Development of High Brain-Penetrant and Reversible Monoacylglycerol Lipase PET Tracers for Neuroimaging

Abstract

Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. (R)-[18F]13 was identified through the preliminary evaluation of two carbon-11-labeled racemic structures [11C]11 and [11C]16. In dynamic positron-emission tomography (PET) scans, (R)-[18F]13 showed a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain. High brain uptake and brain-to-blood ratio were achieved by (R)-[18F]13 in comparison with previously reported reversible MAGL PET radiotracers. Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of (R)-[18F]13 accumulation in the mouse brain. These findings indicate that (R)-[18F]13 ([18F]­YH149) is a highly promising PET probe for visualizing MAGL non-invasively in vivo and holds great potential to support drug development.

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

“…19 3-(2-Fluoro-6-methoxyphenethyl)azetidine 2,2,2-trifluoroacetate (9e) The procedure described for the synthesis of 4d was applied to 9d (110 mg, 0.36 mmol) and trifluoroacetic acid (0.30 mL, 4.27 mmol) to give a crude product, which was directly applied to the next step. LC-MS (ESI): (9). The procedure described for the synthesis of 4 was applied to 15 (28.0 mg, 0.09 mmol), 9e (30.0 mg, 0.09 mmol) and DIPEA (0.10 mL, 0.57 mmol) in MeCN (2 mL).…”

“…The IC 50 values of compounds were measured using MAGL enzyme as previously described [9]. The experiments were carried out at least in triplet using mouse or human MAGL.…”

“…1. 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].…”

Strategies for designing novel positron emission tomography (PET) radiotracers to cross the blood–brain barrier

“…18 F]MAGL-2102, [18 F]MAGL-1902, [ 18 F]YH149, [ 11 C]RO7279991, [ 11 C] PAD, and [18F]MAGL-4-11; Figure7) [119][120][121][122][123][124]. Scaffold selection from the compound libraries are often initially guided by potency measured by the half-maximal inhibitory concentration (IC 50 ), and followed by selectivity, reversibility, metabolic stability, or rate constant data.…”

“…Fortunately, pre-treatment with the P-gp inhibitor elacridar enabled [ 11 C]SCIO-469 to pass the BBB with peak brain uptake of 1.2 SUV, indicating that the radiotracer is a substrate for rodent efflux transporters (Figure8(B)). A subsequent MDCK-MDR1 assay suggested that SCIO-469 is also likely to be a substrate F I G U R E 7 Structures of selected MAGL PET tracers [119][120][121][122][123][124]. Abbreviations: MAGL, monoacylglycerol lipase; PET, positron emission tomography.…”