de Vries Erik F J, Doorduin Janine, Dierckx Rudi A, van Waarde Aren
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
Nucl Med Biol. 2008 Jan;35(1):35-42. doi: 10.1016/j.nucmedbio.2007.07.015. Epub 2007 Sep 19.
Overexpression of cyclooxygenase type 2 (COX-2) is triggered by inflammatory stimuli, but it also plays a prominent role in the initiation and progression of various diseases. This study aims to investigate [(11)C]rofecoxib as a positron emission tomography (PET) tracer for COX-2 expression.
[(11)C]Rofecoxib was prepared by methylation of its sulphinate precursor. Regional brain distribution and specific binding of [(11)C]rofecoxib in healthy rats was studied by ex vivo biodistribution and autoradiography. Regional brain distribution and PET imaging studies were also performed on rats with severe encephalitis, caused by nasal infection with herpes simplex virus (HSV). Finally, ex vivo biodistribution and blocking studies were carried in rats with a sterile inflammation, induced by intramuscular turpentine injection.
[(11)C]rofecoxib brain uptake in control animals corresponded with the known distribution of COX-2. Pretreatment with NS398 significantly reduced tracer uptake in the cingulate/frontopolar cortex, whereas the reduction in hippocampus approached significance. Ex vivo autoradiography also revealed preferential tracer uptake in hippocampus and cortical areas that could be blocked by NS398. In HSV-infected animals, [(11)C]rofecoxib uptake was moderately increased in all brain regions, but it could not be blocked with indomethacin. Yet, some PET images revealed increased tracer uptake in brain areas with microglia activation. In turpentine-injected animals, [(11)C]rofecoxib uptake in inflamed muscle was not higher than in control muscle and could not be blocked with NS398. Indomethacin caused a slight reduction in muscle uptake.
Despite the apparent correlation between [(11)C]rofecoxib uptake and COX-2 distribution in healthy rats, [(11)C]rofecoxib could not unambiguously detect COX-2 overexpression in two rat models of inflammation.
环氧合酶-2（COX-2）的过表达由炎症刺激引发，但其在多种疾病的发生和发展中也起着重要作用。本研究旨在探究[(11)C]罗非昔布作为一种用于COX-2表达的正电子发射断层扫描（PET）示踪剂的情况。
[(11)C]罗非昔布通过其亚磺酸盐前体的甲基化制备。通过离体生物分布和放射自显影研究[(11)C]罗非昔布在健康大鼠中的脑区分布和特异性结合。还对由单纯疱疹病毒（HSV）经鼻腔感染引起的严重脑炎大鼠进行了脑区分布和PET成像研究。最后，对肌肉注射松节油诱导的无菌性炎症大鼠进行离体生物分布和阻断研究。
[(11)C]罗非昔布在对照动物脑中的摄取与已知的COX-2分布相符。用NS398预处理可显著降低扣带回/额极皮质中的示踪剂摄取，而海马中的降低接近显著水平。离体放射自显影还显示海马和皮质区域对示踪剂有优先摄取，且可被NS398阻断。在HSV感染的动物中，[(11)C]罗非昔布在所有脑区的摄取均适度增加，但不能被吲哚美辛阻断。然而，一些PET图像显示小胶质细胞激活的脑区示踪剂摄取增加。在注射松节油的动物中，[(11)C]罗非昔布在发炎肌肉中的摄取并不高于对照肌肉，且不能被NS398阻断。吲哚美辛使肌肉摄取略有降低。
尽管[(11)C]罗非昔布摄取与健康大鼠中COX-2分布之间存在明显相关性，但[(11)C]罗非昔布在两种大鼠炎症模型中无法明确检测到COX-2的过表达。
