Synthesis and in vivo evaluation of [O-methyl- 11 C] N-[3,5-dichloro-2- (methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide as an imaging probe for 5-HT 6 receptors Fei Liu a , Vattoly J. Majo b , Jaya Prabhakaran b , Matthew S. Milak b,c , J. John Mann b,c,d , Ramin V. Parsey b,c , J.S. Dileep Kumar b,c,⇑ a Division of Substance Abuse, Department of Psychiatry, Columbia University Medical Center, New York, USA b Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University Medical Center, New York, USA c New York State Psychiatric Institute, 1051 Riverside Drive, Box #42, New York, NY 10032, USA d Department of Radiology, Columbia University, Medical Center, USA article info Article history: Received 14 April 2011 Revised 10 June 2011 Accepted 16 June 2011 Available online 19 July 2011 Keywords: PET Brain Carbon-11 Radiotracer Serotonin abstract The serotonin receptor 6 (5-HT 6 ) is implicated in the pathophysiology of cognitive diseases, schizophre- nia, 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 30 min at EOB. PET studies with [ 11 C]SB399885 in baboon showed fast uptake fol- lowed 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. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction The 5-hydroxytryptamine 6 receptor (5-HT 6 R) is the most re- cently identified mammalian 5-hydroxytryptamine (5-HT) recep- tor. 1–3 In the central nervous system (CNS), an important role of the 5-HT 6 R has been confirmed in cognitive functions, seizures, feeding behavior, anxiety, epilepsy, dementia psychosis, addiction and affective disorder. 4–11 In vitro studies using 5-HT 6 R antago- nists revealed that 5-HT 6 R are localized almost exclusively in the CNS. 12 Several human postmortem studies demonstrated that the distribution of 5-HT 6 R appear to be similar to that in rats, with the highest 5-HT 6 R densities found in the striatum, nucleus accum- bens and olfactory tubercle, moderate densities in the amygdala, hypothalamus, thalamus, hippocampus and cerebral cortex, but none have been detected in the periphery. 13–15 In vivo imaging of 5-HT 6 R with positron emission tomography (PET) may facilitate the understanding of the pathophysiology of diseases associated with the changes in this receptor and allow occupancy studies to assist new drug development. However, the utility of the currently developed radiotracers for in vivo imaging of 5-HT 6 R are limited in scope. The [ 18 F]-labeled 5-HT 6 ligand [ 18 F]12ST05 did not reveal any specific binding to the 5-HT 6 R in the rats and cat, although the radioligand showed excellent brain penetration. 16 [ 11 C]GSK224558, an undisclosed Glaxo Smithkline’s compound rapidly enters the porcine brain, but undergoes rapid metabolism with peak regional tissue concentrations reached at approximately 20 min post-injection. The research group at Glaxo Smithkline also reported the synthesis and evaluation of a new 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2011.06.090 ⇑ Corresponding author. Tel.: +1 (212) 543 1163; fax: +1 (212) 543 1054. E-mail address: dk2038@columbia.edu (J.S. Dileep Kumar). N S O N 18 F [ 18 F]12ST05 O O N N N S F 11 CH 3 O O [ 11 C]GSK215083 Figure 1. 5-HT 6 PET tracers available in literature. Bioorganic & Medicinal Chemistry 19 (2011) 5255–5259 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc