Effect of endogenous serotonin on the binding of the 5-HT1A PET ligand 18F-MPPF in the rat hippocampus:: kinetic β measurements combined with microdialysis

By using a combination of an original beta(+)-sensitive intracerebral probe and microdialysis, the effect of increased endogenous serotonin on specific binding of F-18-MPPF [4-(2'-methoxy-phenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido]ethyl]piperazine] to the serotonin-1A (5-HT1A) receptors was investigated in the hippocampus of the anaesthetized rat. Our beta-sensitive probe prototype was sensitive enough to obtain Specific F-18-MPPF time-activity curves in the rodent (hippocampus/cerebellum ratio approximate to 2). The serotonin neuronal release was pharmacologically enhanced using fenfluramine at three different doses (1, 2 and 10 mg/kg intravenous) multiplying by 2-15 the extracellular serotonin in the hippocampus. These extracellular variations of extracellular serotonin resulted in dose-ranging decreases in F-18-MPPF-specific binding in the same rat. Our results showed for the first time that F-18-MPPF binding could be modulated by modifications of extracellular serotonin in the rat hippocampus. These results were confirmed by the enhancement of extracellular radioactivity collected in dialysates after the displacement of F-18-MPPF by fenfluramine. After modelization, F-18-MPPF binding could constitute an interesting radiotracer for positron emission tomography in evaluating the serotonin endogenous levels in limbic areas of the human brain.