the CIPE model rats served as controls for both models. The paws with CIA were pathologically examined after PET. Results In CIPE models, uptake in the injected paw was higher compared to the non-injected paw by 52–83%. In CIA models, uptake in the paws with severe inflammation was higher than the averaged controls by 54–173%, while that with mild and no inflammation was slightly higher (33%) and lower (-7%), respectively. Combined overall, the [¹⁸F]FGln uptake in CIA showed a significant positive correlation with inflammation severity (r = 0.88, P = 0.009). The pathological findings confirmed profound inflammation in CIA. Conclusions [¹⁸F]FGln uptake was increased in both acute and chronic inflammation, and the uptake level was significantly correlated with the severity, suggesting its potential utility as a novel metabolic imaging marker for inflammation.

Woo SH, et al. J Clin Neurol. 2022 Nov;18(6):603-609. https://doi.org/10.3988/jcn.2022.18.6.603

Pilloni G, et al. J Clin Neurol. 2022 Jul;18(4):391-400. https://doi.org/10.3988/jcn.2022.18.4.391

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 used ¹¹C‐PBR28 positron emission tomography (PET) imaging to determine whether levels of 18‐kDa translocator protein (TSPO), an inflammation‐specific biomarker, are increased in frontotemporal lobar degeneration (FTLD) patients. ¹¹C‐PBR28, ¹⁸F‐FDG, and ¹¹C‐PIB brain PET scans, as well as magnetic resonance imaging (MRI), were conducted in four FTLD patients and 22 healthy controls. ¹¹C‐PBR28 scans revealed that all FTLD patients showed increased TSPO binding versus controls. Significantly greater increases in TSPO were observed in the frontal, lateral temporal, parietal, and occipital cortices, topographically consistent with individual clinical phenotypes and with brain MRI and ¹⁸F‐FDG PET. Amyloid burden was not increased.

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.