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To mitigate the problem of partially low MALDI ion yields for several of these analyte classes, different post ionization techniques have recently been developed\u2500for example, MALDI-2, where a second UV-laser pulse intersects the initial particle plume to generate additional charges. Here, we show that the MALDI-2 signal intensities of important analyte classes can be further increased upon introducing reactive dopant vapor into the MALDI-2 ion source. Dopant assistance as an optional add-on was realized in prototype form on MALDI-2 ion sources of a Spectroglyph Injector-Orbitrap MSI setup and a timsTOF fleX MALDI-2 instrument. Acetone, anisole, toluene, 2-propanol, and chlorobenzene were tested as dopants. Acetone proved to be the most effective and robust dopant for the given setup and MALDI matrix, and thus was used for further parameter optimization on both instruments. We demonstrate that with dopant-assisted (DA-)MALDI-2, a signal increase of up to 5 orders of magnitude, as compared to regular MALDI, is, for instance, achieved for several classes of sterols, glycerophospholipids, and sphingolipids. Next to the increased intensity of signals for abundant lipids, the total amount of annotated signals (based on MS1) was also majorly increased by the use of dopants. We demonstrate the potential for biomedical imaging applications with the examples of murine spleen and cerebellum sections, analyzed in the positive- and negative-ion mode.<\/jats:p>","DOI":"10.1021\/jasms.6c00149","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:01:59Z","timestamp":1790193719000},"page":"2331-2340","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing Ion Yields\nin MALDI-2-MSI Using Dopant-Assisted\nPost Ionization for High-Resolution MS-Imaging of Lipids and Metabolites"],"prefix":"10.1021","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3479-3841","authenticated-orcid":true,"given":"Christoph","family":"Bookmeyer","sequence":"first","affiliation":[{"name":"University of Mu\u0308nster , , ,","place":["Mu\u0308nster, Germany, 48149"]},{"name":"University of Tarragona , , ,","place":["Tarragona, Spain, 43003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Potthoff","sequence":"additional","affiliation":[{"name":"University of Mu\u0308nster , , ,","place":["Mu\u0308nster, Germany, 48149"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Stauff","sequence":"additional","affiliation":[{"name":"University of Mu\u0308nster , , ,","place":["Mu\u0308nster, Germany, 48149"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Dreisewerd","sequence":"additional","affiliation":[{"name":"University of Mu\u0308nster , , ,","place":["Mu\u0308nster, Germany, 48149"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0258-1561","authenticated-orcid":true,"given":"Jens","family":"Soltwisch","sequence":"additional","affiliation":[{"name":"University of Mu\u0308nster , , ,","place":["Mu\u0308nster, Germany, 48149"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"6231","key":"2026100710064380500_cit1","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1126\/science.aaa1051","article-title":"Mass Spectrometry Imaging with Laser-Induced\nPostionization","volume":"348","author":"Soltwisch","year":"2015","journal-title":"Science"},{"issue":"13","key":"2026100710064380500_cit2","doi-asserted-by":"publisher","first-page":"8697","DOI":"10.1021\/acs.analchem.0c01747","article-title":"MALDI-2 on\na Trapped Ion Mobility\nQuadrupole Time-of-Flight Instrument for Rapid Mass Spectrometry Imaging\nand Ion Mobility Separation of Complex Lipid Profiles","volume":"92","author":"Soltwisch","year":"2020","journal-title":"Anal. Chem."