A reduced extracellular serotonin level increases the 5-HT1A PET ligand 18F-MPPF binding in the rat hippocampus.
4,2'-(Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine ((18)F-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 (18)F-MPPF-specific binding. Because endogenous serotonin is significantly decreased in some pathologies, the aim of this study was to determine whether (18)F-MPPF is sensitive to depletion of this neurotransmitter.


METHODS
Using the beta-microprobe, an original beta(+)-sensitive intracerebral probe, and microdialysis, the effect of decreased serotonin on the specific binding of (18)F-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 (18)F-MPPF-specific binding was significantly enhanced after the decrease of extracellular serotonin. These results were confirmed by the (18)F-MPPF distribution in cerebral tissues (hippocampus-to-cerebellum ratio) and by the decrease of the extracellular (18)F-MPPF collected in hippocampal dialysates.


CONCLUSIONS
This study further supports the view that (18)F-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 (18)F-MPPF clinical PET studies.
Zimmer
Luc
L
Centre d'Exploration et de Recherche Médicales par Emission de Positons, Biomedical Cyclotron, Lyon, France. zimmer@cermep.fr
Rbah
Latifa
L
Giacomelli
Fabrice
F
Le Bars
Didier
D
Renaud
Bernard
B
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D006624:Hippocampus / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate; D010879:Piperazines / Q000493:pharmacokinetics*; D011485:Protein Binding; D011725:Pyridines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012016:Reference Values; D012701:Serotonin / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods
D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C408243:p-ethynylphenylalanine; D012701:Serotonin; C416325:4-(2'-methoxyphenyl)-1-(2'-(N-2'-pyridinyl)-p-(18F)fluorobenzamido )ethylpiperazine; D000409:Alanine