PET of (R)-11C-rolipram binding to phosphodiesterase-4 is reproducible and sensitive to increased norepinephrine in the rat heart.

UNLABELLED Phosphodiesterase-4 (PDE4) plays a critical role in the regulation of β-adrenergic receptor-stimulated cyclic adenosine monophosphate cell signaling in the heart. (R)-rolipram, a PDE4-selective inhibitor, has been studied previously as a radiotracer for the quantification of PDE4 levels. The aim of this study was to characterize (R)-(11)C-rolipram binding in the rat myocardium in vivo, using small-animal PET. METHODS Male Sprague-Dawley rats (n = 30) were administered (R)-(11)C-rolipram and imaged for 60 min to evaluate tracer binding and reproducibility, quantified using Logan slope analysis of the distribution volume. Dynamic (13)N-ammonia imaging was performed to quantify myocardial blood flow and assist in cardiac regional analysis. Saturation studies evaluated the sensitivity of (R)-(11)C-rolipram to PDE4 blocking by unlabeled cold (R)-rolipram (0.0001-1.0 mg/kg), for estimation of the median effective dose (ED(50)) in the heart. (R)-(11)C-rolipram response to enhanced norepinephrine stimulation of the β-adrenergic receptor with desipramine (20 mg/kg, intravenous) was also studied. Intrarat variability studies (n = 5) were conducted with test-retest imaging at 16 ± 7 d. RESULTS A reduction of Logan slope was observed with increasing cold mass coadministered with the tracer, with an ED(50) of 0.0019 mg/kg (95% confidence interval, 0.0014-0.0052) estimated from the saturation studies. This ED(50) predicted less than 10% enzyme occupancy at 0.0002 mg of cold (R)-rolipram per kilogram (mass/body weight). Low-occupancy imaging at 0.00018 ± 0.00002 mg/kg produced a mean Logan slope of 5.5 ± 0.85 mL/cm(3). Enzyme saturation of more than 90%, compared with low-occupancy conditions, occurred at more than 0.02 mg/kg, with a complete blocking dose (>1 mg of (R)-rolipram per kilogram) resulting in a Logan slope of 3.3 ± 0.1 mL/cm(3), representing a 40% reduction. Compared with baseline, a Logan slope of 6.8 ± 0.7 mL/cm(3) in desipramine-challenged animals was observed, representing a 30% increase due to acute norepinephrine stimulation, despite a reduction in myocardial blood flow. Intrarat and intraoperator variability was less than 5% between repeated measures. CONCLUSION (R)-(11)C-rolipram shows the ability to monitor increases and decreases in PDE4 availability in the rat myocardium, with good reproducibility.