(S,S)-2-(α-(2-[18F]Fluoro[2H2]methoxyphenoxy)phenoxy)benzyl)morpholine

Excerpt

(S,S)-2-(α-(2-[¹⁸F]Fluoro[²H₂]methoxyphenoxy)benzyl)morpholine ((S,S)-[¹⁸F]FMeNER-D₂) is a radioligand developed for positron emission tomography (PET) imaging of the brain adrenergic receptors. It is a derivative of reboxetine ((RS)-2-[(RS)-2-ethoxyphenoxy)benzyl]morpholine), a norepinephrine transporter (NET) inhibitor, labeled with ¹⁸F, a positron emitter with a physical half-life (t_½) of 109.8 min (1, 2).

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 norepinephrine (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 of the 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 that 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 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]m-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 (11). 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). The (S,S)-MeNER enantiomer ((S,S)-MRB) is the more potent enantiomer with a IC₅₀ of 3.6 nM for inhibiting NE uptake in rat hypothalamic synaptosomes. ¹¹C-labeled (S,S)-MeNER has been shown to be a promising brain NET imaging agent, but the specific binding peak equilibrium could not be measured because of the short t_½ of ¹¹C. Because of the longer t_½ of ¹⁸F, Shou et al. (1) described the synthesis of the first radiofluorinated ligand, (S,S)-[¹⁸F]FMeNER, for brain NET imaging. The di-deuterated analog, (S,S)-[¹⁸F]FMeNER-D₂, was developed to minimize the in vivo defluorination of (S,S)-[¹⁸F]FMeNER (1).