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Here, we present a scalable and broadly applicable molecular annotation tool for tandem mass spectrometry imaging (MS\n                    <jats:sup>2<\/jats:sup>\n                    I). Our workflow includes parallel image acquisition (PIA) for parallel MS\n                    <jats:sup>2<\/jats:sup>\n                    I and an open\u2010access computational framework for spatial similarity networking (SSN) that enables molecular annotation of MS\n                    <jats:sup>2<\/jats:sup>\n                    I data with isomeric specificity. The PIA enables simultaneous untargeted MSI and targeted MS\n                    <jats:sup>2<\/jats:sup>\n                    I ensuring structure\u2010specific imaging of hundreds of molecules in a single experiment. The SSN increases annotation confidence through graph\u2010based spatial correlation of product ion distributions, opening up new avenues for data investigation and annotation from both MSI and MS\n                    <jats:sup>2<\/jats:sup>\n                    I data. By integrating PIA and SSN into a single workflow, we visualize and annotate 134 phospholipid isomers and isobars in mouse brain tissue. Furthermore, we demonstrate the biological utility of the platform by mapping cholesterol metabolism in human multiple sclerosis brain tissue, revealing lesion\u2010associated cholesterol oxidation pathways. Finally, we propose annotation confidence levels for structural annotation in MSI. Overall, PIA and SSN together provide large\u2010scale, structure\u2010specific MSI, expanding the scope for spatial metabolomics, lipidomics, and chemical pathology through molecular annotation beyond current capabilities.\n                  <\/jats:p>","DOI":"10.1002\/anie.202522119","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T04:59:13Z","timestamp":1774933153000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multiplexed Tandem Mass Spectrometry Imaging Enables Large\u2010Scale Isomer Mapping and Annotation in Tissues"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0572-2697","authenticated-orcid":false,"given":"Varun V.","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Chemistry for Life Science Uppsala University  Uppsala 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