title: [11C]PK11195 PET imaging of spinal glial activation after nerve injury in rats.
abstract: The role of glial activation has been implicated in the development and persistence of neuropathic pain after nerve injury by recent studies. PK11195 binding to the translocator protein 18kDa (TSPO) has been shown to be enhanced in activated microglia. This study was designed to assess PK11195 imaging in spinal microglia during activation after nerve injury. The development of neuropathic pain was induced by partial sciatic nerve ligation (PSL). PSL rats on days 7 and 14 after nerve injury were subjected to imaging with a small-animal positron emission tomography/computed tomography (PET/CT) scanner using [(11)C]PK11195 to detect spinal microglial activation by means of noninvasive in vivo imaging. Spinal [(3)H]PK11195 autoradiography was performed to confirm the results of [(11)C]PK11195 PET in PSL rats. Quantitative RT-PCR of CD11b and GFAP mRNA, and the immunohistochemistry of Iba1 and GFAP were investigated to detect activated microglia and astrocytes. Mechanical allodynia was observed in the ipsilateral paw of PSL rats from day 3 after nerve injury and stably persisted from days 7 to 14. PET/CT fusion images clearly showed large amounts of accumulation of [(11)C]PK11195 in the lumbar spinal cord on days 7 and 14 after nerve injury. [(11)C]PK11195 enhanced images were restricted to the L3-L6 area of the spinal cord. The standardized uptake value (SUV) of [(11)C]PK11195 was significantly increased in the lumbar spinal cord compared to that of the thoracic region. Increased specific binding of [(11)C]PK11195 to TSPO in the spinal cord of PSL rats was confirmed by competition studies using unlabeled (R, S)-PK11195. Increased [(3)H]PK11195 binding was also observed in the ipsilateral dorsal horn of the L3-L6 spinal cord on days 7 and 14 after nerve injury. CD11b mRNA and Iba1 immunoreactive cells increased significantly on days 7 and 14 after nerve injury by PSL. However, changes in GFAP mRNA and immunoreactivity were slight in the ipsilateral side of PSL rats. In the present study, we showed that glial activation could be quantitatively imaged in the spinal cord of neuropathic pain rats using [(11)C]PK11195 PET, suggesting that high resolution PET using TSPO-specific radioligands might be useful for imaging to assess the role of glial activation, including neuroinflammatory processes, in neuropathic pain patients.
authors.affiliation: Department of Innovative Drug Discovery Technologies, Innovative Drug Discovery Research Laboratories, Shionogi & Co, Ltd, Osaka, Japan. natsumi.imamoto@shionogi.co.jp
authors.forename: Natsumi
authors.initials: N
authors.lastname: Imamoto
authors.forename: Sotaro
authors.initials: S
authors.lastname: Momosaki
authors.forename: Masahide
authors.initials: M
authors.lastname: Fujita
authors.forename: Shigeki
authors.initials: S
authors.lastname: Omachi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamato
authors.forename: Mika
authors.initials: M
authors.lastname: Kimura
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanegawa
authors.forename: Shunji
authors.initials: S
authors.lastname: Shinohara
authors.forename: Kohji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008297:Male; D017628:Microglia / Q000000981:diagnostic imaging / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D015203:Reproducibility of Results; D020426:Sciatic Neuropathy / Q000000981:diagnostic imaging / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D007546:Isoquinolines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C037850:PK 11195