PET imaging of α7 nicotinic acetylcholine receptors in a heterotopic xenograft model of brain cancer

Objectives
Molecular imaging by means of PET supports both the molecular profiling of tumors and the validation of corresponding targeted therapies in cancer treatment. The intracellular pathways triggered by nicotinic acetylcholine receptors (nAChR) mediate carcinogenic effects related to tobacco-derived compounds as well as autocrine and paracrine stimulation. In particular the α7 nAChR is of significance for the pathogenesis of cancers and may have potential for novel therapeutic concepts. Accordingly, we investigated with the in-house developed α7 nAChR-specific radioligand [18F]NS10743 the expression of α7 nAChR in the heterotopic U87-MG xenograft mouse model of glioblastoma.
Methods
Subcutaneous U87-MG tumor xenografts were generated in female NMRI nu/nu mice. [18F]NS10743 was obtained by automated radiosynthesis [1]. All animals were scanned in a nanoScan® PET/MRI system for 60 min post injection of [18F]NS10743 under control (n=5) and blocking (n=4) conditions (2 mg/kg NS6740 i.p. 15 min before the radioligand) on two consecutive days. Volumes of interest (VOI) were identified from the co-registered MR images (brain, tumor, and muscle) or from the first frame of the PET images (vena cava). Data analysis was based on the calculation of standardized uptake values (SUVs) and the shape of the time-activity curves (TACs). Intratumoral heterogeneity has been addressed by an additional VOI using a 75%-SUVmax isocontour in the control scans. Perfusion was assessed by Hoechst 33342, and autoradiography, fluorescence microscopy, and immunohistochemistry studies were performed ex vivo.
Results
Within 3-4 weeks after implantation of U87-MG cells, the longest axis of the tumor xenograft reached 5-10 mm. Dynamic PET scans, performed after i.v. administration of 6-12 MBq [18F]NS10743 (7-65 GBq/µmol at time of injection), revealed moderate uptake in the tumor with SUVmax of 0.91±0.16 at 40 min p.i. and tumor-to-muscle ratios of 0.93±0.08 at 60 min p.i. The individual tumor TACs are consistent regarding shape with relatively slow increase in the uptake of activity. NS6740 pre-blocking significantly reduced the activity uptake in the tumor (SUVmax=0.65±0.10; p<0.05).
Conclusions
Dynamic PET with [18F]NS10743 was able to detect α7 nAChR in the subcutaneous U87-MG mouse xenograft model of glioblastoma. The suitability of this approach for detection of α7 nAChR-expressing tumors in the brain remains to be investigated.
References
[1] R. Teodoro et al., Appl Radiat Isot, 2014, 95c,76-84