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

doi:10.1111/j.1471-4159.2005.03202.x

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Wiley InterScience

Journal of Neurochemistry

Volume 94 Issue 2, Pages 337 - 351

Published Online: 15 Jun 2005

Published for the International Society for Neurochemistry

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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

Yu-Shin Ding, Kuo-Shyan Lin, Jean Logan, Helene Benveniste and Pauline Carter

Chemistry and Medical Departments, Brookhaven National Laboratory, Upton, New York, USA

Address correspondence and reprint requests to Yu-Shin Ding, PhD, Chemistry and Medical Departments, Brookhaven National Laboratory, Upton, New York 11973, USA. E-mail: ding@bnl.gov

KEYWORDS

lortalamine • nisoxetine • norepinephrine transporter • oxaprotiline • positron emission tomography • reboxetine

ABSTRACT

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.