{"doi":"10.7150/thno.106592","title":"Sex- and age-specific sensitivities of the endocannabinoid system in Alzheimer's disease revealed by PET imaging with [<sup>18</sup>F]FMPEP-<i>d</i><sub>2</sub> and [<sup>18</sup>F]MAGL-2102","abstract":"The endocannabinoid system is a critical brain signaling pathway that is dysregulated in various brain disorders, including Alzheimer's disease (AD).Cannabinoid-targeted therapies and imaging approaches have gained increasing interest; however, the biological impact of the endocannabinoid system in disease needs further validation.We aimed to study changes in cannabinoid receptor 1 (CB1) and monoacylglycerol lipase (MAGL), components of endocannabinoid signaling and degradation, in a mouse model of AD by PET imaging.Methods: [ 18 F]FMPEP-d2 and [ 18 F]MAGL-2102 were produced on a commercial radiosynthesis module.PET-CT images with both tracers were acquired in a knock-in mouse model of AD bearing mutated human amyloid precursor protein (App NL-G-F ) at 3 ages, and compared to wild-type mice.Excised brains were used for in vitro autoradiography with [ 18 F]FMPEP-d2 and [ 18 F]MAGL-2102, immunofluorescence, and western blotting.Male wild-type and 5xFAD mice were chronically treated with MAGL inhibitor JZL184 and imaged with [ 18 F]MAGL-2102 two days after ending treatment.Results: PET imaging showed sex-, age-and genotype-dependent changes in CB1 and MAGL availability.At 4-months (early-stage -amyloid pathology), female App NL-G-F mice had lower CB1 availability, and MAGL availability was increased in male App NL-G-F , compared to wild-types.At 8-months, no genotype differences in CB1 were observed, yet MAGL availability was reduced in App NL-G-F frontal cortex, and male App NL-G-F mice exhibited higher MAGL than transgenic females brain-wide.At 12-months (late-stage -amyloid pathology), significantly lower uptake of [ 18 F]FMPEP-d2 was observed in App NL-G-F compared to wild-type, with no changes in [ 18 F]MAGL-2102 binding.App NL-G-F plaque staging was confirmed by Thioflavin-S staining.Imaging findings were supplemented by autoradiography, immunofluorescence, and western blots.[ 18 F]MAGL-2102 availability was responsive to target engagement of the MAGL inhibitor JZL184 in wild-type and 5xFAD mice.Conclusions: The present study showed dynamic age-, sex-and pathology-related changes in CB1 and MAGL availability from early-stage -amyloid pathology, suggesting that the endocannabinoid system is a useful target for diagnostics and treatment of AD.Finally, these results highlight that endocannabinoid sex differences should be considered in diagnostics and drug development.","journal":"Theranostics","year":2025,"id":540418,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":355340,"name":"Christopher D. Morrone","orcid":"0000-0002-5887-2691","position":1,"is_corresponding":false},{"id":352770,"name":"Junchao Tong","orcid":"0000-0001-9299-0045","position":2,"is_corresponding":false},{"id":338777,"name":"Jian Rong","orcid":"0000-0002-3960-1669","position":3,"is_corresponding":false},{"id":338771,"name":"Tuo Shao","orcid":"0000-0001-7144-9823","position":4,"is_corresponding":false},{"id":1236756,"name":"Darcy Wear","orcid":"0000-0002-1311-7991","position":5,"is_corresponding":false},{"id":338781,"name":"Steven H. Liang","orcid":"0000-0003-1413-6315","position":6,"is_corresponding":false},{"id":902014,"name":"Wai Haung Yu","orcid":"0000-0001-7186-6731","position":7,"is_corresponding":false},{"id":345082,"name":"Neil Vasdev","orcid":"0000-0002-2087-5125","position":8,"is_corresponding":false},{"id":1241594,"name":"Anna Pees","orcid":"0000-0001-8207-3358","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:52:38.861025Z","pmid":"40093888","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}