Development of fluorinated PET tracers for imaging of sig-2R/TMEM97 in brain tumors

• Applicants: Dr. Winnie Deuther-Conrad; Professor Dr. Bernhard Wünsch
• Subject Area: Pharmacy ; Radiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517293143

Glioblastoma represents a very aggressive brain tumor, which leads to poor prognosis for the patients. Several human tumor cell lines including brain tumors and glioblastoma show high expression levels of 2 receptors. Due to its identity with the transmembrane protein TMEM97, 2 receptors are termed herein sig-2R/TMEM97. In this project, we aim at the development of a diagnostic tool to non-invasively characterize brain tumors regarding the expression of sig-2R/TMEM97 with positron emission tomography (PET). For this purpose, a fluorinated PET tracer will be developed, which exhibits high affinity towards sig-2R/TMEM97, high selectivity over the 1 receptor (sig-1R) and related receptors and appropriate pharmacokinetic properties, in particular a high metabolic stability and the ability to cross the blood-brain barrier. Up to know, [18F]ISO-1 represents the most important sig-2R/TMEM97 radioligand, which however shows only low brain uptake. In preliminary work, we have established an orthotopic F98 rat glioblastoma model to evaluate the potential of novel radioligands as imaging agents targeting sig-2R/TMEM97 in brain tumors. Additionally, a fluorinated PET tracer with pyrrolopyridine substructure ([18F]10) has been developed by us. This PET tracer shows already promising properties in vitro, but some features, including receptor selectivity, metabolic stability, and tumor-to-non-tumor ratio in vivo have to be improved. Starting with the promising pyrrolopyridine [18F]10, novel analogs are designed and synthesized. In particular, the pyrrolopyridine system is replaced by analogous heterocycles and the tetramethylene spacer is exchanged with more rigid and electronically diverse spacers. The affinity towards sig-2R/TMEM97 and sig-1R is determined for all ligands. The selectivity against related and other targets is tested only for high-affinity and selective sig-2R/TMEM97 ligands. Physicochemical (e.g. logD7.4 value) and pharmacokinetic parameters (e.g. plasma protein binding, metabolic stability) are recorded for non-radioactive compounds. After establishment and optimization of the radiosynthesis, in vitro parameters (e.g. logD value, stability in buffer and plasma, cell uptake, autoradiography, plasma protein binding, in vitro metabolism) are recorded for 18-F-labeled ligands. The most promising candidates are evaluated in vivo in healthy animals and in rats bearing the brain glioblastoma.

• DFG Programme: Research Grants