Modeling Midbrain and Brainstem Neuromelanins to Characterize Metal Binding and Associated MRI Contrast in Parkinson's and Alzheimer's Diseases

Abstract Neuromelanin (NM) is a dark pigment that binds potentially toxic metal ions and is crucial for neuronal vulnerability. Magnetic resonance imaging (MRI) was proposed to measure neuromelanin in the substantia nigra or locus coeruleus , 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‐sensitive 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‐metal 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.