Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions including chronic pain, inflammation, cancer and neurodegeneration. Herein we disclose a novel array of reversible and irreversible MAGL inhibitors by means of tail switching on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8, and reversible-binding compounds 17 and 37 which are amenable for radiolabeling with 11 C or 18 F. [ 11 C]8 ([ 11 C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain towards MAGL. Reversible radioligands [ 11 C]17 ([ 11 C]PAD) and [ 18 F]37 ([ 18 F]MAGL-4-11) also demonstrated excellent in vivo binding specificity towards MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography (PET) tracers with tunability in reversible and irreversible binding mechanism.
Monoacylglycerol
lipase (MAGL) is a 33 kDa serine protease primarily
responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory
eicosanoid precursor arachidonic acid in the central nervous system.
Inhibition of MAGL constitutes an attractive therapeutic concept for
treating psychiatric disorders and neurodegenerative diseases. Herein,
we present the design and synthesis of multiple reversible MAGL inhibitor
candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing
reversible MAGL inhibitors by pharmacological evaluations, thus channeling
their radiolabeling with fluorine-18 in high radiochemical yields
and favorable molar activity. Furthermore, evaluation of [18F]10 and [18F]15 ([18F]MAGL-2102) by autoradiography and positron emission tomography
(PET) imaging in rodents and nonhuman primates demonstrated favorable
brain uptakes, heterogeneous radioactivity distribution, good specific
binding, and adequate brain kinetics, and [18F]15 demonstrated a better performance. In conclusion, [18F]15 was found to be a suitable PET radioligand for
the visualization of MAGL, harboring potential for the successful
translation into humans.
A novel soluble functional polyacetylene copolymer (poly(EAAB-co-PA)) of 4-ethynyl-4#-[N,N-diethylamino]azobenzene (EAAB) and phenylacetylene (PA) was synthesized. The structures and properties of the polymers were characterized and evaluated by FTIR, UVevis, 1 H NMR, GPC, optical limiting, and nonlinear optical analyses. The results show that poly(EAAB-co-PA) has the large third-order nonlinear susceptibility, which are two orders of magnitude larger than those of poly(PA) and novel optical limiting property.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.