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Magnetic resonance imaging (MRI) was proposed to measure neuromelanin in the <jats:italic>substantia nigra<\/jats:italic> or <jats:italic>locus coeruleus<\/jats:italic>, potentially providing a marker of Parkinson's disease. Here, synthetic neuromelanin analogues were prepared with iron and copper and used for characterization of metal binding and impact on proton relaxation, a prerequisite for optimizing neuromelanin\u2010sensitive MRI. The results confirm the presence of paramagnetic mononuclear Fe(III) and antiferromagnetically coupled clusters, which enhance relaxation to variable degrees. Further complexity arises from Cu(II), which can compete for binding to mononuclear sites, aggregate in mixed\u2010metal clusters, or bind to proteins associated with the melanin moiety. Unlike the strong relaxant Fe(III), Cu(II) only indirectly impacts relaxation by replacing iron. Overall, MRI primarily provides measures of average neuromelanin concentrations. Information on the distribution of neuromelanins with different metal compositions might be obtained with multiparametric MRI.<\/jats:p>","DOI":"10.1002\/anie.202509102","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T13:55:59Z","timestamp":1758290159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Modeling Midbrain and Brainstem Neuromelanins to Characterize Metal Binding and Associated MRI Contrast in Parkinson's and Alzheimer's Diseases"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4952-7962","authenticated-orcid":false,"given":"Niklas","family":"Wallstein","sequence":"first","affiliation":[{"name":"NMR Methods &amp; Development Group Max Planck Institute for Human Cognitive and Brain Sciences  Stephanstra\u00dfe 1A 04103 Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2731-3547","authenticated-orcid":false,"given":"Andrea","family":"Capucciati","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pavia  Via Taramelli 12 Pavia 27100 Italy"},{"name":"Fondazione Pezzoli per la Malattia di Parkinson  Via Gianfranco Zuretti 35 Milan 20125 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2354-2542","authenticated-orcid":false,"given":"Andreas","family":"P\u00f6ppl","sequence":"additional","affiliation":[{"name":"Felix Bloch Institute for Solid State Physics Leipzig University  Linn\u00e9stra\u00dfe 5 04103 Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3688-7104","authenticated-orcid":false,"given":"Claudia S.","family":"Schnohr","sequence":"additional","affiliation":[{"name":"Felix Bloch Institute for Solid State Physics Leipzig University  Linn\u00e9stra\u00dfe 5 04103 Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8122-6188","authenticated-orcid":false,"given":"Michela","family":"Sturini","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Pavia  Via Taramelli 12 Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9319-5016","authenticated-orcid":false,"given":"Andr\u00e9","family":"Pampel","sequence":"additional","affiliation":[{"name":"NMR Methods &amp; 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