Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM), a metal complex with selective NADH-dependent reduction by complex I in brain mitochondria: a potential radiopharmaceutical for mitochondria-functional imaging with positron emission tomography (PET).
The reductive retention mechanism of copper(II)-pyruvaldehyde-bis (N4-methylthiosemicarbazone) (Cu-PTSM), a generator-produced positron-emitting 62Cu-labeled radiopharmaceutical, was studied with non-radioactive and radioactive copper. Changes in the chemical form of Cu-PTSM were detected by electron spin resonance spectrometry (ESR) with cold copper. The effects of electron transport chain inhibitors on the reduction of Cu-PTSM were also examined. Rotenone and antimycin A activated the reduction of Cu-PTSM in the brain mitochondria by 1.6- and 1.4-fold, respectively, compared with untreated controls, while thenoyltrifluoroacetone (TTFA) had no effect on the reduction. These results were confirmed with radioactive copper. Furthermore, this reduction of Cu-PTSM was dependent on the protein concentration of mouse brain submitochondrial particle (SMP) with 1 mM NADH (0 mg-protein/ml: 1.8 +/- 2.5%, 8 mg-protein/ml: 69.0 +/- 5.5%, each value was % of reduced Cu). Similarly, this reduction depended on NADH concentration at a fixed concentration of SMP (8 mg-protein/ml). These results indicated that the electron transport chain, especially complex I, participated in the reduction of Cu-PTSM in brain mitochondria, and this suggested that Cu-PTSM has the potential to act as a functional imaging agent for diagnosis of the electron transport chain.
Department of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
H
H
Taniuchi
Y
Y
Fujibayashi
H
H
Okazawa
Y
Y
Yonekura
J
J
Konishi
A
A
Yokoyama
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000000981:diagnostic imaging* / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism; D010084:Oxidation-Reduction; D013367:Submitochondrial Particles / Q000378:metabolism; D013882:Thiosemicarbazones / Q000378:metabolism; D014055:Tomography, Emission-Computed
D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D009243:NAD; C052629:copper pyruvaldehyde bis(N(4)-methylthiosemicarbazone) complex; D016660:NAD(P)H Dehydrogenase (Quinone)