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Clinical Investigations |
1 Psychiatry Section, Department of Clinical Neuroscience, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
2 MRC Cyclotron Unit, Hammersmith Hospital, Imperial College School of Medicine, London, United Kingdom
5-Hydroxytryptamine (serotonin)-1A (5-HT1A) receptors are of key interest in research on the pathophysiology and treatment of psychiatric disorders. The PET radioligand [carbonyl-11C]WAY-100635 (11C-WAY), where WAY-100635 is 3H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexane-carboxamide, is commonly used for quantitation of 5-HT1A receptors in the human brain. The aim of this PET study was to compare 11C-WAY with the putative metabolite and selective radioligand [carbonyl-11C]desmethyl-WAY-100635 (11C-DWAY). Methods: A PET examination was performed on each of 5 healthy male volunteers after intravenous injection of 11C-WAY and 11C-DWAY on separate occasions. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. The plasma metabolite–corrected input function was used in a kinetic compartment analysis. The simplified reference tissue model and peak equilibrium method, using the cerebellum as reference region, was applied for comparison of data. Results: For both radioligands, the highest radioactivity was observed in the neocortex and the raphe nuclei, whereas radioactivity was low in the cerebellum. The regional binding potentials were similar for the 2 radioligands. The brain uptake was more than 2-fold higher for 11C-DWAY than for 11C-WAY, in part because of higher delivery (first-order rate constant K1, 0.38 vs. 0.16). The time–activity curves were well described by a 3-compartment model for all regions, whereas uptake in the cerebellum could not be described by a 2-compartment model, supporting the existence of kinetically distinguishable nonspecific binding in the cerebellum or radioactive metabolites in the brain for both radioligands. Both radioligands were rapidly metabolized, and <10% of the radioactivity in plasma represented unchanged 11C-WAY or 11C-DWAY at 10 min after injection. The metabolic pattern was similar for both radioligands, with the formation of radiolabeled cyclohexanecarboxylic acid and more polar components. For 11C-WAY, small amounts of an additional labeled metabolite comigrated with reference desmethyl-WAY-100635. Conclusion: The advantages of 11C-DWAY over 11C-WAY for research on central 5-HT1A receptors is supported by a significantly higher radioactivity signal at equipotent doses, providing improved imaging statistics and advantages in biomathematic modeling and the preclusion of 11C-DWAY as a metabolite interfering with PET measurements.
Key Words: brain • human • PET • 5-hydroxytryptamine-1A receptors • WAY-100635 • desmethyl-WAY-100635 • kinetic modeling
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