A reduced extracellular serotonin level increases the 5-HT1A PET ligand F-18-MPPF binding in the rat hippocampus

4,2'-(Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine (F-18-MPPF) is a radiotracer used in clinical PET studies for the visualization of serotonin-1A (5-HT1A) receptors. In a previous study, we demonstrated that a rapid enhancement of extracellular serotonin concentrations influences F-18-MPPF-specific binding. Because endogenous serotonin is significantly decreased in some pathologies, the aim of this study was to determine whether F-18-MPPF is sensitive to depletion of this neurotransmitter. Methods: Using the beta-microprobe, an original beta(+)-sensitive intracerebral probe, and micro-dialysis, the effect of decreased serotonin on the specific binding of F-18-MPPF to 5-HT1A receptors was investigated in the hippocampus of the anesthetized rat. Extracellular serotonin was pharmacologically decreased in the hippocampus after a single injection of p-ethynylphenylalanine ([p-EPA] 5 mg/kg), a new tryptophan hydroxylase inhibitor. Results: Our results showed that the F-18-MPPF-specific binding was significantly enhanced after the decrease of extracellular serotonin. These results were confirmed by the F-18-MPPF distribution in cerebral tissues (hippocampus-to-cerebellum ratio) and by the decrease of the extracellular F-18-MPPF collected in hippocampal dialysates. Conclusion: This study further supports the view that 18F-MPPF binding potential is increased in the hippocampus if the endogenous serotonin is pharmacologically decreased after a p-EPA injection. This phenomenon will be an additional factor in the interpretation of the results from F-18-MPPF clinical PET studies.