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In order to evaluate the capability of 2- tert-butyl-4-chloro-5-{6-[2-(2-[18F]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, to assess neuronal activation, an activation PET study was conducted in the conscious monkey brain with a continuous unilateral vibrotactile stimulation. PET scans with [15O]H2O, [18F]BCPP-EF, or 2-deoxy-2-[18F]fluoroglucose ([18F]FDG) were conducted under: (1) resting conditions; (2) a continuous vibration stimulation; (3) a continuous vibration stimulation after 15-min pre-vibration; and (4) a continuous vibration stimulation after 30-min pre-vibration. The contralateral/ipsilateral ratio (CIR) in the somatosensory cortex showed significant increases in the uptake of [15O]H2O, [18F]BCPP-EF, and [18F]FDG with the vibration stimulation. The longer pre-vibration duration induced significantly lower CIR in regional cerebral blood flow (rCBF) measured using [15O]H2O, whereas it did not affect the CIR in [18F]BCPP-EF or the regional cerebral metabolic rate of glucose (rCMRglc) measured using [18F]FDG 30–60 min after the injection. These results suggest that the [18F]BCPP-EF response in the later phase of scans was not influenced by the increase in rCBF, indicating the capability of [18F]BCPP-EF to detect acute changes in MC-I activity induced by neuronal activation. However, the metabolic shift from glycolysis to oxidation was not observed under the stimulation used here.

18F-BCPP-EF was applied to assess mitochondrial complex I (MC-I) activity in the brains of Parkinson disease model monkeys prepared by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and also presynaptic dopamine parameters. Methods:11C-β-CFT for the dopamine transporter; 11C-3,4-dihydroxy-phenyl-L-alanine (β-11C-L-DOPA), L-6-18F-fluorodopa (18F-FDOPA), or 6-11C-methyl-m-tyrosine (11C-6MemTyr) for dopamine synthesis; or 2-tert-butyl-4-chrolo-5-{6-[2-(2-18F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one (18F-BCPP-EF) for MC-I was intravenously injected into normal and MPTP monkeys in order to analyze their uptake in the striatum. Results: Significant reductions in presynaptic dopamine parameters and MC-I activity were detected in the striatum of MPTP monkeys. Correlations were observed between MC-I activity and dopamine transporter as well as between MC-I activity and dopamine synthesis in the striatum. The order of detectability of impaired MC-I activity was 11C-6MemTyr >> β-11C-L-DOPA > 18F-FDOPA. Conclusion:18F-BCPP-EF has potential as a PET probe for the quantitative imaging of MC-I damage in the living brains of Parkinson disease model monkeys using PET.

We developed three novel positron-emission tomography (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), 2-tert-butyl-4-chloro-5-[6-(4-[(18) F]fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one ([(18)F]BCPP-BF), and 2-tert-butyl-4-chloro-5-{6-[2-(2-[(11)C]methoxy-ethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([(11)C]BCPP-EM), for quantitative imaging of mitochondrial complex 1 (MC-1) activity in vivo. These three PET probes were successfully labeled by nucleophilic [(18)F]fluorination or by [(11)C]methylation of their corresponding precursor with sufficient radioactivity yield, good radiochemical purity, and sufficiently high specific radioactivity for PET measurement. The specificity of these probes for binding to MC-1 was assessed with rotenone, a specific MC-1 inhibitor, by a rat brain slice imaging method in vitro. Rat whole-body imaging by small-animal PET demonstrated that all probes showed high uptake levels in the brain as well as in the heart sufficient to image them clearly. The rank order of uptake levels in the brain and the heart just after injection was as follows: high in [(18)F]BCPP-BF, intermediate in [(11)C]BCPP-EM, and low in [(18) F]BCPP-EF. The kinetics of [(18)F]BCPP-EF and [(11)C]BCPP-EM provided a reversible binding pattern, whereas [(18)F]BCPP-BF showed nonreversible accumulation-type kinetics in the brain and heart. Metabolite analyses indicated that these three compounds were rapidly metabolized in the plasma but relatively stable in the rat brain up to 60 min post-injection. The present study demonstrated that [(18)F]BCPP-EF could be a useful PET probe for quantitative imaging of MC-1 activity in the living brain by PET.

We have reported on the development of a novel PET probe, 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one (18F-BCPP-EF), for quantitative imaging of mitochondrial complex 1 (MC-1) activity in the brain of the living rat. For clinical application in humans, translational research in the monkey was conducted. PET measurements with 18F-BCPP-EF were performed in young and old monkeys (Macaca mulatta) in a conscious state with arterial blood sampling. The binding specificity of 18F-BCPP-EF was evaluated with rotenone, a specific MC-1 inhibitor, in young animals. The binding (total distribution volume, V T) of 18F-BCPP-EF was calculated using Logan graphical analysis, and one-tissue compartment model (1-TC) and two-tissue compartment model (2-TC) analyses using a metabolite-corrected plasma input function. F-BCPP-EF was rapidly taken up into the brain just after intravenous injection, peaked between 10 and 20 min after injection, and was then gradually eliminated. The 2-TC analysis provided a better fit than the 1-TC analysis, and the V T values from the 2-TC analysis correlated well with those from the Logan plot. With predosing with rotenone, 18F-BCPP-EF showed a higher uptake peak in the brain, followed by more rapid elimination thereafter than in the vehicle condition, resulting in significant reductions in 2-TC V T values in all regions. In old animals, the kinetics of 18F-BCPP-EF were slightly slower with lower peak levels than in young animals, resulting age-related reductions in 18F-BCPP-EF binding in all brain regions. The present study demonstrated that 18F-BCPP-EF may be a potential PET probe for quantitative imaging MC-1 activity in the living brain using PET.