Assessment of radioligands for PET imaging of cyclooxygenase-2 in an ischemic neuronal injury model

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• 作者：Bin Ji ; Katsushi Kumata ; Hirotaka Onoe ; Hiroyuki Kaneko ; Ming-Rong Zhang ; Chie Seki ; Maiko Ono ; Miho Shukuri ; Masaki Tokunaga ; Takeharu Minamihisamatsu ; Tetsuya Suhara ; Makoto Higuchi
• 关键词：Autoradiography ; Brain ischemia ; Inflammation ; Molecular imaging ; Positron emission tomography (PET) ; Cyclooxygenase-2 (COX-2)
• 刊名：Brain Research
• 出版年：2013
• 出版时间：2 October, 2013
• 年：2013
• 卷：1533
• 期：Complete
• 页码：152-162
• 全文大小：6114 K

文摘

Cyclooxygenase-2 (COX-2) plays crucial roles in progressive neuronal death in ischemic brain injury. In the present study, we evaluated two radiolabeled COX-2 selective inhibitors, [¹¹C]celecoxib and [¹¹C]rofecoxib, as positron emission tomography (PET) tracers for COX-2 imaging in normal and ischemic mouse brains. We also took advantage of our newly-generated antibody highly selective for mouse COX-2 to prove accumulation of the radioligands in regions enriched with COX-2. In vitro autoradiography demonstrated specific binding of high-concentration [¹¹C]rofecoxib but not [¹¹C]celecoxib to the cerebellum and brain stem of normal brains wherein COX-2 immunoreactivity in neurons was most abundantly observed. Meanwhile, both of these radioligands failed to detect COX-2 expression in PET assays despite their excellent brain permeability. Hypoperfusion-induced ischemia caused marked necrotic neuron death accompanied by gliosis and enhancement of neuronal COX-2 immunoreactivity in the hippocampus. Correspondingly, in vitro autoradiographic binding of [¹¹C]rofecoxib was increased in the injured hippocampus compared to the uninjured contralateral region, but failed in living brains of ischemia model likewise. Our work provides the rationale for monitoring COX-2 as a biomarker reflecting ischemic brain injuries and demonstrates that [¹¹C]rofecoxib, not [¹¹C]celecoxib, is useful for in vitro assays of COX-2, but its affinity would be insufficient for in vivo PET visualization.