Comparative evaluation of positron emission tomography radiotracers for imaging the norepinephrine transporter: (S,S) and (R,R) enantiomers of reboxetine analogs ([11C]methylreboxetine, 3-Cl-[11C]methylreboxetine and [18F]fluororeboxetine), (R)-[11C]nisoxetine, [11C]oxaprotiline and [11C]lortalamine.
We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with positron emission tomography (PET). Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P = 1.0-3.5), high plasma free fraction and reasonable stability in plasma were selected for further studies. Based on our characterization studies in baboons, including 11C-labeled (R)-nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and new analogs of methylreboxetine (MRB), in conjunction with our earlier evaluation of 11C and 18F derivatives of reboxetine, MRB and their individual (R,R) and (S,S) enantiomers, we have identified the superiority of (S,S)-[11C]MRB and the suitability of MRB analogs [(S,S)-[11C]MRB > (S,S)-[11C]3-Cl-MRB > (S,S)-[18F]fluororeboxetine] as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than in thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge (S,S)-[11C]MRB remains by far the most promising NET ligand for PET studies.
Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973, USA. ding@bnl.gov
Yu-Shin
YS
Ding
Kuo-Shyan
KS
Lin
Jean
J
Logan
Helene
H
Benveniste
Pauline
P
Carter
D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D001923:Brain Chemistry; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005069:Evaluation Studies as Topic; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008376:Maprotiline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D051379:Mice; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics*; D008771:Nordefrin / Q000037:antagonists & inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010215:Papio; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D000077593:Reboxetine; D027981:Symporters / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D018759:Adrenergic Uptake Inhibitors; D001578:Benzopyrans; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D008376:Maprotiline; C027299:hydroxymaprotilin; D000077593:Reboxetine; C031101:lortalamine; D008771:Nordefrin