title: 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-HT6 receptors.
abstract: 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 [(11)C]MeOTf in order to determine the suitability of [(11)C]SB399885 to quantify 5-HT(6)R 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 [(11)C]SB399885 was 30±5% (EOS) and the total synthesis time was 30min at EOB. PET studies with [(11)C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [(11)C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [(11)C]SB399885 compared to known 5-HT(6)R distribution limits its usefulness for the in vivo quantification of 5-HT(6)R with PET.
authors.affiliation: Division of Substance Abuse, Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Milak
authors.forename: J
authors.initials: J
authors.lastname: John Mann
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D010215:Papio; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D000096926:Benzenesulfonamides
chemical_list: D002250:Carbon Radioisotopes; D010879:Piperazines; D019275:Radiopharmaceuticals; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C503990:SB 399885; C097216:serotonin 6 receptor