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内容記述 |
Objectives: Monoacylglycerol lipase (MAGL) is well known as a key enzyme for regulation of endocannabinoid system which retrogradely controlled glutamatergic neurons. So far, a lot of efforts have successfully resulted in developments of some useful covalent inhibitors for MAGL [1]. Simultaneously, some positron emission tomography (PET) probes with irreversible brain kinetics were developed for MAGL imaging. Of these, the radiotracer containing azetidine carbamate showed an unexpected clearance of radioactivity from brain in the manner of the reversible-type radiotracer. Here, we forecasted in vivo behavior of azetidine carbamate radiotracer by referring a previous report [1], demonstrating it by the in vitro assessment. Additionally, utilizing a unique brain kinetic of azetidine carbamate radiotracer, we attempted noninvasive measurement of MAGL activity using PET.Methods: To confirm production of [11C]CO2 derived from hydrolyzation of [11C]azetidine carbamate radiotracer via MAGL, we conducted in vitro assessments using [11C]QST-0837 (Fig. 1B), an azetidine carbamate radiotracer for MAGL [2], and rat brain homogenates. As an opponent, [11C]HPPC, a piperidine carbamate radiotracer [2], was also used. PET imaging with [11C]QST-0837 was carried out using four healthy rats and hydrolysis rate (KH) of [11C]QST-0837 via MAGL was estimated by mono-exponential fitting on time-activity curves of the regions of interests (ROIs).Results: In vitro assessments showed the generation of [11C]CO2 as the final product derived from hydrolysis of [11C]QST-0837 via MAGL, whereas [11C]HPPC has not seen that. In PET study with [11C]QST-0837 using healthy rat, KH values in the brain were successfully estimated around 0.7 /h in each ROI.Conclusions: We successfully developed the method for noninvasive quantifying hydrolysis rate of MAGL using PET with [11C]QST-0837. References: [1] Butler CN, et al., J. Med. Chem. 2017, 60, 9860–9873. [2] Yamasaki T, et al. Brain. Commun. 2024, 6, fcae172. |