},{"issue":"53","key":"2026100710064380500_cit3","doi-asserted-by":"publisher","first-page":"7246","DOI":"10.1039\/C7CC02325A","article-title":"Laser Post-Ionisation\nCombined with a High Resolving\nPower Orbitrap Mass Spectrometer for Enhanced MALDI-MS Imaging of\nLipids","volume":"53","author":"Ellis","year":"2017","journal-title":"Chem. Commun."},{"issue":"29","key":"2026100710064380500_cit4","doi-asserted-by":"publisher","first-page":"15517","DOI":"10.1021\/acs.analchem.4c05249","article-title":"Mass\nSpectrometry Imaging","volume":"97","author":"Ko\u0308rber","year":"2025","journal-title":"Anal. Chem."},{"issue":"10","key":"2026100710064380500_cit5","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1007\/s00216-019-02290-3","article-title":"Evaluation of Lipid Coverage and\nHigh Spatial Resolution MALDI-Imaging Capabilities of Oversampling\nCombined with Laser Post-Ionisation","volume":"412","author":"Bowman","year":"2020","journal-title":"Anal. Bioanal.\nChem."},{"key":"2026100710064380500_cit6","doi-asserted-by":"publisher","first-page":"124795","DOI":"10.1016\/j.talanta.2023.124795","article-title":"Spatial Lipidomics and Metabolomics\nof Multicellular Tumor Spheroids\nUsing MALDI-2 and Trapped Ion Mobility Imaging","volume":"265","author":"Chen","year":"2023","journal-title":"Talanta"},{"key":"2026100710064380500_cit7","doi-asserted-by":"publisher","first-page":"127811","DOI":"10.1016\/j.talanta.2025.127811","article-title":"Enhanced Visualization of Endocannabinoids\nSpatial\nDistribution in Mouse Brain via MALDI-2 Mass Spectrometry Imaging","volume":"290","author":"Salviati","year":"2025","journal-title":"Talanta"},{"issue":"11","key":"2026100710064380500_cit8","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1021\/jasms.4c00241","article-title":"MALDI-2-Enabled Oversampling for\nthe Mass Spectrometry Imaging of Metabolites at Single-Cell Resolution","volume":"35","author":"McKinnon","year":"2024","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"20","key":"2026100710064380500_cit9","doi-asserted-by":"publisher","first-page":"13904","DOI":"10.1021\/acs.analchem.0c02732","article-title":"MALDI-2 for\nthe Enhanced Analysis of N-Linked Glycans by Mass Spectrometry Imaging","volume":"92","author":"Heijs","year":"2020","journal-title":"Anal. Chem."},{"issue":"16","key":"2026100710064380500_cit10","doi-asserted-by":"publisher","first-page":"10840","DOI":"10.1021\/acs.analchem.9b02495","article-title":"Enhanced\nSensitivity Using Maldi Imaging Coupled with Laser Postionization\n(Maldi-2) for Pharmaceutical Research","volume":"91","author":"Barre\u0301","year":"2019","journal-title":"Anal.\nChem."},{"issue":"25","key":"2026100710064380500_cit11","doi-asserted-by":"publisher","first-page":"10294","DOI":"10.1021\/acs.analchem.4c01088","article-title":"Large-Scale Screening of Pharmaceutical\nCompounds to\nExplore the Application Space of On-Tissue MALDI and MALDI-2 Mass\nSpectrometry","volume":"96","author":"Soltwisch","year":"2024","journal-title":"Anal. Chem."},{"issue":"9","key":"2026100710064380500_cit12","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/s41592-019-0536-2","article-title":"Transmission-Mode\nMALDI-2 Mass Spectrometry Imaging of Cells and Tissues at Subcellular\nResolution","volume":"16","author":"Niehaus","year":"2019","journal-title":"Nat. Methods"},{"issue":"11","key":"2026100710064380500_cit13","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.1021\/jasms.0c00237","article-title":"MALDI-2 at Atmospheric Pressure\u2500Parameter\nOptimization and First Imaging Experiments","volume":"31","author":"Niehaus","year":"2020","journal-title":"J. Am. Soc. 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Mass Spectrom."