Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man

The serotonin 5-hydroxytryptamine-1A (5-HT1A) receptor subtype is of central interest in research on the pathophysiology and treatment of psychiatric disorders. Carbonyl-11 C-WAY-100635 is a new radioligand that, in PET experiments, provides high-contrast delineation of brain regions that are rich in 5-HT1A receptors. The aim of this PET study was to examine the prospects for quantitation of carbonyl-11C-WAY-100635 binding to 5-HT1A receptors in the human brain.

A PET examination was performed in each of six healthy male subjects after intravenous injection of carbonyl-11C-WAY-100635. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. The metabolite-corrected arterial input function was used in a kinetic three-compartment analysis, and the cerebellum was used as reference region in linear graphical and transient equilibrium analyses.

The highest radioactivity concentration was observed in the neocortex and the raphe nuclei, whereas radioactivity was low in the cerebellum. The time-activity curves were well-described by a three-compartment model for all regions. Uptake in the cerebellum could not be described by a two-compartment model. The transient equilibrium and linear graphical analyses, which are both dependent on the cerebellum as the reference region, gave lower binding potential values than did the kinetic analysis. The metabolism was rapid, and the fraction of unchanged carbonyl-11C-WAY-100635 was <10% 10 min after injection in all human subjects. The major radioactive metabolites were unidentified polar components. One metabolite comigrated with reference cyclohexanecarboxylic acid, and another comigrated with reference desmethyl-WAY-100635.

The suitability of carbonyl-11C-WAY-100635 for research on central 5-HT1A receptors in neuropsychiatric disorders was supported by the observation that the high signals in the neocortex and raphe nuclei can be described using a kinetic analysis with a metabolite-corrected arterial input function. It cannot be excluded that kinetically distinguishable nonspecific binding or the formation of a metabolite that passes the blood-brain barrier may represent measurable components of the low radioactivity in the cerebellum. Simplified quantitative methods, using the relatively low radioactivity in the cerebellum as reference, should accordingly be applied with some caution until the biochemical nature of the radioactivity is better understood and the reliability of these approaches has been confirmed in larger samples.