{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:36:34Z","timestamp":1789212994320,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinics and Practice"],"abstract":"<jats:p>Background\/Objectives: Magnetic resonance imaging (MRI) is a powerful, non-invasive diagnostic tool capable of capturing detailed anatomical and physiological information. MRI contrast agents enhance image contrast but, especially linear gadolinium-based compounds, have been associated with safety concerns. This has prompted interest in alternative contrast agents. Manganese-based contrast agents offer a promising substitute, owing to manganese\u2019s favorable magnetic properties, natural biological role, and strong T1 relaxivity. This review aims to critically assess the structure, mechanisms, applications, and challenges of manganese-based contrast agents in MRI. Methods: This review synthesizes findings from preclinical and clinical studies involving various types of manganese-based contrast agents, including small-molecule chelates, nanoparticles, theranostic platforms, responsive agents, and controlled-release systems. Special attention is given to pharmacokinetics, biodistribution, and safety evaluations. Results: Mn-based agents demonstrate promising imaging capabilities, with some achieving relaxivity values comparable to gadolinium compounds. Targeted uptake mechanisms, such as hepatocyte-specific transport via organic anion-transporting polypeptides, allow for enhanced tissue contrast. However, concerns remain regarding the in vivo release of free Mn2+ ions, which could lead to toxicity. Preliminary toxicity assessments report low cytotoxicity, but further comprehensive long-term safety studies should be carried out. Conclusions: Manganese-based contrast agents present a potential alternative to gadolinium-based MRI agents pending further validation. Despite promising imaging performance and biocompatibility, further investigation into stability and safety is essential. Additional research is needed to facilitate the clinical translation of these agents.<\/jats:p>","DOI":"10.3390\/clinpract15080137","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:38:41Z","timestamp":1753443521000},"page":"137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Manganese-Based Contrast Agents as Alternatives to Gadolinium: A Comprehensive Review"],"prefix":"10.3390","volume":"15","author":[{"given":"Linda","family":"Poggiarelli","sequence":"first","affiliation":[{"name":"School of Medicine, Universit\u00e0 Campus Bio-Medico di Roma, via Alvaro Del Portillo, 21, 00128 Rome, Italy"},{"name":"Research Unit of Diagnostic Imaging, Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Bernetti","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e0 Campus Bio-Medico di Roma, via Alvaro Del Portillo, 21, 00128 Rome, Italy"},{"name":"Research Unit of Diagnostic Imaging, Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Pugliese","sequence":"additional","affiliation":[{"name":"Radiology Unit, Department of Medical-Surgical Sciences and Translational Medicine, Sant\u2019 Andrea University Hospital, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9477-0238","authenticated-orcid":false,"given":"Federico","family":"Greco","sequence":"additional","affiliation":[{"name":"Research Unit of Diagnostic Imaging, Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, 00128 Rome, Italy"},{"name":"Department of Radiology, Cittadella della Salute, Azienda Sanitaria Locale di Lecce, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Beomonte Zobel","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e0 Campus Bio-Medico di Roma, via Alvaro Del Portillo, 21, 00128 Rome, Italy"},{"name":"Research Unit of Diagnostic Imaging, Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0149-0801","authenticated-orcid":false,"given":"Carlo A.","family":"Mallio","sequence":"additional","affiliation":[{"name":"School of Medicine, Universit\u00e0 Campus Bio-Medico di Roma, via Alvaro Del Portillo, 21, 00128 Rome, Italy"},{"name":"Research Unit of Diagnostic Imaging, Department of Medicine and Surgery, Universit\u00e0 Campus Bio-Medico di Roma, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1097\/RLI.0000000000000431","article-title":"Effect of Age on High T1 Signal Intensity of the Dentate Nucleus and Globus Pallidus in a Large Population Exposed to Gadodiamide","volume":"53","author":"Quattrocchi","year":"2018","journal-title":"Investig. 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