Brain tumour proliferation imaging - Development of PET radioligands for sigma2 receptors

The intracellular sigma2 receptor, also known as transmembrane protein 97 (TMEM97) or meningioma-associated protein 30 (MAC30) due to its role in cell proliferation, is highly expressed in many tumour types including brain, bladder, breast and lung cancer. A correlation between the expression of sigma2 receptors and the expression of the well-established proliferation marker Ki-67 suggests that PET scans using sigma2-targeted tracers may reveal whether a tumour is proliferating and how fast it is growing. The Ki-67 labelling index of brain tumours, determined by immunohistochemical analysis of tumour tissue obtained from surgical resection or biopsy, is positively associated with the degree of malignancy of gliomas and thus has prognostic value.

To develop a non-invasive method for assessing the proliferative capacity of brain tumours, we are using radiochemistry to radiofluorinate small molecule ligands that bind to the sigma2 receptor with high selectivity and affinity and have the potential to cross the blood-brain barrier.  We are combining in vitro and in vivo techniques to investigate the potential of the new ¹⁸F-labelled sigma2 receptor ligands as imaging agents. This project is part of our wider effort to develop radiolabelled biomolecules for targeted nuclear medicine diagnosis of brain tumours. 

	Structure of the 18F-labelled lead compound [18F]RM273, a sigma2-receptor ligand and images of brain slices of a rat with a F98 glioblastoma (Left: Nissl staining; Middle: Digitized autoradiogram after incubation with [18F]RM273; Right: Digitized autoradiogram after co-incubation with [18F]RM273 and a blocking compound). From Moldovan et al., Int. J. Mol. Sci. 2021

Partners

• Prof. Bernhard Wünsch, Department of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany

Financial Support

• Development of fluorinated PET tracers for imaging of sig-2R/TMEM97 in brain tumors (Partner: Prof. Bernhard Wünsch, Department of Pharmaceutical and Medicinal Chemistry, University of Münster; Deutsche Forschungsgemeinschaft), 09/2023 – 08/2026
• Development of a fluorinated PET tracer for imaging of sigma-2 receptors in the brain and in brain tumors (Partner: Prof. Bernhard Wünsch, Department of Pharmaceutical and Medicinal Chemistry, University of Münster; Deutsche Forschungsgemeinschaft), 2015 – 2019

Publications

• Moldovan R-P, Gündel D, Teodoro R, Ludwig F-A, Fischer S, Toussaint M, Schepmann D, Wünsch B, Brust P, Deuther-Conrad W. Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant ¹⁸F-Labelled σ2 Receptor Ligand. International Journal of Molecular Sciences. 2021; 22(11):5447. https://doi.org/10.3390/ijms22115447