First demonstration of in vivo mapping for regional brain monoacylglycerol lipase using PET with [¹¹C]SAR127303

Monoacylglycerol lipase (MAGL) is a main regulator of the endocannabinoid system within the central nervous system (CNS). Recently, [¹¹C]SAR127303 was developed as a promising radioligand for MAGL imaging. In this study, we aimed to quantify regional MAGL concentrations in the rat brain using positron emission tomography (PET) with [¹¹C]SAR127303. An irreversible two-tissue compartment model (2-TCMi, k₄ = 0) analysis was conducted to estimate quantitative parameters (k₃, K_i^2-TCMi, and λk₃). These parameters were successfully obtained with high identifiability (<10 %COV) for the following regions ranked in order from highest to lowest: cingulate cortex > striatum > hippocampus > thalamus > cerebellum > hypothalamus ≈ pons. In vitro autoradiographs using [¹¹C]SAR127303 showed a heterogeneous distribution of radioactivity, as seen in the PET images. The K_i^2-TCMi and λk₃ values correlated relatively highly with in vitro binding (r > 0.4, P < 0.005). The K_i^2-TCMi values showed high correlation and low underestimation (<10%) compared with the slope of a Patlak plot analysis with linear regression (K_i^Patlak). In conclusion, we successfully estimated regional net uptake value of [¹¹C]SAR127303 reflecting MAGL concentrations in rat brain regions for the first time.