( S, S)-2-[α-(2-(2-[ 18 F]Fluoro[ 2 H 4]ethoxy)phenoxy)benzyl]morpholine

Kenneth T. Cheng

PMID: 20641408

Abstract:

(S,S)-2-[α-(2-(2-[18F]Fluoro[2H4]ethoxy)phenoxy)benzyl]morphine ((S,S)-[18F]FRB-D4) is a radioligand developed for positron emission tomography (PET) imaging of the brain adrenergic receptors (1, 2). It is a derivative of reboxetine ((RS)-2-[(RS)-2-ethoxyphenoxy)benzyl]morpholine), which is a norepinephrine (NE) transporter (NET) inhibitor, and is labeled with 18F, which is a positron emitter with a physical half-life (t½) of 109.8 min. Four hydrogens on the ethoxy side chain have been replaced with deuterium (2H) in an attempt to slow defluorination, which was observed in earlier studies.
Many diseases affect the sympathetic nervous system (SNS), and imaging of pathologic changes of adrenergic transmission has been an important area of PET research (3, 4). Most postganglionic sympathetic neurons in the autonomic nervous system release the neurotransmitter NE, which stimulates adrenergic receptors in various effector organs (5). There are different types and subtypes of adrenergic receptors, and they are characterized as α1a to α1c, α2a to α2c, and β1 to β3 (6). All NE receptors belong to the G-protein−linked receptor superfamily and mediate slow neuromodulatory postsynaptic responses. The NET is a transmembrane protein located in the adrenergic nerve terminals and is responsible for active reuptake (uptake-1) of NE released from neurons (7). NE is stored in the neuronal vesicles and is released upon stimulation. Significant expression of NET is found in major organs of the SNS, such as the heart and brain. Brain NETs are involved in various neurologic and psychiatric diseases, including depression, attention deficit hyperactivity disorder, drug addiction, and eating disorders (8). Brain NETs are also the site of action of many antidepressant drugs in the brain (9).
Molecular probes with structures closely related to NE can be used to assess the integrity of presynaptic sympathetic nerve terminals in patients with various diseases. In vivo NE synthesis is similar to dopamine synthesis, and dopamine is converted to NE by the enzyme dopamine-β-hydroxylase (6). [123I]-meta-Iodobenzylguanidine, [11C]meta-hydroxyephedrine, [11C]norepinephrine, and many other radioligands have been developed and used for peripheral neuronal imaging (10). However, this class of tracers is not suitable for the study of the brain NET system because they are not able to cross the normal blood-brain barrier (2). In the brain, NET levels are relatively lower compared with other receptors, such as dopamine transporters (DATs) and serotonin transporters (9). Several NET reuptake inhibitors, such as [11C]desipramine, have been tested, but they showed high nonspecific binding. Reboxetine is a specific NET inhibitor with a high affinity and selectivity [inhibitory concentration (IC50) DAT/NET = 4,000]. PET imaging has shown specific localization and favorable binding kinetics for 11C-labeled reboxetine derivatives [(S,S)-[11C]methylreboxetine ((S,S)-[11C]MRB)] in rats and non-human primates (11). Because of the potential advantages associated with the longer t½ of 18F, Lin et al. (1) synthesized a number of 18F−labeled reboxetine analogs as promising radioligands for NET imaging with PET. (S,S)-[18F]FRB has been shown to have high affinity and selectivity toward NET. (S,S)-[18F]FRB-D4, a tetradeuterated analog, was developed to explore the deuterium isotope effect with the intention of reducing in vivo defluorination.

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