The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo.

Abstract Purpose We aimed to evaluate radiofluorination at the pyridinyl -6 position of the selective 5-HT 1A receptor antagonist, WAY-100635 [ N -(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))- N -(2-pyridinyl)cyclohexanecarboxamide)], on 5-HT 1A receptor radioligand behavior in vivo . Procedures The pyridinyl- 6 [ 18 F]fluoro derivative of WAY-100635 ([ 18 F]6FPWAY) was obtained by direct nucleophilic substitution with [ 18 F]fluoride ion in a bromo precursor. After intravenous injection of [ 18 F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into brain regions was assessed with positron emission tomography (PET) and blood samples analyzed by high performance liquid chromatography (HPLC) for parent radioligand and radioactive metabolites. The experiment was repeated after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5-HT 1A receptors. Results After intravenous injection of [ 18 F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of injected dose at 7.5 min. Uptake was highest in 5-HT 1A receptor-rich regions. Pretreatment with WAY-100635 reduced uptake in these regions to near the levels in receptor-devoid cerebellum. [ 18 F]6FPWAY was rapidly metabolized in vivo, as evidenced by the rapid appearance of radioactive metabolites in plasma. Conclusion [ 18 F]6FPWAY is selective and moderately useful for imaging brain 5-HT 1A receptors in vivo. The pyridinyl -6 position is resistant to defluorination and may be an attractive site for the 18 F-labeling of 6FPWAY analogs that resist hydrolysis.