(,)-[C]Methylreboxetine

(,)-[C]Methylreboxetine ((,)-[C]MRB) is a radioligand developed for positron emission tomography (PET) imaging of the brain adrenergic receptors. It is a derivative of reboxetine, a norepinephrine transporter (NET) inhibitor, labeled with C, a positron emitter with a physical half-life () of 20.4 min (1). Many diseases affect the sympathetic nervous system (SNS), and imaging of pathologic changes of adrenergic transmission has been an important area of PET research (2, 3). Most postganglionic sympathetic neurons in the autonomic nervous system release the neurotransmitter norepinephrine (NE), which stimulates adrenergic receptors in various effector organs (4). There are different types and subtypes of adrenergic receptors, and they are characterized as α to α, α to α, and β to β (5). 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 (6). 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 (7). Brain NETs are involved in various neurologic and psychiatric diseases, including depression, attention deficit hyperactivity disorder, drug addiction, and eating disorders (8). 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. NE synthesis is similar to dopamine synthesis, and dopamine is converted to NE by the enzyme dopamine-β-hydroxylase (5). [I]--Iodobenzylguanidine, [C]-hydroxyephedrine, [C]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 those of other receptors, such as dopamine transporters (DATs) and serotonin transporters (9). Several NET reuptake inhibitors, for example, [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 (IC DAT/NET = 4,000). It has been developed in Europe for the treatment of depressive illness. Reboxetine is available as a racemic mixture of the () and () enantiomers. The (S,S) enantiomer has been found to be more potent, with a IC of 3.6 nM for inhibiting NE uptake in rat hypothalamic synaptosomes. Among the different reboxetine derivatives that have been tested, (,)-MRB has an IC of 2.5 nM ((,)-MRB has an IC of 85 nM) and is considered a promising candidate to be developed as a PET ligand for studying the brain NET system.