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

The Journal of Nuclear Medicine

article

Min-Jeong Kim¹  Fernanda Juarez Anaya¹  Lester S. Manly¹  Jae-Hoon Lee¹  Jinsoo Hong¹  Stal Shrestha¹  Sanjay Telu¹  Katharine Henry¹  Jose A. Montero Santamaria¹  Jeih-San Liow¹  Paolo Zanotti-Fregonara¹  H. Umesha Shetty¹  Sami S. Zoghbi¹  Victor W. Pike¹  Robert B. Innis¹ 

[1] Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health;Department of Psychiatry and Behavioral Health, Stony Brook University School of Medicine

关键词: cyclooxygenase-1;    PET;    inflammation;    aspirin;    celecoxib;   

DOI  :  10.2967/jnumed.122.264061

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 (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.

【 授权许可】

CC BY