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.
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.


CONCLUSIONS
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.
Andrée
Bengt
B
Psychiatry Section, Department of Clinical Neuroscience, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. bengt.andree@ks.se
Halldin
Christer
C
Pike
Victor W
VW
Gunn
Roger N
RN
Olsson
Hans
H
Farde
Lars
L
D000328:Adult; D001810:Blood Volume; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism; D002560:Cerebrovascular Circulation; D006801:Humans; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011985:Receptors, Serotonin / Q000032:analysis* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
D002250:Carbon Radioisotopes; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C112544:desmethyl-WAY 100635; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide