CU-PYRUVALDEHYDE-BIS(N-4-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 II)-pyruvaldehyde-bis(N-4-methylt hiosemicarbazone) (Cu-PTSM), a generator-produced positron-emitting Cu -62-labeled radiopharmaceutical, was studied with non-radioactive and radioactive copper. Changes in the chemical form of Cu-PTSM were detec ted by electron spin resonance spectrometry (ESR) with cold copper. Th e effects of electron transport chain inhibitors on the reduction of C u-PTSM were also examined. Rotenone and antimycin A activated the redu ction of Cu-PTSM in the brain mitochondria by 1.6- and 1.4-fold, respe ctively, compared with untreated controls, while thenoyltrifluoroaceto ne (TTFA) had no effect on the reduction. These results were confirmed with radioactive copper. Furthermore, this reduction of Cu-PTSM was d ependent on the protein concentration of mouse brain submitochondrial particle (SMP) with 1 mM NADH (0 mg-protein/ml: 1.8+/-2.5%, 8 mg-prote in/ml: 69.0+/-5.5%, each value was % of reduced Cu). Similarly, this r eduction depended on NADH concentration at a fixed concentration of SM P (8 mg-protein/ml). These results indicated that the electron transpo rt chain, especially complex I, participated in the reduction of Cu-PT SM in brain mitochondria, and this suggested that Cu-PTSM has the pote ntial to act as a functional imaging agent for diagnosis of the electr on transport chain.