National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA.
Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, USA.
J Neuroinflammation. 2020 May 2;17(1):140. doi: 10.1186/s12974-020-01804-6.
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.
The novel PET tracer [C]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 [C]PS13.
COX-2 binding, expressed as the ratio of specific to nondisplaceable uptake (BP) of [C]MC1, increased on day 1 post-LPS injection; no such increase in COX-1 expression, measured using [C]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 BP (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 [C]MC1 can localize inflammation peripheral to the brain. In patients with rheumatoid arthritis, [C]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.
Taken together, these results indicate that [C]MC1 can image and quantify COX-2 upregulation in both monkey brain after LPS-induced neuroinflammation and in human peripheral tissue with inflammation.
ClinicalTrials.gov NCT03912428. Registered April 11, 2019.
环氧化酶-2（COX-2）可被炎症迅速上调，是催化几种炎症前列腺素合成限速步骤的关键酶。COX-2 的正电子发射断层扫描（PET）放射性配体成像如果成功，将成为评估大脑和外周炎症反应的潜在强大工具。然而，迄今为止，COX-2 的 PET 放射性配体的开发一直没有取得成功。
使用新型 PET 示踪剂 [C]MC1 检查[1]四头恒河猴在对照期和右壳核注射炎症原脂多糖（LPS）后的 COX-2 表达，以及[2]在两名类风湿关节炎患者和两名健康个体的关节中。在灵长类动物研究中，两只猴子接受了一次 LPS 注射，另外两只猴子分别在第一次 LPS 注射后 33 天和 44 天接受了第二次 LPS 注射。作为对照，使用 [C]PS13 测量 COX-1 的表达。
COX-2 结合，以 [C]MC1 特异性与不可置换摄取（BP）的比值表示，在 LPS 注射后第 1 天增加；使用 [C]PS13 测量的 COX-1 表达没有增加。在第二次 LPS 注射后的第二天，观察到一个直径约 0.5 厘米的大脑病变，COX-2 密度高且 BP（1.8）高。死后脑分析在基因转录或蛋白水平上证实了体内 PET 结果。在一只无关的猴子中发现了一个偶然发现，颅骨肌肉的切口处有一条 COX-2 阳性线，表明 [C]MC1 可以定位大脑周围的炎症。在类风湿关节炎患者中，[C]MC1 成功地对关节炎手部和肩部以及明显的大脑中的 COX-2 上调进行了成像。摄取被 COX-2 优先抑制剂塞来昔布阻断。
总之，这些结果表明，[C]MC1 可以在 LPS 诱导的神经炎症后猴脑中以及有炎症的人外周组织中成像和定量 COX-2 的上调。
ClinicalTrials.gov NCT03912428。2019 年 4 月 11 日注册。
