Synthesis and in vivo evaluation of [O-methyl- ¹¹C] N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl) benzenesulfonamide as an imaging probe for 5-HT ₆ receptors

The serotonin receptor 6 (5-HT ₆) is implicated in the pathophysiology of cognitive diseases, schizophrenia, anxiety and obesity and in vivo studies of this receptor would be of value for studying the pathophysiology of these disorders. Therefore, N-[3,5-dichloro-2-(methoxy) phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB399885), a selective and high affinity (pK _i = 9.11) 5-HT ₆ antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue with [ ¹¹C]MeOTf in order to determine the suitability of [ ¹¹C]SB399885 to quantify 5-HT ₆R in living brain using PET. Desmethyl-SB399885 was prepared, starting from 1-(2-methoxyphenyl) piperazine hydrochloride, in excellent yield. The yield obtained for radiolabeling of [ ¹¹C]SB399885 was 30 ± 5% (EOS) and the total synthesis time was 30 min at EOB. PET studies with [ ¹¹C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [ ¹¹C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [ ¹¹C]SB399885 compared to known 5-HT ₆R distribution limits its usefulness for the in vivo quantification of 5-HT ₆R with PET.