title: Iodinated tomoxetine derivatives as selective ligands for serotonin and norepinephrine uptake sites.
abstract: In order to develop selective radioactive ligands for the study of presynaptic monoamine uptake sites, iodinated derivatives of tomoxetine were synthesized and evaluated in radioligand binding assays. Iodotomoxetine derivatives showed high affinity for serotonin (5-HT) uptake sites using a rat cortical membrane preparation. Compound 1R,(R)-(-)-N-methyl-3-(4-iodo-2-methylphenoxy)-3-phenylpropanamine , was the most potent and showed high stereoselectivity for 5-HT uptake sites (Ki, R isomer = 0.65 nM, S isomer = 13.9 nM). Changing the position of the methyl group or eliminating the methyl group at the phenoxy ring resulted in a loss of stereoselectivity. Substitution of the methyl group of tomoxetine with iodine gave the R and S isomers of N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine 4R and 4S. These compounds displayed stereoselectivity for the norepinephrine (NE) (Ki values = 0.24 and 9.35 nM for R and S isomers, respectively). The in vitro binding data suggest that 1R and 4R are potential radioiodinated ligands for pharmacological studies of 5-HT and NE uptake sites, respectively.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia 19104.
authors.forename: S
authors.initials: S
authors.lastname: Chumpradit
authors.forename: M P
authors.initials: MP
authors.lastname: Kung
authors.forename: C
authors.initials: C
authors.lastname: Panyachotipun
authors.forename: V
authors.initials: V
authors.lastname: Prapansiri
authors.forename: C
authors.initials: C
authors.lastname: Foulon
authors.forename: B P
authors.initials: BP
authors.lastname: Brooks
authors.forename: S A
authors.initials: SA
authors.lastname: Szabo
authors.forename: S
authors.initials: S
authors.lastname: Tejani-Butt
authors.forename: A
authors.initials: A
authors.lastname: Frazer
authors.forename: H F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001665:Binding Sites / Q000187:drug effects; D007457:Iodine Radioisotopes; D008024:Ligands; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D011437:Propylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D014179:Neurotransmitter Uptake Inhibitors; D011437:Propylamines; D012701:Serotonin; D000069445:Atomoxetine Hydrochloride; D009638:Norepinephrine