[C]-Hydroxyephedrine

[C]--Hydroxyephedrine ([C]mHED) is a radioligand developed for positron emission tomography (PET) imaging of the sympathetic nervous system (SNS). It is a catecholamine analog labeled with C, a positron emitter with a physical of 20.4 min (1). Many diseases affect the 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 of various effector organs (4). There are different types of adrenergic receptors, and NE stimulates α, β and certain β receptors. The NE transporter (NET) is a transmembrane protein located in the adrenergic nerve terminals that 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). Molecular probes with structures closely related to NE can be used to assess the integrity of presynaptic sympathetic nerve terminals in various diseases. [I]-iodobenzylguanidine ([I]MIBG), a single-photon emission tomography (SPECT) agent, has been developed and used for neuronal imaging. Efforts have been made to develop a posiron-emitting tracer because of the inadequate quantitative information and lower spatial resolution obtained by SPECT imaging with MIBG. [C]mHED was developed based on metaraminol, a synthetic false transmitter analog of NE, that accumulates in nerve terminals in the same way as NE (1, 7). Metaraminol is released by nerve stimulation but only has weak postsynaptic effects. Unlike NE, metaraminol is not metabolized by catechol−−methyl transferase (COMT). The α methyl group on the side chain of metaraminol also renders the compound resistant to oxidative deamination by monoamine oxidase (MAO). [C]mHED is a metaraminol analog and is a good substrate for the NET. It shares the same neuronal uptake mechanism as NE and is also resistant to metabolism by COMT and MAO. Retention of [C]mHED in the NET-expressing tissue appears to be the result of rapid NET-mediated reuptake of the radiotracer.