Fenfluramine evokes 5‐HT2A receptor‐mediated responses but does not displace [11C]MDL 100907: Small animal PET and gene expression studies

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Abstract
The in vivo binding of the 5‐HT2A receptor‐selective positron emission tomography (PET) ligand [11C]MDL 100907 and its sensitivity to endogenous 5‐HT were quantified in rat brain using quad‐HIDAC, a novel high‐resolution PET camera for small animals. Specific binding of [11C]MDL 100907, estimated using volume of interest (VOI) to cerebellum ratios, corresponded well with both the known distribution of 5‐HT2A receptors and tissue:cerebellum ratios obtained using ex vivo dissection. Specific binding was blocked by predosing with either nonradioactive MDL 100907 (0.2 or 0.4 mg/kg i.v.) or the 5‐HT2A/2C receptor antagonist ketanserin (2 mg/kg i.v.), but was unaffected in rats pretreated with the 5‐HT releasing agent, fenfluramine (10 mg/kg i.p.). In parallel studies, the same dose of fenfluramine was shown to be sufficient to cause an increase in the expression of the immediate early genes (IEG) c‐fos and Arc mRNA in cortical regions with high 5‐HT2A receptor density. This increase was blocked by MDL 100907 (0.2 mg/kg i.v.), confirming a 5‐HT2A receptor‐mediated effect. The results demonstrate that PET with [11C]MDL 100907 is insensitive to an increased concentration of synaptic 5‐HT, implying that the ligand can be used clinically to monitor 5‐HT2A receptor function or dysfunction in disease or during therapy, without the need to consider concomitant changes in neurotransmitter concentration. Synapse 50:251–260, 2003.