Highly Specific Miniaturized Fluorescent Monoacylglycerol Lipase Probes Enable Translational Research

• DOI: 10.1021/jacs.4c15223
• Publication Date: 2025-03-10T18:38:41Z
• Authors: Axel Hentsch; Mónica Guberman; Silke Radetzki; Sofia Kaushik; Mirjam Huizenga; Yingfang He; Jörg Contzen; Bernd Kuhn; Jörg Benz; Maria Schippers; Jerome Paul; Lea Leibrock; Ludovic Collin; Matthias Wittwer; Andreas Topp; Fionn O’Hara; Dominik Heer; Remo Hochstrasser; Julie Blaising; Jens P. von Kries; Linjing Mu; Mario van der Stelt; Philipp Mergenthaler; Noa Lipstein; Uwe Grether; Marc Nazaré

Monoacylglycerol lipase (MAGL) is the pivotal catabolic enzyme responsible for signal termination in endocannabinoid system. Inhibition of MAGL offers unique advantages over direct activation cannabinoid receptors treating cancer, metabolic disorders, and inflammatory diseases. Although specific fluorescent molecular imaging probes are commonly used real-time analysis localization distribution drug targets cells, they almost invariably composed a linker connecting pharmacophore with large fluorophore. In this study, we have developed miniaturized targeting by incorporating highly boron-dipyrromethene (BODIPY) moiety into inhibitor structure that interacts active site. These exhibit favorable drug-like properties such as high solubility permeability, picomolar potency across various species, cell selectivity specificity. A range translational investigations were conducted, including cell-free fluorescence polarization assays, fluorescence-activated sorting analysis, confocal microscopy live cancer primary neurons, human-induced pluripotent stem cell-derived brain organoids. Furthermore, application red-shifted analogs or 18F positron emission labeling illustrated significant versatility adaptability ligands experimental contexts.