title: Assessment of radioligands for PET imaging of cyclooxygenase-2 in an ischemic neuronal injury model.
abstract: 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.
authors: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, Chiba 263-8555, Japan.
authors: Bin
authors: B
authors: Ji
authors: Katsushi
authors: K
authors: Kumata
authors: Hirotaka
authors: H
authors: Onoe
authors: Hiroyuki
authors: H
authors: Kaneko
authors: Ming-Rong
authors: MR
authors: Zhang
authors: Chie
authors: C
authors: Seki
authors: Maiko
authors: M
authors: Ono
authors: Miho
authors: M
authors: Shukuri
authors: Masaki
authors: M
authors: Tokunaga
authors: Takeharu
authors: T
authors: Minamihisamatsu
authors: Tetsuya
authors: T
authors: Suhara
authors: Makoto
authors: M
authors: Higuchi
mesh_terms: D000818:Animals; D000906:Antibodies; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000201:enzymology; D002250:Carbon Radioisotopes; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography / Q000379:methods; D011720:Pyrazoles / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D013450:Sulfones / Q000008:administration & dosage*
chemical_list: D000906:Antibodies; D002250:Carbon Radioisotopes; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib
keywords: Autoradiography; Brain ischemia; Cyclooxygenase-2 (COX-2); Inflammation; Molecular imaging; Positron emission tomography (PET)