Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase.

Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC ₅₀  = 18.6 nM and (S)-6, IC ₅₀  = 1.6 nM). In vitro autoradiography studies of [ ¹⁸ F](R)-6 (codenamed [ ¹⁸ F]MAGL-2304) and [ ¹⁸ F](S)-6 (codenamed [ ¹⁸ F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [ ¹⁸ F](S)-6. Dynamic PET imaging studies revealed that [ ¹⁸ F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [ ¹⁸ F](S)-6 uptake in the brain, suggesting that [ ¹⁸ F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Steven Liang reports financial support was provided by Emory University. Ming-Rong Zhang reports financial support was provided by National Institutes for Quantum Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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