},{"issue":"4","key":"2026100710064380500_cit16","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1021\/jasms.1c00020","article-title":"Infrared MALDI Mass Spectrometry with Laser-Induced\nPostionization for Imaging of Bacterial Colonies","volume":"32","author":"Brockmann","year":"2021","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"1","key":"2026100710064380500_cit17","doi-asserted-by":"publisher","DOI":"10.1002\/anse.202100052","article-title":"Selective\nMass Spectrometry Imaging\nof Aromatic Antioxidants Using Sequential Matrix-Assisted Laser Desorption\nand Resonant Photoionisation","volume":"2","author":"Sarretto","year":"2022","journal-title":"Anal. Sens."},{"key":"2026100710064380500_cit18","doi-asserted-by":"publisher","DOI":"10.1002\/anie.4492989","article-title":"Beyond the Fixed\nCharge: A New On-Tissue Derivatisation\nStrategy Employing Photoionisable Chromophores for Mass Spectrometry\nImaging of Amino-Containing Metabolites","author":"McGowan","year":"2026","journal-title":"Angew.\nChem. Int. Ed."},{"key":"2026100710064380500_cit19","doi-asserted-by":"publisher","first-page":"4174","DOI":"10.1021\/ac8013675","article-title":"Light and\nMolecular Ions: The Emergence of Vacuum UV\nSingle-Photon Ionization in MS","volume":"81","author":"Hanley","year":"2009","journal-title":"Anal. Chem."},{"issue":"11","key":"2026100710064380500_cit20","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1016\/j.jasms.2004.07.006","article-title":"Mechanism\nof [M + H] + Formation in Photoionization Mass Spectrometry","volume":"15","author":"Syage","year":"2004","journal-title":"J. Am. Soc. Mass Spectrom."},{"issue":"34","key":"2026100710064380500_cit21","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202202165","article-title":"Single-Photon-Induced\nPost-Ionization to Boost Ion Yields in MALDI Mass Spectrometry Imaging","volume":"61","author":"Bookmeyer","year":"2022","journal-title":"Angew. Chem. Int. Ed."},{"issue":"3","key":"2026100710064380500_cit22","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1002\/mas.21477","article-title":"Recent Developments\nin Atmospheric\nPressure Photoionization-mass Spectrometry","volume":"36","author":"Kauppila","year":"2017","journal-title":"Mass Spectrom. Rev."},{"issue":"7","key":"2026100710064380500_cit23","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1002\/cplu.202000462","article-title":"Low-Pressure\nPhotoionization in a Dual-Ion Funnel Injector Coupled to an Orbitrap\nMass Spectrometer for Direct Analysis of Human Breath and Head-Space\nSampled Coffee Roasts","volume":"85","author":"Bookmeyer","year":"2020","journal-title":"ChemPluschem"},{"issue":"16","key":"2026100710064380500_cit24","doi-asserted-by":"publisher","first-page":"5106","DOI":"10.1016\/j.jprot.2012.07.026","article-title":"ImzML \u2500\nA Common Data Format for the Flexible Exchange and Processing of Mass\nSpectrometry Imaging Data","volume":"75","author":"Schramm","year":"2012","journal-title":"J. Proteomics"},{"issue":"11","key":"2026100710064380500_cit25","doi-asserted-by":"publisher","first-page":"3618","DOI":"10.1093\/bioinformatics\/btaa142","article-title":"RMSIproc: An R Package\nfor Mass Spectrometry Imaging Data Processing","volume":"36","author":"Ra\u0300fols","year":"2020","journal-title":"Bioinformatics"},{"issue":"D1","key":"2026100710064380500_cit26","doi-asserted-by":"publisher","first-page":"D502","DOI":"10.1093\/nar\/gkv1229","article-title":"EnviPath -The\nEnvironmental Contaminant\nBiotransformation Pathway Resource","volume":"44","author":"Wicker","year":"2016","journal-title":"Nucleic\nAcids Res."},{"key":"2026100710064380500_cit27","doi-asserted-by":"publisher","first-page":"114936","DOI":"10.1016\/j.microc.2025.114936","article-title":"Comprehensive\nMSI-Based Protocols for the Spatial Lipidomics Characterization of\nMicroscale Organisms","volume":"217","author":"Mene\u0301ndez-Pedriza","year":"2025","journal-title":"Microchem. J."