PET Imaging of Norepinephrine Transporters

Abstract

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., Alzheimer's disease (AD) and Parkinson's 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)-[11 C]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)-[11 C]MRB remains by far the most promising NET ligand for PET studies.

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

“…Due to the disadvantages of the 11 C labeled imaging agents described above, there is strong impetus to develop 18 F labeled probes for NET. 18 Fig.1) [17,18] derivatives of reboxetine have been reported.…”

“…18 Fig.1) [17,18] derivatives of reboxetine have been reported. These ligands showed poor in vivo stability due to defluorination.…”

Functional Neuroimaging in Geriatric Depression

“…Given the role of the norepinephrine transporter in the mechanism of action of antidepressant agents, a suitable radiotracer would permit drug occupancy studies, as well as studies of pathophysiology. Such studies would be especially critical in older patients, given the side effects associated with noradrenergic agents (84). …”

Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder

“…ADHD etiology, although multigenetic (Faraone et al, 2005; Gizer et al, 2009; Kuntsi and Klein, 2012), has been associated with polymorphisms of the norepinephrine transporter (NET) gene (Barr et al, 2002; Kollins et al, 2008; McEvoy et al, 2002). However, altered noradrenergic function in ADHD has not been verified in clinical studies (Zimmer, 2009), in part, due to the paucity of suitable radioligands probing NET for use in positron emission tomography studies (Ding et al, 2006). Importantly, compelling evidence supporting the involvement of the noradrenergic system in ADHD pathology comes from the common mechanism of action of all of the currently available FDA-approved therapeutics for ADHD.…”