First-in-human in vivo imaging and quantification of monoacylglycerol lipase in the brain: a PET study with ¹⁸F-T-401

Purpose: Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand ¹⁸F-T-401. Methods: Seven healthy males underwent 120-min dynamic ¹⁸F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with ¹⁸F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test–retest reproducibility of ¹⁸F-T-401-PET were also evaluated. Results: ¹⁸F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (V_T) values by best identifiability. V_T values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated V_T values with a minimal bias even using truncated 60-min scan data. Test–retest reliability was also excellent with the use of MA1. Conclusions: Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. ¹⁸F-T-401 showed excellent test–retest reliability, reversible kinetics, and stable estimation of V_T values consistent with known regional MAGL expressions. PET with ¹⁸F-T-401-PET is promising tool for measurement of central MAGL.