NOVEL HALOGENATED ANALOGS OF TOMOXETINE THAT ARE POTENT AND SELECTIVEINHIBITORS OF NOREPINEPHRINE UPTAKE IN BRAIN

Halogenated analogs of the potent norepinephrine (NE) uptake inhibitor , tomoxetine, were synthesized and their affinities for the serotonin (5HT) and NE uptake sites evaluated. One of the most potent was the 2- iodo substituted analog (289306) that inhibited [H-3]tomoxetine bindin g to rat cerebral cortex with a K-i of 0.37 nM. The compound also inhi bited the uptake of [3H]NE into rat hypothalamic synaptosomes with a K -i of 3.5 nM. This analog was significantly less potent at the 5HT upt ake site, as exhibited by a K-i of 25 nM in the inhibition of [H-3]par oxetine binding and a K-i of 121 nM in [H-3]5HT uptake. The resolved ( R) enantiomer (303926) was 10 times more potent as a [H-3]Ne uptake in hibitor and 29 times more potent as an inhibitor of [H-3]tomoxetine bi nding than the (S) enantiomer (303884). Administration of 289306 to ra ts prior to an i.c.v. injection of 6-hydroxydopamine prevented the dep letion of hypothalamic NE and Epi with ED(50) values of 0.28 and 0.47 mg/kg, respectively. Thus, 289306 was a potent inhibitor of NE uptake in vitro and in vivo. In addition, these compounds provide structures for potential ligands for the study of NE uptake sites by autoradiogra phy, PET or SPECT imaging.