CYP3A4 inhibitors may influence the quantification of [123I]I-FP-CIT SPECT scans

Abstract

Purpose: [¹²³I]I-FP-CIT SPECT is an imaging tool to support the diagnosis of parkinsonian syndromes characterized by nigrostriatal dopaminergic degeneration. After intravenous injection, [¹²³I]I-FP-CIT is metabolized for a small part by the enzyme CYP3A4, leading to the formation of [¹²³I]I-nor-β-CIT. [¹²³I]I-nor-β-CIT passes the blood-brain barrier and has a very high affinity for the serotonin transporter (SERT). The SERT is expressed in the striatum and cortical areas. So, at least theoretical, the use of frequently used CYP3A4 inhibitors (like amiodarone) may influence the specific to non-specific striatal [¹²³I]I-FP-CIT ratio. Here we tested this novel hypothesis.

Methods: Using a retrospective design, we determined the specific to non-specific striatal [¹²³I]I-FP-CIT ratio (using BRASS software) in 6 subjects that were using an CYP3A4 inhibitor and 18 matched controls. Only subjects were included with a normal rated [¹²³I]I-FP-CIT SPECT scan, and all participants were scanned on the same brain-dedicated SPECT system.

Results: The specific to non-specific (assessed in the occipital cortex) striatal [¹²³I]I-FP-CIT binding ratio was significantly higher in CYP3A4 users than in the control group (3.52 ± 0.33 vs. 2.90 ± 0.78, p < 0.001).

Conclusion: Our preliminary data suggest that the use of CYP3A4 inhibitors may influence striatal [¹²³I]I-FP-CIT binding ratios. This information, when reproduced in larger studies, may be relevant for studies in which quantification of [¹²³I]I-FP-CIT SPECT imaging is used for diagnostic or research purposes.

Keywords: CYP3A4 inhibitors; DaTSCAN; Dopamine transporter imaging; Drug interactions; [123I]I-FP-CIT.

Fig. 1

The metabolism of [¹²³I]I-FP-CIT after intravenous injection. The main metabolic pathway involves the hydrolysis of the ester group. In this process, the ester bond is cleaved, resulting in the formation of [¹²³I]I-FP-CIT acid. This metabolite is likely not lipophilic enough to cross the blood-brain barrier (BBB). Another metabolic route involves N-demethylation, catalyzed by the enzyme CYP3A4, leading to the formation of a small amount of lipophilic [¹²³I]I-nor-β-CIT, which can pass the BBB, and binds to both the serotonin and dopamine transporter. This Figure is largely reproduced from Fig. 2 [3]

Fig. 2

Specific to non-specific [¹²³I]I-FP-CIT binding ratios for the whole striatum (mean left and right sides) for the control group (n = 18) and the 6 cases which were using an CYP3A4 inhibitor

Fig. 3

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)