Evaluation of Two Potent and Selective PET Radioligands to Image COX-1 and COX-2 in Rhesus Monkeys

Abstract

This study assessed whether the newly developed PET radioligands ¹¹C-PS13 and ¹¹C-MC1 could image constitutive levels of cyclooxygenase (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 2 radioligands were also performed after administration of a nonradioactive drug preferential for either COX-1 or COX-2. Concurrent venous samples were obtained to measure parent radioligand concentrations. SUVs were calculated from 10 to 90 min. 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.

Keywords: cyclooxygenase-1; cyclooxygenase-2; inflammation; nonsteroidal antiinflammatory agents; positron-emission tomography.

FIGURE 1.

Chemical structures and in vitro potencies of PS13 and MC1 to inhibit COX-1 and COX-2, respectively, in fresh whole blood of rhesus monkeys (–16). Almost identical potencies were found in human blood. IC₅₀ = half-maximal inhibitory concentration.

FIGURE 2.

(A and B) Maximum-intensity projections after injection of ¹¹C-PS13 under baseline conditions (A) and after injection of PS13 (0.3 mg/kg) (B). (C and D) Time–activity curves under baseline conditions (C) and after injection of PS13 (1.0 mg/kg) (D). High uptake was observed in brain, spleen, gastrointestinal tract, and kidney medulla at baseline. Uptake was blocked by pharmacologic doses of PS13. Upper arrow = spleen; lower arrow = left kidney; Conc = concentration.

FIGURE 3.

Maximum-intensity projections after injection of ¹¹C-MC1 under baseline conditions (A) and after injection of MC1 (0.3 mg/kg) (B). High uptake was observed only in excretory organs at baseline and was not blocked by pharmacologic dose of MC1.

FIGURE 4.

Whole-body PET images after injection of ¹¹C-MC1 under baseline conditions (A) and after injection of MC1 (0.3 mg/kg) (B), as well as corresponding CT images (C). High uptake was observed in both ovaries (arrows) and was blocked by pharmacologic dose of MC1, consistent with specific binding to COX-2. PET images are shown as SUV.