Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635

Radioligands that are specific for the serotonin 5-HT(1A) receptor will be useful in characterizing the physiological action of this receptor subtype. With radioligands of varying pharmacokinetic properties, investigators can measure not only receptor density, but also the effect of endogenous serotonin concentration. To this end, three additional fluorinated analogs of WAY 100635 were prepared and evaluated as 5-HT(1A) receptor ligands of varying pharmacokinetic properties based on our previous studies. These four compounds are cis-4-fluoro-, trans-4-fluoro-, cis-3-fluoro-, and trans-3-fluoro-N-{2-4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamides (FCWAYs). All four compounds were characterized and radiolabeled with fluorine-18, a 109.7 min half-life radionuclide used in positron emission tomography. We then determined in vitro inhibition constants at the 5-HT(1A) receptor; in vitro metabolic profile, using rat hepatocytes and liquid chromatography/mass spectroscopy (LC/MS); and the rate of defluorination and hippocampus to cerebellum ratio ex vivo. This led to the conclusion that high affinity 4-trans-F-18 FCWAY had the best properties for measuring receptor density given its high hippocampus to cerebellum ratio and 3-cis-F-18 FCWAY had the best properties for measuring dynamic change in receptors, with lower affinity and faster pharmacokinetics.