Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter.
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.
Wilson
Alan A
AA
PET Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada. aaw@camhpet.on.ca
Johnson
David Patrick
DP
Mozley
David
D
Hussey
Doug
D
Ginovart
Nathalie
N
Nobrega
Jose
J
Garcia
Armando
A
Meyer
Jeffery
J
Houle
Sylvain
S
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
D002250:Carbon Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493226:Slc6a2 protein, rat; D027981:Symporters; D000077593:Reboxetine