In Vivo PET Imaging of Cardiac Presynaptic Sympathoneuronal Mechanisms in the Rat

The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: 11 C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; 11 C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and 11 C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans. Methods: We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart wererecordedfor60minafterradiotracerinjection.Amyocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determinedbymonoexponentialfittingofmyocardialtime‐activity curves. Results: At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (6 SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% 6 0.82%/min, 3.43% 6 0.45%/min, and 4.24% 6 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% 6 0.23%/min, 1.13% 6 0.35%/min, and 0.50% 6 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%. Conclusion: Kinetic profiles of HED in the rat myocardium were similar to those of HED in hu