(2S,αS)-2-(α-(2-[I]Iodophenoxy)benzyl)morpholine

Many diseases affect the sympathetic nervous system (SNS), and imaging of pathological changes of adrenergic transmission has been an important area of radiopharmaceutical research (1, 2). Most postganglionic sympathetic neurons in the autonomic nervous system release the neurotransmitter norepinephrine (NE), which stimulates adrenergic receptors in various effector organs (3). There are different types and subtypes of adrenergic receptors, and they are characterized as α to α, α to α, and β to β (4). All of the NE adrenergic receptors belong to the G-protein–linked receptor superfamily and mediate slow neuromodulatory postsynaptic responses. The NE transporter (NET) is a transmembrane protein located in the adrenergic nerve terminals, and it is responsible for active reuptake (uptake-1) of NE released from neurons (5). 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. There is substantial evidence that aberrations in cardiac SNS function contribute to the morbidity and mortality associated with cardiac diseases (6). Brain NET is involved in various neurological and psychiatric diseases, including depression, attention deficit hyperactivity disorder, drug addiction, and eating disorders (7). NET is also the site of action in the brain for many antidepressant drugs (8). Molecular probes with structures closely related to NE can be used to assess the integrity of presynaptic sympathetic nerve terminals in various diseases. NE synthesis is similar to dopamine synthesis, and dopamine is converted to NE by the enzyme dopamine-β-hydroxylase (4). [I]--Iodobenzylguanidine, [C]-hydroxyephedrine, [C]norepinephrine, and many other radioligands have been developed and used for peripheral neuronal imaging (9). However, this class of tracers is not suitable for the study of the brain NET system because they are not able to cross the blood–brain barrier (10). In the brain, NET levels are relatively low compared with those of other transporters, such as dopamine transporter (DAT) and serotonin transporter (SERT) (8). Several NET reuptake inhibitors such as [C]desipramine have been tested, but they showed high nonspecific binding. Reboxetine (()-2-[(()-2-ethoxyphenoxy)benzyl]morpholine) is a specific NET inhibitor with a high affinity and selectivity. Reboxetine is available as a racemic mixture of the () and () enantiomers. The (,) enantiomer has been found to be more potent, with a 50% inhibition concentration (IC) value of 3.6 nM, for inhibiting NET in rat hypothalamic synaptosomes. Among the different reboxetine derivatives that have been tested, (2,α)-2-(α-(2-[I]iodophenoxy)benzyl)morpholine ((,)-[I]IPBM) is considered a potential candidate to be developed as a single-photon emission computed tomography (SPECT) ligand for studying the brain and heart NET system (11, 12).