Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors.
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.
Musachio
John L
JL
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.
Hong
Jinsoo
J
Ichise
Masanori
M
Seneca
Nicholas
N
Brown
Amira K
AK
Liow
Jeih-San
JS
Halldin
Christer
C
Innis
Robert B
RB
Pike
Victor W
VW
He
Rong
R
Zhou
Jia
J
Kozikowski
Alan P
AP
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
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