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Introduction: The sigma2 receptor (TMEM97) expression correlates well with the Ki67 expression in tumours [1, 2] and therefore represents an attractive marker for the proliferative status. An assessment of the sigma2 receptors in brain tumours by a non-invasive technique as PET depends on the radioligand’s suitability to cross the blood-brain barrier (BBB), which is actually one of the major challenges. Our aim was to develop an 18F-labelled radioligand for sigma2 receptor imaging in brain tumours, based on the well-described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds. On the basis of a series of novel fluorinated derivatives for 18F-labelling the promising sigma2 receptor ligand [18F]RM273 was synthesized and investigated in healthy mice and an orthotopic rat glioma model. Methods: [18F]RM273 (2-[4-(6-[18F]fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) has been obtained by automated synthesis by Cu-mediated oxidative radiofluorination of the aryl boronic acid pinacol ester precursor. Radiometabolite analysis was performed ex vivo in mouse plasma samples 30 min p.i. The target specificity was investigated by in vitro autoradiographic studies with or without the sigma2 receptor antagonist ISO-1 in rat brain cryosections with a stereotactically implanted F98 glioma [3]. The biodistribution of [18F]RM273 in healthy mice (female, CD1; n = 4, 7.2 ± 1.1 MBq) and the tumour uptake into the F98 glioma (male, F344; n = 2; 21 – 25 MBq) were investigated by dynamic PET imaging for 60 min (nanoScan®PET-1T MRI, Mediso Kft., Hungary). Results: [18F]RM273 has been produced with a molar activity of 69 – 233 GBq/μmol at moderate radiochemical yield (8%) and high purity (≥99%). Polar radiometabolites of [18F]RM273, detected in blood plasma samples of mice, were not crossing the BBB, as 100 % parent fraction were detected in brain extracts at 30 min p.i.). We validated the target-specific binding of [18F]RM273 towards the F98 glioma in vitro and determined a 3-times higher density of binding sites in comparison to the healthy brain [3]. PET studies revealed a peak value of the time activity curve of 1.3 at 2.25 min p.i. with a t1/2 of 13.1 min after peak time and a peak-to-endpoint ratio of 6.4 ± 0.9 in the brain of healthy mice [3], whereas in the F98 glioma an SUVmean of 0.8 – 1.3 at 30 – 60 min p.i. was found, which was two times higher than measured in the contralateral brain region. Conclusions: The reasonable brain penetration in rodents and the tumour specific accumulation of [18F]RM273 in the F98 glioma indicate the suitability of this radioligand for future imaging studies regarding the role of sigma2 receptors in neuro-oncological diseases. Our preliminary finding of a high density of sigma2 receptors in highly proliferative brain tumour cells deserves further investigation by use of larger sample sizes and complementation with immunohistochemistry. Acknowledgements: This work was supported by the Deutsche Forschungsgemeinschaft (DFG: BR 1360/13-1). References: [1] Shoghi et al. Plos One 2013, 8: e74188; [2] Yang et al. Molecules 2020, 25 (22): 5439 [3] Moldovan et al. Int. J. Mol. Sci. 2021, 22: 5447 |
