Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter

• Published in: Nuclear medicine and biology 2003-02, Vol.30 (2), p.85-92
• Main Authors: Wilson, Alan A, Patrick Johnson, David, Mozley, David, Hussey, Doug, Ginovart, Nathalie, Nobrega, Jose, Garcia, Armando, Meyer, Jeffery, Houle, Sylvain
• Format: Article
• Language: English
• Subjects: Animals; Autoradiography; Autoradiography - methods; Biological and medical sciences; Brain - cytology; Brain - diagnostic imaging; Brain - metabolism; Carbon Radioisotopes - blood; Carbon Radioisotopes - chemistry; Carbon Radioisotopes - pharmacokinetics; Carbon-11; Feasibility Studies; Isomerism; Isotope Labeling - methods; Male; Medical sciences; Metabolic Clearance Rate; Morpholines - blood; Morpholines - chemical synthesis; Morpholines - pharmacokinetics; Norepinephrine Plasma Membrane Transport Proteins; Norepinephrine transporter; PET; Radiopharmaceuticals - blood; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rat; Rats; Reboxetine; Reference Values; Symporters - metabolism; Tissue Distribution; Tomography, Emission-Computed - methods
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/S0969-8051(02)00420-1

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 [ 11C]-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)-[ 11C]-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)-[ 11C]-MeNER produced a regional distribution pattern that was consistent with the reported distribution of NET. (S,S)-[ 11C]-MeNER has the potential to be the first successful PET ligand to image NET.