Discovery, synthesis and evaluation of novel reversible monoacylglycerol lipase radioligands bearing a morpholine-3-one scaffold

Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain

“…0.4-0.5 in mice brain. Compared to the increasing brain accumulation of [ 11 C]2 overtime [10], [ 11 C]7 reached its maximal accumulation in WT mice within 20 min p.i. and slowly washed out afterwards.…”

“…In our previous work, we identified [ 11 C]2 from an industrial morpholin-3-one library (F. Hoffmann-La Roche Ltd) to serve as an entirely novel structure to image MAGL in the CNS [10]. The specificity of [ 11 C]2 was confirmed in vivo using MAGL KO and WT mice.…”

“…Eleven compounds were designed and synthesized based on the lead structure 2. Their IC 50 values indicated that [10]). This could be attributed to the faster metabolism of [ 11 C]7 in periphery in addition to its increased dissociation from MAGL protein as determined in the SPR assay (Table 1).…”

“…The key intermediate, (4aR,8aS)-hexahydro-2H-pyrido [4,3-b] [1,4]oxazin-3(4H)-one (14), was prepared from its racemic commercial source (ChemBridge Corporation) and purified by preparative chiral HPLC (ReprosilChiral NR column) using an isocratic mixture of EtOH (containing 0.05% of NH 4 OAc): nheptane (30:70). The 4-nitrophenyl (4aR,8aS)-3-oxohexahydro-2H-pyrido [4,3-b] [1,4]oxazine-6(5H)-carboxylate (15) was prepared according to the previously described method [10]. All the reactions were monitored by thin-layer chromatography (TLC) performed on Merck TLC glass sheets (silica gel 60 F254) or a Waters Acquity ultra-performance liquid chromatography (UPLC) equipped with a single quadrupole mass spectrometer (MS).…”

“…Except [ 18 F]T-401 and [ 18 F]YH149 [8,9], the rest of reversible MAGL PET tracers encountered a common issue: a relatively slow brain accumulation within the practical time frame [13]. Among them, [ 11 C]1 and [ 11 C]2 were recently developed in our laboratory [10]. Our preliminary results showed that they were recognized by P-glycoprotein (P-gp) in rodents but not in humans.…”