Abstract
The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimers disease (AD) and Parkinsons disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, the design and biological evaluation of several radioligands for imaging the brain NET system with PET are discussed. Based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[11C]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than 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.
Keywords: Norepinephrine transporter, PET, depression, substance abuse, ADHD, methylreboxetine, reboxetine, nisoxetine
Current Pharmaceutical Design
Title: PET Imaging of Norepinephrine Transporters
Volume: 12 Issue: 30
Author(s): Yu-Shin Ding, Kuo-Shyan Lin and Jean Logan
Affiliation:
Keywords: Norepinephrine transporter, PET, depression, substance abuse, ADHD, methylreboxetine, reboxetine, nisoxetine
Abstract: The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimers disease (AD) and Parkinsons disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, the design and biological evaluation of several radioligands for imaging the brain NET system with PET are discussed. Based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[11C]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than 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.
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Cite this article as:
Ding Yu-Shin, Lin Kuo-Shyan and Logan Jean, PET Imaging of Norepinephrine Transporters, Current Pharmaceutical Design 2006; 12 (30) . https://dx.doi.org/10.2174/138161206778559687
DOI https://dx.doi.org/10.2174/138161206778559687 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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