Synthesis and evaluation of radionuclide therapy probe for metabotropic glutamate receptor 1 in melanoma

Objectives: Metabotropic glutamate receptors (mGlus) are one of the G protein-coupled receptor families, which regulate excitatory neurotransmissions on the central nerves system. Of these, mGluR1 is originally found to be highly expressed in the brain. Further, mGluR1 was found ectopically in melanomas and the overexpressed mGluR1 receptor was examined to exhibit oncogenic characteristics. Therefore, mGluR1 may be a promising molecular imaging and therapy target for melanoma. Recently, we developed [18F]FITM as a PET probe for imaging of mGluR1 in brain and melanoma [1]. To support its clinical application, we developed the iodine analog [11C]1 as a specific tumor imaging probe, with high uptake in tumor and very low uptake in brain [2]. In this study, we synthesized [131I]1 as a target-radionuclide-therapy probe, and evaluated its anti-tumoral potential in mice bearing B16F10 melanoma. Methods: Unlabeled 1 and tin precursor for the radioiododestannylation was prepared according to previously reported method from our laboratory [2,3]. Radioiodonation of tin precursor was carried out with [131I]NaI and H2O2 as a oxidant. To evaluate the therapeutic effect, [131I]1 was administered intravenously in mice bearing B16F10 melanoma at 7 and 14 days after transplantation. For imaging of mGluR1 level, PET with [18F]FITM was conducted on the mice at 20 days after transplantation. Results: Radiosynthesis of [131I]1 was performed by reaction of tin precursor in EtOH, [131I]NaI (280 MBq in 0.5 M NaOH) and 30% H2O2 in the presence of CH3CO2H at room temperature for 2 h. After purification and formulation, [131I]1 was obtained in 45 ± 20% radiochemical yield (based on the total [131I]NaI, corrected for decay). The molar radioactivity was 40 ± 4 GBq/μmol (n = 3) at the end of synthesis and the radiochemical purity was >99%. The treatment of [131I]1 at 18 MBq and 9 MBq/ mouse in 2 doses was significantly reduced tumor volume in comparison with untreated B16F10-bearing mice (P < 0.05). Whereas, [131I]NaI or unlabeled 1 treatment was without significant anti-tumoral effect (P > 0.05). In addition, PET with [18F]FITM exhibited very low accumulation of radioactivity in [131I]1 treated B16F10 tumors. Conclusions: [131I]1 was successfully synthesized and showed strong anti-tumoural effect in mice bearing B16F10 melanoma. [131I]1 may be a useful candidate as a radionuclide therapy probe. Acknowledgements: This work was supported by JSPS KAKENHI Grant Number 25293269. References: [1] L. Xie, et al, Int J Cancer., 2014, 135(8), 1852-1859. [2] M. Fujinaga, et al, J. Med. Chem., 2015, 58(3), 1513–1523. [3] M. Fujinaga, et al, J. Med. Chem., 2012, 55(24), 11042–11051.
22nd International symposium on radiopharmaceutical science (ISRS)