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MAGL inhibition results in indirect activation of the cannabinoid receptors, which offers unique advantages for the treatment of, e.g., multiple sclerosis, epilepsy, and other neurological disorders. Molecular imaging techniques are valuable tools to overcome the current poor understanding of MAGL's distribution and role in patho\u2010 and physiological processes within ECS signaling. Herein, we report the design, synthesis, and validation of highly selective versatile fluorescent and click\u2010chemistry probes for MAGL. Structure\u2010based design combined with a reverse\u2010design approach allowed the development of a structural unit that selectively and effectively recognizes MAGL while offering a versatile platform to attach different fluorophores and further reporter units. In this way, labeled probes with sub\u2010nanomolar potency carrying diverse fluorescent dyes were obtained. Probe affinity and selectivity remained invariant to changes in the fluorophore subunit, showing the remarkable robustness of this platform in delivering tailor\u2010made probes. Highly consistent inhibition across species supports pharmacological model translatability. Extensive profiling and validation in various cellular systems shows the ability of these highly potent and selective probes to elucidate the complex role of MAGL in ECS cellular signaling, inflammatory processes, and disease progression.<\/jats:p>","DOI":"10.1002\/anie.202413405","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T03:31:01Z","timestamp":1738899061000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A Highly Selective and Versatile Probe Platform for Visualization of Monoacylglycerol Lipase"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-1199","authenticated-orcid":false,"given":"Axel","family":"Hentsch","sequence":"first","affiliation":[{"name":"Leibniz Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP)  Robert-Roessle-Strasse 10 13125 Berlin GER"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2407-4771","authenticated-orcid":false,"given":"M\u00f3nica","family":"Guberman","sequence":"additional","affiliation":[{"name":"Leibniz Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP)  Robert-Roessle-Strasse 10 13125 Berlin GER"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2688-2868","authenticated-orcid":false,"given":"Silke","family":"Radetzki","sequence":"additional","affiliation":[{"name":"Leibniz Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP)  Robert-Roessle-Strasse 10 13125 Berlin GER"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5757-764X","authenticated-orcid":false,"given":"Sofia","family":"Kaushik","sequence":"additional","affiliation":[{"name":"Leibniz Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP)  Robert-Roessle-Strasse 10 13125 Berlin GER"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Huizenga","sequence":"additional","affiliation":[{"name":"Leiden Institute of Chemistry (LIC) Universiteit Leiden  Einsteinweg 55 2333 CC Leiden NL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Paul","sequence":"additional","affiliation":[{"name":"Leibniz Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP)  Robert-Roessle-Strasse 10 13125 Berlin GER"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Schippers","sequence":"additional","affiliation":[{"name":"Pharma Research &amp; Early Development (pRED) F. 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