},{"issue":"41","key":"2026100710064380500_cit28","doi-asserted-by":"publisher","first-page":"16127","DOI":"10.1021\/acs.analchem.4c00258","article-title":"Experimental\nand Computational Evaluation of Lipidomic In-Source Fragmentation\nas a Result of Postionization with Matrix-Assisted Laser Desorption\/Ionization","volume":"96","author":"Vandergrift","year":"2024","journal-title":"Anal. Chem."},{"issue":"7","key":"2026100710064380500_cit29","doi-asserted-by":"publisher","first-page":"3150","DOI":"10.1063\/1.437009","article-title":"Molecular\nBeam Photoionization Study\nof Acetone and Acetone- d 6","volume":"69","author":"Trott","year":"1978","journal-title":"J. Chem. Phys."},{"issue":"10","key":"2026100710064380500_cit30","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41580-024-00758-4","article-title":"Pitfalls in Lipid Mass\nSpectrometry of Mammalian Samples\n\u2500 a Brief Guide for Biologists","volume":"25","author":"Skotland","year":"2024","journal-title":"Nat.\nRev. Mol. Cell Biol."},{"issue":"4","key":"2026100710064380500_cit31","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/s41556-024-01377-z","article-title":"A Lipid Atlas of Human and Mouse\nImmune Cells Provides\nInsights into Ferroptosis Susceptibility","volume":"26","author":"Morgan","year":"2024","journal-title":"Nat.\nCell Biol."},{"key":"2026100710064380500_cit32","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/978-1-4419-6741-1_9","article-title":"Ceramide-1-Phosphate in Phagocytosis and Calcium Homeostasis","volume-title":"Sphingolipids as Signaling and Regulatory Molecules.\nAdvances in Experimental Medicine and Biology","author":"Hinkovska-Galcheva","year":"2010"},{"issue":"1","key":"2026100710064380500_cit33","doi-asserted-by":"publisher","first-page":"9377","DOI":"10.1038\/s41598-017-09980-x","article-title":"Changes of\nPlasmalogen Phospholipid Levels during Differentiation of Induced\nPluripotent Stem Cells 409B2 to Endothelial Phenotype Cells","volume":"7","author":"Nakamura","year":"2017","journal-title":"Sci. Rep."},{"issue":"1","key":"2026100710064380500_cit34","doi-asserted-by":"publisher","first-page":"9129","DOI":"10.1038\/s41467-025-64603-8","article-title":"Spatial Biology Using Single-Cell\nMass Spectrometry\nImaging and Integrated Microscopy","volume":"16","author":"Potthoff","year":"2025","journal-title":"Nat. Commun."},{"key":"2026100710064380500_cit35","doi-asserted-by":"publisher","first-page":"6161","DOI":"10.1039\/D3AN01495A","article-title":"State-of-the-Art\nMass Spectrometry\nImaging Applications in Biomedical Research","volume":"148","author":"Krestensen","year":"2023","journal-title":"Analyst"},{"issue":"1","key":"2026100710064380500_cit36","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/s43586-026-00492-5","article-title":"Matrix-Assisted\nLaser Desorption\/Ionization Imaging Mass Spectrometry","volume":"6","author":"Spraggins","year":"2026","journal-title":"Nat. Rev. Methods Primers"}],"container-title":["Journal of the American\nSociety for Mass Spectrometry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jasms.6c00149","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jamsef\/article-pdf\/37\/10\/2331\/68626418\/jasms.6c00149.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jamsef\/article-pdf\/37\/10\/2331\/68626418\/jasms.6c00149.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:23:47Z","timestamp":1791383027000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jamsef\/article\/37\/10\/2331\/5436941\/Enhancing-Ion-Yields-in-MALDI-2-MSI-Using-Dopant"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,23]]},"published-print":{"date-parts":[[2026,10,7]]}},"URL":"https:\/\/doi.org\/10.1021\/jasms.6c00149","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv.15006458\/v1","asserted-by":"object"}]},"ISSN":["1044-0305","1879-1123"],"issn-type":[{"value":"1044-0305","type":"print"},{"value":"1879-1123","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]}}}