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A Reduced Extracellular Serotonin Level Increases the 5-HT_1A PET Ligand ¹⁸F-MPPF Binding in the Rat Hippocampus

¹ Centre d’Exploration et de Recherche Médicales par Émission de Positons, Biomedical Cyclotron, Lyon, France
² Institut National de la Santé et de la Recherche Médicale, Unité 512, Neurochimie et Neuropharmacologie, Lyon 1 University, Lyon, France
³ Cyclotron Research Center, Liège University, Liège, Belgium

4,2'-(Methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-fluorobenzamido]ethylpiperazine (¹⁸F-MPPF) is a radiotracer used in clinical PET studies for the visualization of serotonin-1A (5-HT_1A) receptors. In a previous study, we demonstrated that a rapid enhancement of extracellular serotonin concentrations influences ¹⁸F-MPPF-specific binding. Because endogenous serotonin is significantly decreased in some pathologies, the aim of this study was to determine whether ¹⁸F-MPPF is sensitive to depletion of this neurotransmitter. Methods: Using the ß-microprobe, an original ß⁺-sensitive intracerebral probe, and microdialysis, the effect of decreased serotonin on the specific binding of ¹⁸F-MPPF to 5-HT_1A 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 ¹⁸F-MPPF-specific binding was significantly enhanced after the decrease of extracellular serotonin. These results were confirmed by the ¹⁸F-MPPF distribution in cerebral tissues (hippocampus-to-cerebellum ratio) and by the decrease of the extracellular ¹⁸F-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 ¹⁸F-MPPF clinical PET studies.

Key Words: serotonin receptors • p-ethynylphenylalanine • 4,2'-(methoxyphenyl)-1-[2'-(N-2''-pyridinyl)-p-fluorobenzamido]-ethylpiperazine • serotonin • microdialysis • ß-microprobe

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