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

• Published in: The Journal of nuclear medicine (1978) Vol. 64; no. 1; pp. 159 - 164
• Main Authors: Kim, Min-Jeong, Anaya, Fernanda Juarez, Manly, Lester S, Lee, Jae-Hoon, Hong, Jinsoo, Shrestha, Stal, Telu, Sanjay, Henry, Katharine, Montero Santamaria, Jose A, Liow, Jeih-San, Zanotti-Fregonara, Paolo, Shetty, H Umesha, Zoghbi, Sami S, Pike, Victor W, Innis, Robert B
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.01.2023
• Subjects: Acetylation; Anti-inflammatory agents; Arachidonic acid; Aspirin; Binding; Blood; Celecoxib; Clinical Investigation; COX-2 inhibitors; Cyclooxygenase-1; Cyclooxygenase-2; Drug metabolism; Drugs; Gastrointestinal system; Gastrointestinal tract; In vivo methods and tests; Inflammation; Ketoprofen; Kidneys; Leukocytes; Nonsteroidal anti-inflammatory drugs; Organs; Positron emission; Prostaglandin H2; Selectivity; Spleen; Substrate inhibition
• ISSN: 0161-5505; 1535-5667
• DOI: 10.2967/jnumed.122.264061

Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) convert arachidonic acid to prostaglandin H2, which has proinflammatory effects. The recently developed PET radioligand 11C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in nonhuman primates. This study sought to evaluate the selectivity of 11C-PS13 binding to COX-1 in humans and assess the utility of 11C-PS13 to measure the in vivo potency of nonsteroidal antiinflammatory drugs. Methods: Baseline 11C-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, 11C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning). Results: High 11C-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 IC50), 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 11C-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 IC50 could not be determined. Conclusion: 11C-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 11C-PS13.