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Visual, voxel, and volumetric region of interest (<jats:styled-content style=\"fixed-case\">VOI<\/jats:styled-content>) analyses were used to elucidate synaptic density patterns in the <jats:styled-content style=\"fixed-case\">MSA<\/jats:styled-content> brain and establish diagnostic criteria. The diagnostic performances of both visual and <jats:styled-content style=\"fixed-case\">VOI<\/jats:styled-content>\u2010based diagnostics were evaluated using receiver operating characteristic <jats:styled-content style=\"fixed-case\">(ROC)<\/jats:styled-content> analysis. Spearman correlation analyses were conducted to investigate the relationship between brain synaptic density and disease severity<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with MSA displayed extensive reductions in synaptic density throughout the brain, notably affecting both primary VOIs (the cerebellum and putamen) and secondary VOIs including the medulla oblongata, ventral tegmental area, and pons. Notably, patients with MSA\u2010C exhibited a remarkable decrease in cerebellar synaptic density, whereas patients with MSA\u2010P demonstrated significant synaptic loss within the posterior putamen. Compared with patients with PD, the patients with MSA show a more pronounced reduction in synaptic density in infratentorial brain regions. VOI\u2010based diagnosis significantly outperformed visual analysis in diagnosing and differentiating MSA and its subtypes. Synaptic density in primary and multiple secondary VOIs correlated significantly with motor scales in patients with MSA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our study identified widespread synaptic density reductions in MSA, particularly in the basal ganglia and infratentorial region, suggesting [<jats:sup>18<\/jats:sup>F]SynVesT\u20101 PET as a potential biomarker for diagnosing and evaluating the disease, and guiding synaptic restoration trials. 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