@misc{oai:repo.qst.go.jp:00076736,
 author = {Xie, Lin and Hanyu, Masayuki and Fujinaga, Masayuki and Zhang, Yiding and Kuan, Hu and Minegishi, Katsuyuki and Jiang, Cuiping and Kurosawa, Fuki and Morokoshi, Yukie and Li, Huizi and Hasegawa, Sumitaka and Nagatsu, Kotaro and Ming-Rong, Zhang and Xie, Lin and Hanyu, Masayuki and Fujinaga, Masayuki and Zhang, Yiding and Kuan, Hu and Minegishi, Katsuyuki and Kurosawa, Fuki and Morokoshi, Yukie and Li, Huizi and Nagatsu, Kotaro and Ming-Rong, Zhang},
 month = {Sep},
 note = {Background and Objectives: Designing small-molecule radiopharmaceuticals targeting an oncoprotein, such as the ectopic metabotropic glutamate receptor 1 (mGluR1) in melanoma [1], is an attractive strategy to increases our ability to deliver therapeutics to tumor tissues with high precision in targeted radionuclide therapy (TRT). Herein, we focused on 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide (FITM), a small-molecule compound with high affinity and specificity for the oncoprotein mGluR1[2,3], as the target carrier, with an -emitter (211At) to design and synthesize a novel TRT radiopharmaceutical: 4-211At-astato-N-[4-(6-(isopropylamino)pyridine-4-yl)-1,3-thiazol-2-yl]-N-methylbenzamide (211At-AITM), and investigated its therapeutic efficacy and safety in mGluR1-expressing B16F10 melanomas. 
Methods: Radiosynthesis of 211At-AITM was carried out by reacting the stannyl precursor with 211At (Fig. 1A). The binding specificity of 211At-AITM to mGluR1-expressing melanoma cells was assessed with and without the parent compound containing no radionuclide, FITM. Therapeutic effect and safety assessment were performed with a single injection of 211At-AITM with conservative doses (0–2.96 MBq) to B16F10-bearing C57BL/6J mice.
Results: 211At-AITM were stably obtained with radiochemical purity >99% and radiochemical yields of 28.9 ± 9.9% (n = 20), based on the radioactivity of the cyclotron-produced 211At. The radiopharmaceuticals 211At-AITM bound to B16F10 cells with 12.87 %ICD/mg, and were specifically displaced by the non-radiolabeled FITM. TRT with 211At-AITM markedly inhibited melanoma growth compared to the 0 MBq (saline) treated controls. Dose-dependent tumor inhibition was observed in melanoma mice treated with 0.11, 1.11, 1.85 or 2.96 MBq 211At-AITM. A single 0.11 MBq dose of  211At-AITM resulted in approximately 32.24% tumor reduction, but this was not statistically significant; other reductions based on the concentration administered include 73.48% at 1.11 MBq; 87.38% at 1.85 MBq; 95.68% at 2.96 MBq compared to the 0 MBq group at 19 days post-administration (Fig. 1B). Throughout the examination period, no weight loss, hepatotoxicity or nephrotoxicity were observed in melanoma mice injected with 0–2.96 MBq 211At-AITM (Fig. 1C).
Conclusions: Our results demonstrated the 211At labeled small-molecule radiopharmaceutical 211At-AITM possess high therapeutic efficiency and minimal health risks, thus could be attractive for clinical development as high-precision TRT weapons directed at the oncoprotein mGluR1 for melanoma therapy.
References:
1.Pollock PM, Cohen-Solal K, Sood R, et al. Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nat Genet. 2003; 34:108-112.
2.Xie L, Yui J, Fujinaga M, et al. Molecular imaging of ectopic metabotropic glutamate 1 receptor in melanoma with a positron emission tomography radioprobe 18 F-FITM. Int J Cancer. 2014;135:1852-9.
3.Fujinaga M1, Xie L, Yamasaki T, et al. Synthesis and evaluation of 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-[11C]methylbenzamide for imaging of metabotropic glutamate 1 receptor in melanoma. J Med Chem. 2015;58:1513-23., WMIC2019でのポスター発表},
 title = {Effective therapy against melanoma using 211At labeled small-molecule radiopharmaceutical 211At-AITM by targeting oncoprotein metabotropic glutamate receptor 1},
 year = {2019}
}