(S, S)-2-[α-(2-(2-[18F]Fluoroethoxy)phenoxy)benzyl]morpholine

Excerpt

(S,S)-2-[α-(2-(2-[¹⁸F]Fluoroethoxy)phenoxy)benzyl]morphine ((S,S)-[¹⁸F]FRB) 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), a norepinephrine (NE) transporter (NET) inhibitor, labeled with ¹⁸F, a positron emitter with a physical half-life (t_½) of 109.8 min.

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 α_1a to α_1c, α_2a to α_2c, 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 on 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 brain NET system because they are not able to cross the blood-brain barrier (2). In the brain, NET levels are relatively lower than 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]. ¹¹C-labeled reboxetine derivatives ((S,S)-[¹¹C]methylreboxetine((S,S)-[¹¹C]MRB)) have shown specific localization and favorable binding kinetics in rats and non-human primates with PET imaging (11). Because of the potential advantages associated with the longer t_½ of ¹⁸F, Lin et al. (1) synthesized a number of ¹⁸F labeled reboxetine analogs as promising radioligands for NET imaging with PET.