Target occupancy study and whole-body dosimetry with a MAGL PET ligand [(11)C]PF-06809247 in non-human primates

BACKGROUND: Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system. To develop [(11)C]PF-06809247 into a clinically usable MAGL positron emission tomography (PET) radioligand, we assessed the occupancy of MAGL by an inhibitor in the non-human primate (NHP) brain. Additionally, we measured the whole-body distribution of [(11)C]PF-06809247 in NHP and estimated human effective radiation doses. METHODS: Seven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements along with arterial blood sampling were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a pro-drug of a selective MAGL inhibitor (total of seven doses between 0.01 and 1.27 mg/kg). Kinetic parameters K(1), k(2) and k(3) were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. k(4) was set as 0 according to the irreversible binding of [(11)C]PF-06809247. K(i) by 2TC and Patlak analysis were calculated as the influx constant. The target occupancy was calculated using K(i) at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model. RESULTS: Radioactivity retention was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4–100.5% in a dose dependent manner. Whole-body PET showed high radioactivity uptake values in the liver, small intestine, kidney, and brain. The effective dose of [(11)C]PF-06809247 was calculated as 4.3 μSv/MBq. CONCLUSIONS: [(11)C]PF-06809247 is a promising PET ligand for further studies of MAGL in the human brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-022-00882-2.