title: Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-I activity.
abstract: The development of a diagnostic technology that can accurately determine the pathological progression of ischemic stroke and evaluate the therapeutic effects of cerebroprotective agents has been desired. We previously developed a novel PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-(18)F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([(18)F]BCPP-EF) for detecting activity of mitochondrial complex I (MC-I). This probe was shown to visualize neuronal damage in the living brain of rodent and primate models of neurodegenerative diseases. In the present study, [(18)F]BCPP-EF was applied to evaluate the therapeutic effects of a neuroprotectant, liposomal FK506 (FK506-liposomes), on cerebral ischemia/reperfusion (I/R) injury in transient middle cerebral artery occlusion rats. The PET imaging using [(18)F]BCPP-EF showed a prominent reduction in the MC-I activity in the ischemic brain hemisphere. Treatment with FK506-liposomes remarkably increased the uptake of [(18)F]BCPP-EF in the ischemic side corresponding to the improvement of blood flow disorders and motor function deficits throughout the 7 days after I/R. Additionally, the PET scan could diagnose the extent of the brain damage accurately and showed the neuroprotective effect of FK506-liposomes at Day 7, at which 2, 3, 5-triphenyltetrazolium chloride staining couldn't visualize them. Our study demonstrated that the PET technology using [(18)F]BCPP-EF has a potent capacity to evaluate the therapeutic effect of drug candidates in living brain.
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.|Japan Society of the Promotion of Science (JSPS), 5-3-1 Kojimachi, Chiyoda-ku, Tokyo 102-0083, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukuta
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koide
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kiyokawa
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hirakuchi, Hamakita-ku, Hamamatsu, Shizuoka 434-8601, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Harada
authors.affiliation: PET Center, Central Research Laboratory, Hamamatsu Photonics K.K., Hirakuchi, Hamakita-ku, Hamamatsu, Shizuoka 434-8601, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.affiliation: Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D002544:Cerebral Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000517:prevention & control*; D042967:Electron Transport Complex I / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery; D008081:Liposomes; D008297:Male; D009043:Motor Activity; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000008:administration & dosage
chemical_list: D008081:Liposomes; D018696:Neuroprotective Agents; D042967:Electron Transport Complex I; D016559:Tacrolimus