Biodistribution and blood metabolism of 1-¹¹C-methyl-4- piperidinyl n-butyrate in humans: An imaging agent for in vivo assessment of butyrylcholinesterase activity with PET

1-¹¹C-Methyl-4-piperidinyl n-butyrate (¹¹C-MP4B) is a new radiopharmaceutical for the in vivo assessment of butyrylcholinesterase (BuChE) activity using PET. To quantify in vivo activity of BuChE with a kinetic model, investigators must determine the time course of radioactivity associated with unchanged ¹¹C-MP4B. We aimed at clarifying the metabolic fate and whole-body distribution of intravenously administered ¹¹C-MP4B in man. Methods: High-performance liquid chromatography and thin-layer chromatography assays were performed to determine the amounts of intact ¹¹C-MP4B and its radioactive hydrolysis product in blood withdrawn during PET. In addition, we evaluated the distribution and kinetics of ¹¹C-MP4B uptake in human brain and main organs. Results: The analysis of plasma samples of 28 human subjects (10 patients with Alzheimer's disease [AD] and 18 healthy controls) showed that the level of unmetabolized ¹¹C-MP4B decreases rapidly from 28% ± 14% (mean ± SD) at 0.5 min to 7% ± 6% at 15 min after injection. Large individual variation was observed in the rate of plasma ¹¹C-MP4B hydrolysis, but no significant differences were found in the degradation of ¹¹C-MP4B either between male and female or between healthy subjects and patients. The whole-body distribution of ¹¹C-MP4B showed the highest activities in the urinary bladder, renal pelvis, stomach, salivary glands, liver, kidneys, spleen, vertebral column, and brain. In patients with AD, ¹¹C-MP4B activity in the brain was highest in cerebellum, followed by striatum, pons, and thalamus. Lower ¹¹C-MP4B activity was seen in cortical areas. Conclusion: Our results indicate that ¹¹C-MP4B is excreted rapidly through the renal system. Careful analysis of plasma metabolites is required to determine the accurate arterial input function for quantitative PET measurement. Biodistribution of ¹¹C-MP4B in the brains of patients with AD appears to be in accordance with the distribution of BuChE seen in postmortem studies of human brain, except for the observed higher activity in striatum than in cortex. Further studies of the cerebral distribution and regional kinetic analysis of ¹¹C-MP4B are in progress.