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 (rCMRO 2 ), 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 ( V T ) 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 rCMRO 2 , the V T values of 18 F-BCPP-EF provided better correlation with rCMRO 2 than with rCBF. In the inflammatory regions (region of interest, ROI PBR ) of the ischemic hemisphere detected with 11 C-PBR28, higher 18 F-FDG uptake and lower V T of 18 F-BCPP-EF, 11 C-FMZ, and rCMRO 2 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.