[¹¹C]-p-Hydroxyphenethylguanidine ([¹¹C]-p-hydroxy-PG) is a radioligand developed for positron emission tomography (PET) imaging of the cardiac sympathetic nervous system (SNS) and adrenergic tumors. It is a catecholamine analog labeled with ¹¹C, a positron emitter with a physical half-life (t_½) 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 α₁, β₁, and certain β₂ receptors. The NE transporter (NET) is a transmembrane protein located in the adrenergic nerve terminals that are responsible for active reuptake (uptake-1) of NE released from neurons (5). Inside the neurons, NE is transported by the vesicular monoamine transporter (VMAT2) into the neuronal vesicles and stored there until it is released on stimulation. Significant expression of NET is found in major organs of the SNS such as the heart and brain. The NET expression is also increased or altered in adrenergic tumors (6, 7). There is also substantial evidence that aberrations in cardiac SNS function contribute to the morbidity and mortality associated with cardiac diseases (8).

Molecular probes with structures closely related to NE can be used to assess the integrity of cardiac sympathetic innervation and image adrenergic tumors (9, 10). Single-photon emission tomography (SPECT) agents such as [¹²³I]meta-iodobenzylguanidine ([¹²³I]MIBG) has been developed and used for neuronal imaging (11). Efforts have been made to develop a positron-emitting tracer because of the inadequate quantitative information and lower spatial resolution obtained with SPECT imaging. PET molecular imaging probes such as [¹¹C]meta-hydroxyephedrine ([¹¹C]mHED), [¹¹C]norephinephrine, [¹¹C]phenylephrine, and R-(–)-[¹¹C]-epinephrine have been evaluated because they accumulate in nerve terminals in the same way that NE does (12-15). Although they all localize in cardiac sympathetic neurons, there are significant differences in their NET transport rates, enzyme metabolism, vesicular storage efficiency, and diffusion rates from neurons (16). All of the current probes also have cardiac sympathetic neuronal uptake rates that are too rapid for robust and reliable compartmental modeling of their kinetics. On the basis of this observation, Raffel et al. (1) proposed the development of new radioligands with slower neuronal uptake rates and a long neuronal retention time through storage vesicle trapping. Because many phenethylguanidines have avid neuronal uptake and long retention inside storage vesicles, they synthesized and evaluated a series of [¹¹C]phenethylguanidine analogs. In their study, Raffel et al. (1) suggested that a minimum structural requirement for long neuronal retention is a β-carbon or phenyl ring hydroxyl group substitution. Among this group of [¹¹C]phenethylguanidines, [¹¹C]-p-hydroxy-PG appeared to be one of the most promising for detecting adrenergic tumors, with a high tumor/background radioactivity ratio in mice. In rats, [¹¹C]-p-hydroxy-PG also exhibited high uptake in heart due to localization in cardiac sympathetic neurons, with low uptake in liver and lungs. A structurally related [¹¹C]phenethylguanidine, N-[¹¹C]guanyl-m-octopamine, showed greatly improved myocardial kinetics for quantitative tracer kinetic analyses in non-human primates.