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.
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.


CONCLUSIONS
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.
Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan.
Hideo
H
Tsukada
Shingo
S
Nishiyama
Dai
D
Fukumoto
Masakatsu
M
Kanazawa
Norihiro
N
Harada
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002417:Cattle; D042967:Electron Transport Complex I / Q000378:metabolism*; D008297:Male; D049268:Positron-Emission Tomography; D011724:Pyridazines; D011725:Pyridines; D051381:Rats; D017207:Rats, Sprague-Dawley
C588084:2-tert-butyl-4-chloro-5-(6-(2-(2-fluoroethoxy)ethoxy)pyridin-3-ylmethoxy)-2H-pyridazin-3-one; C588085:2-tert-butyl-4-chloro-5-(6-(4-fluorobutoxy)pyridin-3-ylmethoxy)-2H-pyridazin-3-one; C525920:BMS 747158-02; D011724:Pyridazines; D011725:Pyridines; C062482:pyridazine; D042967:Electron Transport Complex I
18F-BCPP-EF; PET; brain; ischemia; mitochondria complex I