한빛사논문
- 조회612
National Institute of Mental Health, 현 Stony Brook University School of Medicine
Min-Jeong Kim, Fernanda Juarez Anaya, Lester S Manly, Jae-Hoon Lee, Jinsoo Hong, Stal Shrestha, Sanjay Telu, Katharine Henry, Jose A Montero Santamaria, Jeih-San Liow, Paolo Zanotti-Fregonara, H. Umesha Shetty, Sami S Zoghbi, Victor W. Pike and Robert B. Innis
National Institute of Mental Health, United States
For correspondence or reprints contact: Robert B. Innis
Abstract
Both cyclooxygenase-1 (COX-1) and COX-2 convert arachidonic acid to prostaglandin H2, which has pro-inflammatory effects. The recently developed positron emission tomography (PET) radioligand 11C-PS13 has excellent in vivo selectivity for COX-1 over COX-2 in non-human 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 anti-inflammatory drugs (NSAIDs). Methods: Baseline 11C-PS13 whole-body PET scans were obtained in 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 (1-75mg p.o.) blocked uptake in these organs far more effectively than celecoxib (100-400mg p.o.). Based on the plasma concentration to inhibit 50% of the maximum radioligand binding in the spleen (in vivo IC50), ketoprofen (<0.24µM) was >10-fold more potent than celecoxib (>2.5µM) 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 (972-1,950mg p.o.) 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 NSAIDs 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 non-steroidal inhibitor 11C-PS13.
논문정보
- Research article
- 2022년 07월 (BRIC 등록일 2022-11-30)
- 국외 연구진
- 바이오·의료융합 > 뇌인지과학
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