PT - JOURNAL ARTICLE AU - Min-Jeong Kim AU - Jae-Hoon Lee AU - Fernanda Juarez Anaya AU - Prachi Singh AU - Jinsoo Hong AU - Cheryl Morse AU - Michelle Cortes AU - Katharine Henry AU - Stal Shrestha AU - Jeih-San Liow AU - Sami Zoghbi AU - Masahiro Fujita AU - Victor Pike AU - Robert Innis TI - <strong>First-In-Human Evaluation of <sup>11</sup>C-PS13 for Imaging Cyclooxygenase-1 in Brain and Peripheral Organs</strong> DP - 2019 May 01 TA - Journal of Nuclear Medicine PG - 321--321 VI - 60 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/60/supplement_1/321.short 4100 - http://jnm.snmjournals.org/content/60/supplement_1/321.full SO - J Nucl Med2019 May 01; 60 AB - 321Objectives: Cyclooxygenase (COX)-1 is constitutively expressed in most organs and produces prostanoids that mediate physiological functions. However, recent studies suggest that, because of its proinflammatory properties, COX-1 may also be a potential therapeutic target in brain disorders such as Alzheimer’s disease. Our laboratory recently developed 11C-PS13 as a novel PET radioligand for COX-1. Human whole blood assays indicated that PS13 was highly potent and selective for COX-1 (IC50 = 1 nM) versus COX-2 (IC50 &gt; 1,000 nM). This human study used 11C-PS13 to evaluate: 1) whole body in vivo selectivity of COX-1, and 2) test-retest reproducibility in brain. Methods: Approximately 740 MBq of 11C-PS13 was injected intravenously into 28 healthy human subjects for dynamic positron emission tomography (PET). Seventeen whole-body scans and 11 brain test-retest scans were obtained. To measure radioligand selectivity in vivo, whole-body scans were also obtained after administration of blocking drugs that preferentially target COX-1 (aspirin and ketoprofen) or COX-2 (celecoxib). Concurrent venous samples for whole-body scans and arterial samples for brain scans were obtained to measure concentrations of parent radioligand and radiometabolites. Results: Under baseline conditions, substantial uptake of radioactivity from 11C-PS13 was observed in most major organs, including the spleen, gastrointestinal tract, kidneys, and brain (Fig. 1). Uptake of radioactivity in these organs was blocked by preferential COX-1 inhibitors (aspirin or ketoprofen) but not by a preferential COX-2 inhibitor (celecoxib). In the brain, 11C-PS13 showed high uptake in the bilateral hippocampus and occipital cortices as well as bilateral pericentral cortices (Fig. 2). When total distribution volume was calculated using the two tissue-compartment model in the brain, the overall test-retest variability was within 15%, and the intraclass correlation coefficient was about 0.9. Conclusions: Our results suggest that COX-1 is constitutively expressed in major organs such as the spleen, gastrointestinal tract, kidneys, and brain; in the latter, uptake was particularly high in the hippocampus and occipital and pericentral cortices. The in vivo selectivity of 11C-PS13 was well demonstrated by pharmacological blockade in whole-body scans, and the test-retest reproducibility was also validated in brain scans. 11C-PS13 is the first radioligand for COX-1 that acts directly at this target. It is a potential probe for measuring neuroinflammation in brain disorders as well as target engagement by therapeutic drugs.