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

• Published in: Journal of neurochemistry 2005-07, Vol.94 (2), p.337-351
• Main Authors: Ding, Yu‐Shin, Lin, Kuo‐Shyan, Logan, Jean, Benveniste, Helene, Carter, Pauline
• Format: Article
• Language: English
• Subjects: Adrenergic Uptake Inhibitors - blood; Adrenergic Uptake Inhibitors - pharmacokinetics; Animals; Autoradiography - methods; Benzopyrans - blood; Benzopyrans - pharmacokinetics; Binding, Competitive - drug effects; Biological and medical sciences; Brain - diagnostic imaging; Brain - metabolism; Brain Chemistry; Brain Mapping; Carbon Radioisotopes - pharmacokinetics; Cell physiology; Chromatography, High Pressure Liquid - methods; Comparative analysis; Dose-Response Relationship, Drug; Drug Interactions; Emissions; Evaluation Studies as Topic; Fluorine Radioisotopes - pharmacokinetics; Fluoxetine - analogs & derivatives; Fluoxetine - blood; Fluoxetine - pharmacokinetics; Fundamental and applied biological sciences. Psychology; Image Processing, Computer-Assisted - methods; lortalamine; Magnetic Resonance Imaging - methods; Maprotiline - analogs & derivatives; Maprotiline - blood; Maprotiline - pharmacokinetics; Medical sciences; Membrane and intracellular transports; Mice; Molecular and cellular biology; Monkeys & apes; Morpholines - blood; Morpholines - pharmacokinetics; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; nisoxetine; Nordefrin - antagonists & inhibitors; Norepinephrine Plasma Membrane Transport Proteins; norepinephrine transporter; oxaprotiline; Papio; Pharmacology. Drug treatments; Positron-Emission Tomography; Positrons; Protein Binding - drug effects; Radioligand Assay - methods; reboxetine; Serotoninergic system; Symporters - metabolism; Time Factors; Tissue Distribution; Tomography
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03202.x

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.