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

Abstract

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 [¹¹C]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 [¹¹C]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 K₁, k₂ and k₃ were estimated by a two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. k₄ was set as 0 according to the irreversible binding of [¹¹C]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 [¹¹C]PF-06809247 was calculated as 4.3 μSv/MBq.

Conclusions: [¹¹C]PF-06809247 is a promising PET ligand for further studies of MAGL in the human brain.

Keywords: MAGL; Non-human primate; Occupancy; PET; Radiation dose.

Fig. 1

Representative MRI and PET summation images (0–63 min) of [¹¹C]PF-06809247 at baseline and following pretreatment with a selective MAGL inhibitor (NHP4; 0.42 mg/kg)

Fig. 2

Representative time activity curves of [¹¹C]PF-06809247 in the NHP brain at a baseline and b following pretreatment with a selective MAGL inhibitor (NHP4; 0.42 mg/kg). cer cerebellum, cau caudate, put putamen, tha thalamus, fro frontal cortex, tem temporal cortex, hip hippocampus

Fig. 3

Radio-HPLC of baseline condition at 4- and 30-min post administration of [¹¹C]PF-06809247

Fig. 4

Correlation of K_i measured by 2TC model and Patlak slope

Fig. 5

Relationship between plasma concentration of PF-06807893 and MAGL occupancy

Fig. 6

Representative whole-body PET images of [¹¹C]PF-06809247

Fig. 7

Representative time activity curves of [¹¹C]PF-06809247 in a high accumulation organs and b low accumulation organs