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OBJECTIVE To explore the feasibility of a neuroprotection trial in prodromal synucleinopathy, using idiopathic REM sleep behavior disorder (iRBD) as the target population and 123 I-FP-CIT-SPECT as a biomarker of disease progression. METHODS Consecutive iRBD patients were randomly assigned to a treatment arm, receiving selegiline and symptomatic RBD treatment, or to a control arm, receiving symptomatic treatment only. Selegiline was chosen because of a demonstrated neuroprotection effect in animal models. Patients underwent123 I-FP-CIT-SPECT at baseline and after 30 months in average. The clinical outcome was the emergence of parkinsonism and/or dementia. A repeated-measures general linear model (GLM) was applied, using group (control and treatment) as 'between' factor, and both time (baseline and follow-up) and regions (123 I-FP-CIT-SPECT putamen and caudate uptake) as 'within' factors, adjusting for age. RESULTS Thirty iRBD patients completed the study (68.2±6.9 years; 29 males; 21% drop-out rate), 13 in the treatment arm and 17 in the control arm. At follow-up (29.8±9.0 months), three patients in the control arm developed dementia and one parkinsonism while two patients in the treatment arm developed parkinsonism. Both putamen and caudate uptake decreased over time in the control arm. In the treatment arm, only the putamen uptake decreased over time while caudate uptake remained stable. GLM analysis demonstrated an effect of treatment on the 123 I-FP-CIT-SPECT uptake change, with a significant interaction between the effect of group, time and regions (p=0.004). CONCLUSION A 30-months neuroprotection study for prodromal synucleinopathy is feasible, using iRBD as the target population, and 123 I-FP-CIT-SPECT as a biomarker of disease progression.