Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [(18)F]T-401 and PET

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [(18)F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [(18)F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume (V(T)), and the rank order of V(T) was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [(18)F]T-401 retentions in the brain, and V(T). Lassen's graphical analysis indicated a V(ND) of 0.69 mL/cm(3) and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [(18)F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.