Magali Toussaint ¹, Winnie Deuther-Conrad ¹, Mathias Kranz ^{1 2 3}, Steffen Fischer ¹, Friedrich-Alexander Ludwig ¹, Tareq A Juratli ⁴, Marianne Patt ⁵, Bernhard Wünsch ⁶, Gabriele Schackert ⁴, Osama Sabri ⁵, Peter Brust ¹

¹ Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research site Leipzig, 04318 Leipzig, Germany.

² PET Imaging Center, University Hospital of North Norway (UNN), 9009 Tromsø, Norway.

³ Nuclear Medicine and Radiation Biology Research Group, The Arctic University of Norway, 9009 Tromsø, Norway.

⁴ Department of Neurosurgery, Technische Universität Dresden (TUD), University Hospital Carl Gustav Carus, 01307 Dresden, Germany.

⁵ Department of Nuclear Medicine, University Hospital Leipzig, 04318 Leipzig, Germany.

⁶ Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, 48149 Münster, Germany.

https://doi.org/10.3390/molecules25092170

Summary

Glioblastoma multiforme (GBM) is the most common primary tumors of the central nervous system. The survival rate for patients with GBM is dramatically low compared to patients with other brain tumor types. An important aspect contributing to this poor outcome is the genetic heterogeneity of GBM, which translates into heterogeneous expression patterns of potentially druggable targets. Hence the understanding of how spatiotemporal patterns evolve and change during pathogenesis would help to develop new targeted therapies, and biomarkers for treatment response.

The sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterization of GBM. The authors have used a selective sig1R ligand (S)-(−)-[18F]fluspidine to test this hypothesis with PET noninvasive molecular imaging.

In conclusion, the data obtained in the U87-MG mouse model of GBM along with the detection of sig1R in human GBM tissue for the first time by a PET radioligand, indicate not only the relevance of this target but also the suitability of (S)-(−)-[18F]fluspidine for sig1R-targeted cancer research and drug development.

Results from nanoScan PET/MRI

• Dynamic PET imaging showed that the uptake of (S)-(−)-[18F]fluspidine has higher retention in the tumor region compared to the CL at 60 min p.i., with SUVs of 0.38 and 0.28, respectively (Figure 4.)

Figure 4. PET/MR imaging of sig1R in mice with orthotopic xenograft of human GBM cells (U87-MG). Average time-activity curves after i.v. administration of (S)-(−)-[18F]fluspidine of the tumor (red dots) and the contralateral (black squares) regions of interest (n = 3). Statistical test: Student t-test, * p < 0.05.

• The early dynamic PET images between 2 and 9 min after injection show a heterogeneous uptake of (S)-(−)-[18F]fluspidine into the tumor (Figure 5D, upper panel), which may be caused by reduced blood supply to the tumor center. The PET image at later time points (45 to -60 min p.i.; Figure 5D, lower panel) pictures a more homogenous uptake of the tracer, along with a low slope, reflecting an accumulation.

Figure 5. (D) Representatives coronal PET/MR images of U87-MG tumor-bearing mouse after i.v. administration of (S)-(−)-[18F]fluspidine. The upper panel exhibits the distribution of (S)-(−)-[18F]fluspidine at early times p.i. (averaged time frames from 2 to 9 min), and the lower panel exhibits the distribution of (S)-(−)-[18F]fluspidine at later times (averaged time frames from 45 to 60 min). The regions-of-interest (ROIs) were delineated on the T2-weighted MR images and then applied on the PET data to generate the regional TACs.