Investigation of the availablity of sigma-1 receptors in orthotopic human glioblastoma-bearing mice with positron emission tomography (PET) using (S)-(−)-[18F]fluspidine

Introduction
The sigma-1 receptor (S1R) is a chaperone protein of the mitochondrion-associated endoplasmic reticulum membrane. Its expression is dysregulated in various cancers including glioblastoma. S1R characterization in glioblastoma could help to better understand the pathophysiology of this cancer and thus help in improving diagnosis or treatment follow-up.
Objectives
In this context, we aim to evaluate the potential of (S)-(−)-[18F]fluspidine to characterize S1R expression in an orthotopic glioblastoma model in mice with small animal PET/MR imaging.
Materials & Methods
11 female nude mice Rj:NMRI-Foxn1nu/nu (24-30 g) aged of 8 weeks (Janvier labs; France), underwent a stereotactic xenograft of U87 human glioblastoma cells (50 000 cells/1 µl) in the right striatum (AP:0.5, L: -2.0, DV:-3.0 mm) (Stoelting Europe, Ireland). PET scans were performed on tumor of a median size of 5.15 mm3. 3 healthy female nude mice Rj:NMRI-Foxn1nu/nu (25-30 g) were used as control group.
(S)-(-)-[18F]Fluspidine (5.6±2.5 MBq; Am: 140±50 GBq/µmol, EOS) was injected intravenously followed by 60 min dynamic PET scans (Mediso nanoScan®, PET/MRI, Hungary). 20 scans were performed and time-activity curves (TAC) from the tumor and the contralateral region were analyzed (PMOD v3.9, PMOD Technologies LLC, Switzerland). Peak-to-end ratios (peak: SUV mean from 2-9 min, end: SUV mean from 45-60 min) were used to compare regions. Paired two-tailed student t-test (p<0.05) was used for statistics.
Results
The TACs from the striatum of healthy mice and from the contralateral side of U87 tumor bearing mice display similar profiles along with comparable peak-to-end SUV ratios (2.11±0.38 vs. 2.19±0.59).
By contrast, the profile of the average TAC of the tumor region is different from the contralateral side, with a lower initial uptake (mean SUV2-9 min p.i.: 0.95 vs. 1.1) and a higher uptake at the end of the scan (mean SUV45-60 min p.i.: 0.6 vs. 0.5). Accordingly, the peak-to-end ratio of the tumor region is significantly different from the ratio of the contralateral region (1.65±0.49 vs. 2.19±0.59, p=0.001).
Conclusion
The PET investigation revealed a significant difference in the pharmacokinetics of (S)-(-)-[18F]fluspidine between tumor and contralateral region, probably related to different S1R availabilities. Further investigations, such as autoradiography, will help to characterize this effect. These first results show the suitability of (S)-(-)-[18F]fluspidine for characterization of U87 S1R status.