PET imaging of ischemia-induced impairment of mitochondrial complex I function in monkey brain.
To assess the capability of (18)F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ((18)F-BCPP-EF), a novel positron emission tomography (PET) probe for mitochondrial complex I (MC-I) activity, as a specific marker of ischemia-induced neuronal death without being disturbed by inflammation, translational research was conducted using an animal PET in ischemic brains of Cynomolgus monkeys (Macaca fascicularis). Focal ischemia was induced by the right middle cerebral artery occlusion for 3 hours, then PET scans were conducted at Day-7 with (15)O-gases for regional cerebral blood flow (rCBF) and regional cerebral metabolism of oxygen (rCMRO₂), and (18)F-BCPP-EF for MC-I with arterial blood sampling. On Day-8, the additional PET scans conducted with (11)C-flumazenil ((11)C-FMZ) for central-type benzodiazepine receptors, (11)C-PBR28 for translocator protein, and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) for regional cerebral metabolic rate of glucose (rCMRglc). The total distribution volume (VT) values of (18)F-BCPP-EF showed the significant reduction in MC-I activity in the damaged area at Day-7. When correlated with rCBF and rCMRO₂, the VT values of (18)F-BCPP-EF provided better correlation with rCMRO₂ than with rCBF. In the inflammatory regions (region of interest, ROIPBR) of the ischemic hemisphere detected with (11)C-PBR28, higher (18)F-FDG uptake and lower VT of (18)F-BCPP-EF, (11)C-FMZ, and rCMRO2 than those in normal contralateral hemisphere were observed. These results strongly suggested that (18)F-BCPP-EF could discriminate the neuronal damaged areas with neuroinflammation, where (18)F-FDG could not owing to its high uptake into the activated microglia.
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Hideo
H
Tsukada
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Hiroyuki
H
Ohba
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Shingo
S
Nishiyama
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Masakatsu
M
Kanazawa
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Takeharu
T
Kakiuchi
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan.
Norihiro
N
Harada
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016923:Cell Death; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D011724:Pyridazines; D011725:Pyridines
C588084:2-tert-butyl-4-chloro-5-(6-(2-(2-fluoroethoxy)ethoxy)pyridin-3-ylmethoxy)-2H-pyridazin-3-one; D015415:Biomarkers; D011724:Pyridazines; D011725:Pyridines; D042967:Electron Transport Complex I