Mitochondrial Complex I Deficit in the Olfactory Systems of Age-related Neurodegenerative Monkey Models: A PET Study using 18F-BCPP-EF

Objective: Dysfunction of olfactory bulb area (OBA) is reported in several types of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although pathophysiological mechanisms responsible for changes in olfactory function remain unclear, the quantitative parameters for olfactory function are expected for diagnose of neurodegenerative diseases. We developed a novel probe for positron emission tomography (PET), 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one (18F-BCPP-EF), for quantitative analysis of mitochondrial complex I (MC-I) activity in the living brain. In the present study, the applicability of 18F-BCPP-EF to predict age-related neurodegenerative damage in the monkey brain as an MC-I deficit in the OBA was investigated. Methods: PET measurements with 11C-PiB for amyloid--β (Aβ), 11C-DPA-713 for translocator protein (TSPO) and 18F-BCPP-EF were performed in aged monkeys. The binding specificity of 18F-BCPP-EF to MC-I in the OBA was evaluated with rotenone, a specific MC-1 inhibitor, in young animals. 11C-PiB binding to Aβ and 11C-DPA-713 binding to TSPO were calculated as standard uptake value ratios (SUVRs). The total distribution volume (VT) of 18F-BCPP-EF was calculated using a Logan graphical analysis using metabolite-corrected plasma input function, and correlations between the olfactory VT of 18F-BCPP-EF and SUVRs of 11C-PiB or 11C-DPA-713 in several brain regions were analyzed. Results: Pre-dosing of rotenone resulted in the significant reduction of VT values in all brain regions including the OBA. MC-I activity in the OBA exhibited age-related reduction, which positively correlated with MC-I activity in the olfactory-related and cortical regions. OBA MC-I and TSPO as measured using 11C-DPA-713 were inversely correlated in the olfactory-related and cortical regions, but association between OBA MC-I and Aβ deposition as measured using 11C-PiB were observed only in olfactory-related regions. Conclusion: The present study demonstrated that OBA MC-I activity could be a potential predictive parameter of neurodegenerative damages related Aβ deposition and TSPO/neuroinflammation in the living brain.