Brain and whole body imaging of phosphodiesterase 4 using (R)-[C-11]R lipram in human and rhesus monkey

Introduction: Rolipram binds to phosphodiesterase 4 (PDE4), the enzyme that catabolizes the second messenger cAMP. cAMP cascade is a major signal transduction pathway in neurons and inflammatory cells, and inhibitors of PDE4 are expected to have therapeutic effects in mood disorders and inflammatory diseases. (R)-[C-11]rolipram has been successfully used to image brain PDE4 in rat (1), non-human primate (3), and human (2). The purposes of this study were to quantify (R)-[C-11]rolipram binding in rhesus monkey and human brain, examine the test retest reproducibility of the measurement, and to study whole body distribution of radioactivity and radiation-absorbed doses. Methods: Following (R)-[C-11]rolipram scans were performed. Monkey brain: n = 2, human brain test retest: n = 9, monkey whole body baseline: n = 3, monkey whole body with co-injection of non-radiolabeled (R)-rolipram (1 mg/kg): n = 1. HRRT and GE Advance cameras were used for 2 h brain and whole body scans, respectively. The injection activity was ∼185, ∼370, and ∼740 MBq in monkey, human brain, and human whole body scans, respectively. Arterial blood samples were obtained in all monkey and human brain scans to measure metabolite-corrected arterial input function. Plasma free fraction (f1) was also measured in human brain scans. Distribution volume (V) in brain was calculated by one- (1C) and two-tissue compartment (2C) models. Radiation-absorbed doses were estimated using the MIRD scheme. Results: As expected from postmortem studies, both monkey and human brain scans showed widespread distribution of (R)-[C-11]rolipram binding. Peak brain activity was 150 - 300% standard uptake value with higher levels in monkeys than in humans. Fraction of (R)-[C-11]rolipram in arterial plasma decreased to 50% in 10 and 75 min in monkeys and humans, respectively. In both of these species, 2C showed significantly better goodness-of-fit than 1C. 2C well identified V with ∼5% COV and showed fairly uniform distribution in cortical and subcortical areas with average of 4.9 and 0.66 mL/cc in monkeys and humans, respectively. In humans, average V/f1 was 10 mL/cc. Test retest reproducibility of V/f1 was ∼15% in eight subjects while one subject who reported job-related stress at the time of one scan showed big variability of ∼65%. In whole body scans, brain, heart contents, lungs, liver, kidneys, and bladder were visible. The monkey blocking scan did not show apparent specific binding in peripheral organs. In human whole body scans, the organ with the highest dose was urinary bladder wall (17 μGy/MBq) and the effective dose was 5.5 μSv/MBq. Conclusion: V in human brain scans was consistent with the Results: of a previous study (2) and smaller than in rats (1) as expected from known binding site density. V/f1 showed modest reproducibility in most subjects. However, there may be confounding factors such as stress. Radiation-absorbed doses were low enough for human use. (R)-[C-11]rolipram is a promising ligand to image PDE4 in human brain.