title: Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter.
abstract: The (R,R) and (S,S) enantiomers of 2-[(2-methoxyphenoxy)phenylmethyl]morpholine (MeNER) have been radiolabelled with carbon-11 in good yield and at high specific activity. These radiotracers are close analogues of reboxetine, a potent and selective ligand for the norepinephrine transporter (NET). They were examined as potential ligands for imaging NET in vivo by positron emission tomography (PET). The in vivo brain distribution of both [(11)C]-labeled enantiomers were evaluated in rats. Following tail-vein injection of the (R,R)-enantiomer regional brain uptake and washout of radioactivity was homogeneous at all time points examined (5-60 min). In contrast, administration of the (S,S)-enantiomer produced a heterogeneous distribution of radioactivity in brain with highest uptake in the hypothalamus, a NET rich region, and lowest uptake in the striatum, a brain region devoid of NET. Hypothalamus to striatum ratios of 2.5 to one were achieved at 60 min post injection of (S,S)-[(11)C]-MeNER. Pre-injection of the norepinephrine reuptake inhibitors, reboxetine or desipramine, reduced hypothalamus to striatum ratios to near unity while reuptake inhibitors of dopamine and serotonin had no significant effect on binding. In vitro autoradiography studies (rat brain slices) with (S,S)-[(11)C]-MeNER produced a regional distribution pattern that was consistent with the reported distribution of NET. (S,S)-[(11)C]-MeNER has the potential to be the first successful PET ligand to image NET.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada. aaw@camhpet.on.ca
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: David Patrick
authors.initials: DP
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Mozley
authors.forename: Doug
authors.initials: D
authors.lastname: Hussey
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: Jose
authors.initials: J
authors.lastname: Nobrega
authors.forename: Armando
authors.initials: A
authors.lastname: Garcia
authors.forename: Jeffery
authors.initials: J
authors.lastname: Meyer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000166:cytology / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D005240:Feasibility Studies; D007536:Isomerism; D007553:Isotope Labeling / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D009025:Morpholines / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D000077593:Reboxetine; D012016:Reference Values; D027981:Symporters / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods
chemical_list: D002250:Carbon Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493226:Slc6a2 protein, rat; D027981:Symporters; D000077593:Reboxetine