BACKGROUND Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success. METHODS The novel PET tracer [11C]MC1 was used to examine COX-2 expression [1] in the brains of four rhesus macaques at baseline and after injection of the inflammogen lipopolysaccharide (LPS) into the right putamen, and [2] in the joints of two human participants with rheumatoid arthritis and two healthy individuals. In the primate study, two monkeys had one LPS injection, and two monkeys had a second injection 33 and 44 days, respectively, after the first LPS injection. As a comparator, COX-1 expression was measured using [11C]PS13. RESULTS COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BPND) of [11C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [11C]PS13, was observed. The day after the second LPS injection, a brain lesion (~ 0.5 cm in diameter) with high COX-2 density and high BPND (1.8) was observed. Postmortem brain analysis at the gene transcript or protein level confirmed in vivo PET results. An incidental finding in an unrelated monkey found a line of COX-2 positivity along an incision in skull muscle, demonstrating that [11C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [11C]MC1 successfully imaged upregulated COX-2 in the arthritic hand and shoulder and apparently in the brain. Uptake was blocked by celecoxib, a COX-2 preferential inhibitor. CONCLUSIONS Taken together, these results indicate that [11C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation. TRIAL REGISTRATION ClinicalTrials.gov NCT03912428. Registered April 11, 2019.

中文翻译：

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使用新型放射性配体的PET测量环氧合酶2：灵长类动物神经炎症和人体首次研究的上调。

背景技术由炎症迅速上调的环氧合酶2（COX-2）是催化几种炎性前列腺素合成中限速步骤的关键酶。在体内成功进行COX-2的正电子发射断层扫描（PET）放射配体成像可能是评估脑部和外周炎症反应的潜在强大工具。然而，迄今为止，用于COX-2的PET放射性配体的开发取得了有限的成功。方法使用新型PET示踪剂[11C] MC1在基线和向右壳核中注射炎症原脂多糖（LPS）后，在四个恒河猴的脑中检查COX-2表达[1]，并在脑中检查[2]。两个患有类风湿关节炎的人类参与者和两个健康个体的关节。在灵长类动物研究中，两只猴子进行了一次LPS注射，第一次LPS注射后，两只猴子分别进行了33和44天的第二次注射。作为比较，使用[11C] PS13测量COX-1表达。结果在LPS注射后第1天，COX-2结合力以[11C] MC1的特异性与不可取代摄取（BPND）之比表示；没有观察到使用[11C] PS13测量的COX-1表达的这种增加。第二次LPS注射后的第二天，观察到具有高COX-2密度和高BPND（1.8）的脑部病变（直径约0.5 cm）。在基因转录物或蛋白质水平上的事后脑部分析证实了体内PET结果。在不相关的猴子中偶然发现了一个沿颅骨切口处的COX-2阳性线，表明[11C] MC1可以定位于大脑周围的炎症。在类风湿关节炎患者中，[11C] MC1成功地在关节炎的手和肩膀以及显然在大脑中成像了上调的COX-2。吸收被塞来昔布（一种COX-2优先抑制剂）阻断。结论综上所述，这些结果表明[11C] MC1可以成像并量化LPS诱发的神经炎症后猴脑和发炎的人外周组织中COX-2的上调。试验注册ClinicalTrials.gov NCT03912428。注册于2019年4月11日。试验注册ClinicalTrials.gov NCT03912428。注册于2019年4月11日。试验注册ClinicalTrials.gov NCT03912428。注册于2019年4月11日。