In four patients suspected of Parkinson’s disease, we found a sertraline-induced significant dose-dependent reduction of [18F]FE-PE2I SBR in caudate nucleus that has not previously been described. The findings are in line with sertraline’s known high binding affinity for the DaT and may possess clinical implications due to the rather frequent use of sertraline. Thus, possible sertraline medication must be kept in mind when interpreting [18F]FE-PE2I PET scans. Other SSRIs have much lower affinity for DaT and should not influence DaT imaging. It is not known to what degree these findings are transferable to other radiolabelled DaT tracers, as [123I]FP-CIT show increased SBR during SSRI treatment [15]. Thus, we do not know how [123I]FP-CIT SPECT is influenced by sertraline. PET tracers targeting the dopamine synthesis, e.g. [18F]FDOPA or vesicular monoamine transporter, [18F]FP-DTBZ, should not be susceptible to sertraline. Optimally, sertraline should be discontinued before [18F]FE-PE2I PET, but the risk of a discontinuation syndrome with flu-like symptoms, imbalance, strange skin sensations, hyperarousal, and insomnia needs to be kept in mind [16, 17].

The SBR reduction induced by sertraline is in the order of magnitude of daily treatment with 100 mg Modafinil (normal dose for elderly patients), which is known to reduce DaT-activity.

The magnitude of [18F]FE-PE2I reduction significantly influencing the interpretation of DaT imaging may be highly variable between patients as normal limits of striatal SBR are from 3 to 7 on our scanner system. We found that SBR is reduced by 0.38 for each increase in P-sertraline of 0.01 mg/mL. Thus, a 75-kg male taking 50 mg per day results in a SBR reduction of 0.32, while a 65-kg female is reduced by 0.44. Depending on bodyweight and gender, a dose of 50 mg may be acceptable if the reduction is kept in mind when interpreting the scan. Higher doses can be switched to another SSRI with low affinity for the DaT such as escitalopram [18]. Alternatively, only patients with equivocal scan results could be rescanned after a 5-day sertraline pause as most patients with neurodegenerative diseases affecting the dopamine system show a characteristic “neurodegenerative pattern”. Such patterns including reduced binding in the posterior putamen or sometimes striking left–right asymmetry are not expected with pharmacological DaT blockade, where the entire striatum shows more globally and homogeneously reduced binding.

There are limitations to the study, including the sample size. However, the dose-dependent decrease in all subjects combined with sertraline’s high affinity for DaT supports the influence of sertraline for [18F]FE-PE2I PET imaging. Further, [18F]FE-PE2I PET has previously been shown to have good test–retest reproducibility [19, 20] supporting that the present results are trustworthy. All patients had a number of comorbidities, which may have influenced the results. Further, only patients with equivocal scan results were rescanned as the study was performed in a clinical setting. And a number of patients who despite of sertraline usage still showed marked asymmetry due to Parkinson’s disease may not even have been identified.

The biological half-life of sertraline is highly variable and discontinuation for five days may not be sufficient in all cases, and remaining sertraline in plasma or receptor bound may still be interfering with the second [18F]FE-PE2I PET. Furthermore, the major metabolite of sertraline, N-desmethyl-sertraline, has a half-life of 60–70 h and a low KD for DaT at 129 nM [9, 14]. Thus, our findings may have underestimated the blocking effect of sertraline. The present study cannot robustly determine a cut-off value for daily sertraline ingestion or determine the optimal length for discontinuation. The suggested cut-off of 50 mg and 5-day sertraline pause is a rough estimate, and a prospective dose response study is warranted.

In conclusion, the significant dose-dependent reduction of [18F]FE-PE2I uptake in sertraline-treated patients should be taken into account in future [18F]FE-PE2I PET imaging.