Development of two novel I-131 or At-211 labeled radioprobes for targeted radiotherapy of melanoma

Metabotropic glutamate receptor 1 (mGluR1) is found ectopically in various kinds of cancers, such as melanoma and breast cancer. It has been reported that overexpressed mGluR1 exhibited oncogenic characteristics that independently trigger melanocyte tumorigenesis. Further, inhibition or inactivation of mGlu1 was demonstrated to prevent growth and progression of melanomas. Emipirical data indicate that mGlu1 is a promising molecular imaging target and could be applied for the diagnosis and personalized treatment of melanomas. Recently, we developed 4-[18F]fluoro-N-[4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide ([18F]FITM) and its other halogen-substituted analogs as PET probes for in vivo imaging of mGluR1 in melanoma [1,2]. In this study, we radiosynthesized 4-[131I]iodo ([131I]1)- or 4-[211At]astatine ([211At]1)- N-[4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide as two target-radionuclide-therapy probes and evaluated their antitumoral effects on mice bearing B16F10 melanoma. Unlabeled 1 and its tin precursor for the present radiosynthesis were prepared according to the method reported by our laboratory [2,3]. Radiosynthesis of [131I]1 was performed by reaction of tin precursor with [131I]NaI (280 MBq in 0.5 M NaOH) in the presence of 30% H2O2 at room temperature for 2 h (Fig.1a). After purification and formulation, [131I]1 was obtained in 45 ± 20% radiochemical yield (n > 3, based on the total [131I]NaI). The molar radioactivity and radiochemical purity of [131I]1 were 40 ± 4 GBq/μmol and >99% at the end of synthesis. Treatment the B16F10-bearing mice with [131I]1 at 18 MBq and 9 MBq in 2 doses/mouse significantly reduced the tumor volumes (P < 0.05), compared to the untreated group (Fig.1b), whereas treatment with [131I]NaI or unlabeled 1 did not show significant antitumoral effect (P > 0.05). PET with [18F]FITM further confirmed reduced uptake of radioactivity in the [131I]1-treated B16F10 tumor. 211At for radiolabeling was produced using a remotely controlled versatile system developed in house [4]. [211At]1 was successfully synthesized by the reaction of tin precursor with 211At in the presence of N-chlorosuccinimide at room temperature for 1 h. The radiochemical conversion of [211At]1 exceeded 40%. Optimized radiosynthesis and radiotherapy by [211At]1 for melanoma are on progress. \nReferences: [1] L. Xie, et al. Int J Cancer, 2014, 135, 1852-59. [2] M. Fujinaga, et al. J Med Chem, 2015, 58, 1513-23. [3] M. Fujinaga, et al. J Med Chem, 2012, 55, 11042-51. [4] K. Nagatsu, et al. Appl Radiat Isot, 2014, 94, 363-71. \nFigure 1. Radiosynthesis of [131I]1 and effect of [131I]1-targeted radiotherapy in B16F10 melanoma-bearing mice. (a) Synthesis of [131I]1. (b) [131I]1 was administered intravenously at days 7 (18 MBq) and 14 (9 MBq) after B16F10 transplantation, in comparison with untreated control mice (n=5, respectively). Tumor volume in cm3 was evaluated twice a week.
2017 World Molecular Imaging Congress(WMIC2017)