Whole-Body PET Imaging in Humans Shows That 11 C-PS13 Is Selective for Cyclooxygenase-1 and Can Measure the In Vivo Potency of Nonsteroidal Antiinflammatory Drugs.

Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H ₂ , which has proinflammatory effects. The recently developed PET radioligand ¹¹ C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of ¹¹ C-PS13 binding to COX-1 in humans and assess the utility of ¹¹ C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs. Methods: Baseline ¹¹ C-PS13 whole-body PET scans were obtained for 26 healthy volunteers, followed by blocked scans with ketoprofen ( n = 8), celecoxib ( n = 8), or aspirin ( n = 8). Ketoprofen is a highly potent and selective COX-1 inhibitor, celecoxib is a preferential COX-2 inhibitor, and aspirin is a selective COX-1 inhibitor with a distinct mechanism that irreversibly inhibits substrate binding. Because blood cells, including platelets and white blood cells, also contain COX-1, ¹¹ C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning). Results: High ¹¹ C-PS13 uptake was observed in major organs with high COX-1 density, including the spleen, lungs, kidneys, and gastrointestinal tract. Ketoprofen (1-75 mg orally) blocked uptake in these organs far more effectively than did celecoxib (100-400 mg orally). On the basis of the plasma concentration to inhibit 50% of the maximum radioligand binding in the spleen (in vivo IC ₅₀ ), ketoprofen (<0.24 μM) was more than 10-fold more potent than celecoxib (>2.5 μM) as a COX-1 inhibitor, consistent with the in vitro potencies of these drugs for inhibiting COX-1. Blockade of ¹¹ C-PS13 uptake from blood cells acquired during the PET scans mirrored that in organs of the body. Aspirin (972-1,950 mg orally) blocked such a small percentage of uptake that its in vivo IC ₅₀ could not be determined. Conclusion: ¹¹ C-PS13 selectively binds to COX-1 in humans and can measure the in vivo potency of nonsteroidal antiinflammatory drugs that competitively inhibit arachidonic acid binding to COX-1. These in vivo studies, which reflect the net effect of drug absorption and metabolism in all organs of the body, demonstrated that ketoprofen had unexpectedly high potency, that celecoxib substantially inhibited COX-1, and that aspirin acetylation of COX-1 did not block binding of the representative nonsteroidal inhibitor ¹¹ C-PS13.
(© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)