Novel PET Probes 18F-BCPP-EF and 18F-BCPP-BF for Mitochondrial Complex I: a PET Study in Comparison with 18F-BMS-747158-02 in Rat Brain

Unlabelled: We developed novel PET probes, 2-tert-butyl-4-chloro-5-{6-[2-(2-(18)F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ((18)F-BCPP-EF) and 2-tert-butyl-4-chloro-5-[6-(4-(18)F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one ((18)F-BCPP-BF), for quantitative imaging of mitochondrial complex I (MC-I) activity in the brain and preliminarily evaluated their properties in comparison with (18)F-BMS-747158-02 ((18)F-BMS).

Methods: The affinity of (18)F-BCPP-EF, (18)F-BCPP-BF, and (18)F-BMS to MC-I was analyzed using in vitro binding assays with (3)H-dihydrorotenone and bovine cardiomyocyte submitochondrial particles. (18)F-BCPP-EF, (18)F-BCPP-BF, or (18)F-BMS was intravenously injected into rats, and the uptake (standardized uptake value) in each organ was determined by dissection method. The effects of rotenone, a specific MC-I inhibitor, on the uptake of each probe were assessed by whole-body PET imaging in rats. Ischemic brain model rats were imaged using (18)F-BCPP-EF.

Results: The rank order of affinity to MC-I was (18)F-BCPP-BF > (18)F-BMS > (18)F-BCPP-EF. The uptake of (18)F-BCPP-EF and (18)F-BMS was high in the heart, intermediate in brain, and low in muscle and bone 60 min after the injection. (18)F-BCPP-BF provided increasing bone uptake with time after the injection. The uptake of (18)F-BCPP-EF and (18)F-BMS into the brain and heart was significantly decreased by preadministration of rotenone; however, the reduction degree of (18)F-BCPP-EF was more pronounced than that of (18)F-BMS. Rotenone did not affect (18)F-BCPP-BF uptake in either the brain or the heart. (18)F-BCPP-EF imaged the cortical ischemic neuronal damage without any disturbance by microglial activation even on day 7 when (18)F-FDG showed high uptake in the damaged area.

Conclusion: The present study demonstrated that (18)F-BCPP-EF could be a potential PET probe for quantitative imaging of MC-I activity and its ischemic damage in the living brain with PET.