PET imaging of ischemia-induced impairment of mitochondrial complex i function in monkey brain

Abstract

To assess the capability of 18F-2-tert-butyl-4-chloro-5-{6-[2- (2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ( 18F-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 15O-gases for regional cerebral blood flow (rCBF) and regional cerebral metabolism of oxygen (rCMRO2), and 18F-BCPP-EF for MC-I with arterial blood sampling. On Day-8, the additional PET scans conducted with 11C-flumazenil ( 11C-FMZ) for central-type benzodiazepine receptors, 11C-PBR28 for translocator protein, and 18F-fluoro-2- deoxy-D-glucose (18F-FDG) for regional cerebral metabolic rate of glucose (rCMRglc). The total distribution volume (VT) values of 18F-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 18F-BCPP-EF provided better correlation with rCMRO2 than with rCBF. In the inflammatory regions (region of interest, ROIPBR) of the ischemic hemisphere detected with 11C-PBR28, higher 18F-FDG uptake and lower VT of 18F-BCPP-EF, 11C-FMZ, and rCMRO2 than those in normal contralateral hemisphere were observed. These results strongly suggested that 18F-BCPP-EF could discriminate the neuronal damaged areas with neuroinflammation, where 18F-FDG could not owing to its high uptake into the activated microglia. © 2014 ISCBFM All rights reserved.