title: Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors.
abstract: 11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346, 10 Center Drive, Bethesda, MD 20892-1003, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Musachio
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Hong
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichise
authors.forename: Nicholas
authors.initials: N
authors.lastname: Seneca
authors.forename: Amira K
authors.initials: AK
authors.lastname: Brown
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000588:Amines / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000431:Ethanol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008253:Macaca mulatta; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D049268:Positron-Emission Tomography
chemical_list: D000588:Amines; D008024:Ligands; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010880:Piperidines; C466798:methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate; C512287:trans-2-(((3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl)methylsulfanyl)-1-(piperidin-1-yl)ethanone; C512288:trans-2-(((3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl)methylsulfanyl)ethanol; D000431:Ethanol