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Background and Purpose: We investigated the relationship between serotonergic and dopaminergic specific binding transporter ratios (SBRs) over 4 years in Parkinson's disease (PD) patients. We assessed serotonergic innervation's potential compensatory role for dopaminergic denervation, association with PD symptoms, and involvement in the development of levodopa-induced dyskinesia (LID)., Methods: SBRs of the midbrain and striatum were evaluated from [I-123] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane SPECT images at baseline and after 4 years. Correlations between SBRs and PD symptoms were analyzed, alongside interval changes., Results: Study included 177 PD patients (110 males, 67 females; mean age 61.0 ± 9.0 years). Significant worsening was observed in Hoehn and Yahr staging and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and III scores over 4 years (p < 0.05, p < 0.001, and p < 0.001, respectively). SBRs of the caudate, putamen, and midbrain declined significantly (p < 0.001). Midbrain and striatal SBRs correlated significantly at both baseline and 4-year follow-up (p < 0.0001). Striatal SBRs correlated significantly with MDS-UPDRS II and III scores at both time points, while midbrain SBRs correlated with changes in MDS-UPDRS III scores over the 4 years (p < 0.01). Putamen and midbrain SBRs at 4 years were significantly lower in patients who developed LID compared to those who did not (p < 0.05)., Conclusion: The study demonstrates correlations between midbrain and putamen SBRs and MDS-UPDRS scores over 4 years in PD patients. Midbrain serotonin dysfunction may contribute to the development of LID., (© 2025 American Society of Neuroimaging.)