Here we show, to our knowledge for the first time, preliminary data that the use of CYP3A4 inhibitors may influence striatal [123I]I-FP-CIT binding ratios.

It is reported that a small amount of [123I]I-nor-β-CIT will be formed by the enzyme CYP3A4 after [123I]I-FP-CIT administration [5]. Since [123I]I-nor-β-CIT can pass the BBB and has a very high affinity for the SERT and also a high affinity for the DAT, we postulated that the use of CYP3A4 inhibitors may influence striatal [123I]I-FP-CIT binding ratios [11]. On the one hand, our findings indeed supported this hypothesis. On the other hand, we postulated that lower formation of [123I]I-nor-β-CIT, due to the use of CYP3A4 inhibitors, may induce lower non-specific binding, which was not supported by our present data. In fact, the occipital counts were comparable between both groups, but the striatal counts were statistically higher in the group using CYP3A4 inhibitors than in the control group. It is well known that SERTs are expressed throughout the body [7]. So, it is possible that the use of CYP3A4 inhibitors will increase the availability of parent [123I]I-FP-CIT to enter the brain, due to lower formation of [123I]I-nor-β-CIT. This may lead to higher striatal [123I]I-FP-CIT binding ratios in CYP3A4 inhibitors users. Given the variability in the activity of CYP3A4 enzymes by up to a factor of 100 between individuals [12], it is expected that the use of CYP3A4 inhibitors will make the formation of [123I]I-nor-β-CIT more uniform. These more consistently lower levels of [123I]I-nor-β-CIT can explain the relatively narrow SD of the binding ratios in CYP3A4 inhibitor users (Fig. 2). Consequently, this may reduce the variability in the interindividual striatal [123I]I-FP-CIT to nonspecific binding ratio. These postulates can be tested in future studies.

In a recent systematic review, we examined medications that may reduce striatal [123I]I-FP-CIT binding ratios, and as such may induce false-positive cases [2]. However, our present data do not suggest that use of CYP3A4 inhibitors may induce lower binding ratios. If this finding is confirmed in future larger studies, then it is unlikely that the use of CYP3A4 inhibitors will lead to false-positive results. For illustration purposes, see a PD case who underwent [123I]I-FP-CIT SPECT imaging while using an CYP3A4 inhibitor (Fig. 3). Thus, a false-positive result will not be likely when a visual analysis is performed, also because it is unlikely that asymmetry and putamen-to-caudate ratios will be influenced by CYP3A4 inhibitors. Nevertheless, we cannot exclude that use of this class of drugs may increase the striatal binding ratios, e.g., in an early PD case, to borderline levels. Future studies may address this relevant topic.

An [123I]I-FP-CIT SPECT scan performed in a patient suffering from Parkinson’s disease (PD), imaged while using an CYP3A4 inhibitor. Transversal slide at the level of the striatum. Please note the asymmetric striatal binding, and lower binding in the putamen than in the caudate nucleus. This pattern is typical of PD. This scan was rated as being abnormal based on the visual analysis as well as the quantitative analysis performed in BRASS, which showed decreased age-corrected binding ratios for the putamen bilaterally (data not shown)

Our present study has several limitations. Due to its retrospective design, we had to rely on the accuracy of the digitally reported data, introducing uncertainty about whether all included CYP3A4 users were indeed on this drug during DAT imaging. Nevertheless, it is unlikely that they were not using this medication, especially given that drugs like amiodarone and diltiazem are chronically used for severe clinical conditions such as heart arrhythmias. Additionally, in routine practice we do not advice to withdrawn these medications before DAT imaging. Furthermore, we had to rely on a small cross-sectional design. In future studies it may be of interest to perform a larger placebo-controlled study. Alternatively, a study can be designed in which the first [123I]I-FP-CIT SPECT scan is acquired just before starting the use of an CYP3A4 inhibitor, while a second scan will be acquired several weeks, in which the drug is taken under supervision at a standardized time before tracer injection. Furthermore, it may be relevant to examine the metabolism of [123I]I-FP-CIT during both imaging sessions. Also, in the present study we determined the non-specific binding in the occipital cortex. This is clinically relevant since many centers use commercially available software to quantify [123I]I-FP-CIT SPECT scans in routine practice. When using software such as BRASS and DaTQUANT, the occipital cortex is commonly used to assess the non-specific binding. However, to gain a better understanding of how CYP3A4 inhibitors may influence [123I]I-FP-CIT binding, it may also be of interest to evaluate binding in the ventral striatum, and non-specific binding in the inferior parts of the cerebellum, as these brain areas are devoid of DAT and SERT expression [7, 8]. Finally, here we focused on CYP3A4 inhibitors. In future studies it may be of interest to evaluate also the potential effects of CYP3A4 inducers on the striatal [123I]I-FP-CIT binding ratios.

In conclusion, our preliminary retrospective data suggest that the use of CYP3A4 inhibitors may influence striatal [123I]I-FP-CIT binding ratios. This finding may initiate larger prospective studies to reproduce our present novel finding, and to examine the mechanism by which CYP3A4 inhibitors may influence the quantification of [123I]I-FP-CIT SPECT scans.