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

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 NADH2.S%, 8mg-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 (8mg-protein/ml). These results indicated that the electron transport chain, especially complex I, participate in the reduction mitochondria, and this suggested that Cu-PTSM has the potential to act as a functional imaging agent for diagnosis of the electron transport chain. (author)