title: Comparison of (R)-[3H]tomoxetine and (R/S)-[3H]nisoxetine binding in rat brain.
abstract: (R)-[3H]Tomoxetine is a radioligand that binds to the norepinephrine (NE) uptake site with high affinity but also binds to a second, lower-affinity site. The goal of the present study was to identify the nature of this low-affinity site by comparing the binding properties of (R)-[3H]tomoxetine with those of (R/S)-[3H]nisoxetine, a highly selective ligand for the NE uptake site. In homogenate binding studies, both radioligands bound to the NE uptake site with high affinity, whereas (R)-[3H]tomoxetine also bound to a second, lower-affinity site. The autoradiographic distribution of binding sites for both radioligands is consistent with the known distribution of NE-containing neurons. However, low levels of (R)-[3H]tomoxetine binding were seen in the caudate-putamen, globus pallidus, olfactory tubercle, and zona reticulata of the substantia nigra, where (R/S)-[3H]nisoxetine binding was almost absent. In homogenates of the caudate-putamen, the NE uptake inhibitors desipramine and (R)-nisoxetine and the serotonin (5-HT) uptake inhibitor citalopram produced biphasic displacement curves. Autoradiographic studies using 10 nM (R)-nisoxetine to mask the binding of (R)-[3H]tomoxetine to the NE uptake site produced autoradiograms that were similar to those produced by [3H]citalopram. Therefore, (R)-[3H]tomoxetine binds to the NE uptake site with high affinity and the 5-HT uptake site with somewhat lower affinity.
authors.affiliation: Central Nervous System Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: D A
authors.initials: DA
authors.lastname: Schober
authors.forename: S L
authors.initials: SL
authors.lastname: Gackenheimer
mesh_terms: D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D011437:Propylamines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014316:Tritium
chemical_list: D011437:Propylamines; D005473:Fluoxetine; D015283:Citalopram; D014316:Tritium; C011386:nisoxetine; D000069445:Atomoxetine Hydrochloride; D003891:Desipramine; D009638:Norepinephrine