title: (R)-N-Methyl-3-(3-(125)I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters.
abstract: Alterations in serotonin and norepinephrine neuronal functions have been observed in patients with major depression. Several antidepressants bind to both serotonin transporters and norepinephrine transporters (NET). The ability to image NET in the human brain would be a useful step toward understanding how alterations in NET relate to disease. In this study, we report the synthesis and characterization of a new series of derivatives of iodonisoxetine, a known radioiodinated probe. The most promising, (R)-N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine (PYINXT), displayed a high and saturable binding to NET, with a K(d) value of 0.53+/-0.03 nM. Biodistribution studies of (R)-N-methyl-3-(3-(125)I-pyridin-2-yloxy)-3-phenylpropan-1-amine in rats showed moderate initial brain uptake (0.54% dose/organ at 2 min) with a relatively fast washout from the brain (0.16% dose/organ at 2 h) as compared to [(125)I]INXT. The hypothalamus (a NET-rich region)-to-striatum (a region devoid of NET) ratio was found to be 2.14 at 4 h after intravenous injection. Preliminary results suggest that this improved iodinated ligand, when labeled with (123)I, may be useful for mapping NET-binding sites with single photon emission computed tomography in the living human brain.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Balagopal
authors.initials: B
authors.lastname: Lakshmi
authors.forename: Mei-Ping
authors.initials: MP
authors.lastname: Kung
authors.forename: Brian
authors.initials: B
authors.lastname: Lieberman
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Rikki
authors.initials: R
authors.lastname: Waterhouse
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D007457:Iodine Radioisotopes; D018374:LLC-PK1 Cells; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D011437:Propylamines / Q000138:chemical synthesis / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; C528134:N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D011725:Pyridines; D019275:Radiopharmaceuticals; D005473:Fluoxetine; C011386:nisoxetine