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Effective therapy against melanoma using 211At labeled small-molecule radiopharmaceutical 211At-AITM by targeting oncoprotein metabotropic glutamate receptor 1
https://repo.qst.go.jp/records/76736
https://repo.qst.go.jp/records/76736951ac466-40d5-49b0-91d7-d62a38173511
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2019-09-06 | |||||
| タイトル | ||||||
| タイトル | Effective therapy against melanoma using 211At labeled small-molecule radiopharmaceutical 211At-AITM by targeting oncoprotein metabotropic glutamate receptor 1 | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Xie, Lin
× Xie, Lin× Hanyu, Masayuki× Fujinaga, Masayuki× Zhang, Yiding× Kuan, Hu× Minegishi, Katsuyuki× Jiang, Cuiping× Kurosawa, Fuki× Morokoshi, Yukie× Li, Huizi× Hasegawa, Sumitaka× Nagatsu, Kotaro× Ming-Rong, Zhang× Xie, Lin× Hanyu, Masayuki× Fujinaga, Masayuki× Zhang, Yiding× Kuan, Hu× Minegishi, Katsuyuki× Kurosawa, Fuki× Morokoshi, Yukie× Li, Huizi× Nagatsu, Kotaro× Ming-Rong, Zhang |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | 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. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | WMIC2019でのポスター発表 | |||||
| 発表年月日 | ||||||
| 日付 | 2019-09-07 | |||||
| 日付タイプ | Issued | |||||
