The PET radioligand (carbonyl-(11)C)desmethyl-WAY-100635 binds to 5-HT(1A) receptors and provides a higher radioactive signal than (carbonyl-(11)C)WAY-100635 in the human brain.

摘要

5-Hydroxytryptamine (serotonin)-1A (5-HT(1A)) receptors are of key interest in research on the pathophysiology and treatment of psychiatric disorders. The PET radioligand [carbonyl-(11)C]WAY-100635 ((11)C-WAY), where WAY-100635 is (3)H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexane-carboxamide, is commonly used for quantitation of 5-HT(1A) receptors in the human brain. The aim of this PET study was to compare (11)C-WAY with the putative metabolite and selective radioligand [carbonyl-(11)C]desmethyl-WAY-100635 ((11)C-DWAY). METHODS: A PET examination was performed on each of 5 healthy male volunteers after intravenous injection of (11)C-WAY and (11)C-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 (11)C-DWAY than for (11)C-WAY, in part because of higher delivery (first-order rate constant K(1), 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 (11)C-WAY or (11)C-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 (11)C-WAY, small amounts of an additional labeled metabolite comigrated with reference desmethyl-WAY-100635. CONCLUSION: The advantages of (11)C-DWAY over (11)C-WAY for research on central 5-HT(1A) 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 (11)C-DWAY as a metabolite interfering with PET measurements.