{"title":"使用新戊二醇结构的体内稳定 211At 标记前列腺特异性膜抗原靶向示踪剂。","authors":"Hiroyuki Suzuki, Kento Kannaka, Mizuki Hirayama, Tomoki Yamashita, Yuta Kaizuka, Ryota Kobayashi, Takahiro Yasuda, Kazuhiro Takahashi, Tomoya Uehara","doi":"10.1186/s41181-024-00278-8","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC. Astatine-211 (<sup>211</sup>At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, <sup>211</sup>At-labeled PSMA compounds could be useful for TAT; however, <sup>211</sup>At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable <sup>211</sup>At-labeled PSMA derivatives, we designed and synthesized <sup>211</sup>At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain <sup>211</sup>At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.</p><h3>Results</h3><p>We designed and synthesized <sup>211</sup>At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)<sub>2</sub> linker used) and NpG-D-PSMA ((D-Glu)<sub>2</sub> linker used)). First, we evaluated the characteristics of <sup>125</sup>I-labeled NpG derivatives because <sup>125</sup>I was readily available. [<sup>125</sup>I]I-NpG-L-PSMA and [<sup>125</sup>I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [<sup>125</sup>I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [<sup>125</sup>I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [<sup>125</sup>I]I-NpG-D-PSMA showed higher tumor accumulation than [<sup>125</sup>I]I-NpG-L-PSMA. We then developed <sup>211</sup>At-labeled PSMA using the NpG-D-PSMA structure. [<sup>211</sup>At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [<sup>211</sup>At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [<sup>125</sup>I]I-NpG-D-PSMA.</p><h3>Conclusions</h3><p>[<sup>211</sup>At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [<sup>211</sup>At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00278-8","citationCount":"0","resultStr":"{\"title\":\"In vivo stable 211At-labeled prostate-specific membrane antigen-targeted tracer using a neopentyl glycol structure\",\"authors\":\"Hiroyuki Suzuki, Kento Kannaka, Mizuki Hirayama, Tomoki Yamashita, Yuta Kaizuka, Ryota Kobayashi, Takahiro Yasuda, Kazuhiro Takahashi, Tomoya Uehara\",\"doi\":\"10.1186/s41181-024-00278-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC. Astatine-211 (<sup>211</sup>At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, <sup>211</sup>At-labeled PSMA compounds could be useful for TAT; however, <sup>211</sup>At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable <sup>211</sup>At-labeled PSMA derivatives, we designed and synthesized <sup>211</sup>At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain <sup>211</sup>At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.</p><h3>Results</h3><p>We designed and synthesized <sup>211</sup>At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)<sub>2</sub> linker used) and NpG-D-PSMA ((D-Glu)<sub>2</sub> linker used)). First, we evaluated the characteristics of <sup>125</sup>I-labeled NpG derivatives because <sup>125</sup>I was readily available. [<sup>125</sup>I]I-NpG-L-PSMA and [<sup>125</sup>I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [<sup>125</sup>I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [<sup>125</sup>I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [<sup>125</sup>I]I-NpG-D-PSMA showed higher tumor accumulation than [<sup>125</sup>I]I-NpG-L-PSMA. We then developed <sup>211</sup>At-labeled PSMA using the NpG-D-PSMA structure. [<sup>211</sup>At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [<sup>211</sup>At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [<sup>125</sup>I]I-NpG-D-PSMA.</p><h3>Conclusions</h3><p>[<sup>211</sup>At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [<sup>211</sup>At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.</p></div>\",\"PeriodicalId\":534,\"journal\":{\"name\":\"EJNMMI Radiopharmacy and Chemistry\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-06-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00278-8\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EJNMMI Radiopharmacy and Chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://link.springer.com/article/10.1186/s41181-024-00278-8\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, INORGANIC & NUCLEAR\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EJNMMI Radiopharmacy and Chemistry","FirstCategoryId":"1085","ListUrlMain":"https://link.springer.com/article/10.1186/s41181-024-00278-8","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, INORGANIC & NUCLEAR","Score":null,"Total":0}
In vivo stable 211At-labeled prostate-specific membrane antigen-targeted tracer using a neopentyl glycol structure
Background
Prostate cancer is a common cancer among men worldwide that has a very poor prognosis, especially when it progresses to metastatic castration-resistant prostate cancer (mCRPC). Therefore, novel therapeutic agents for mCRPC are urgently required. Because prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC, targeted alpha therapy (TAT) for PSMA is a promising treatment for mCRPC. Astatine-211 (211At) is a versatile α-emitting radionuclide that can be produced using a cyclotron. Therefore, 211At-labeled PSMA compounds could be useful for TAT; however, 211At-labeled compounds are unstable against deastatination in vivo. In this study, to develop in vivo stable 211At-labeled PSMA derivatives, we designed and synthesized 211At-labeled PSMA derivatives using a neopentyl glycol (NpG) structure that can stably retain 211At in vivo. We also evaluated their biodistribution in normal and tumor-bearing mice.
Results
We designed and synthesized 211At-labeled PSMA derivatives containing two glutamic acid (Glu) linkers between the NpG structure and asymmetric urea (NpG-L-PSMA ((L-Glu)2 linker used) and NpG-D-PSMA ((D-Glu)2 linker used)). First, we evaluated the characteristics of 125I-labeled NpG derivatives because 125I was readily available. [125I]I-NpG-L-PSMA and [125I]I-NpG-D-PSMA showed low accumulation in the stomach and thyroid, indicating their high in vivo stability against deiodination. [125I]I-NpG-L-PSMA was excreted in urine as hydrophilic radiometabolites in addition to the intact form. Meanwhile, [125I]I-NpG-D-PSMA was excreted in urine in an intact form. In both cases, no radioactivity was observed in the free iodine fraction. [125I]I-NpG-D-PSMA showed higher tumor accumulation than [125I]I-NpG-L-PSMA. We then developed 211At-labeled PSMA using the NpG-D-PSMA structure. [211At]At-NpG-D-PSMA showed low accumulation in the stomach and thyroid in normal mice, indicating its high stability against deastatination in vivo. Moreover, [211At]At-NpG-D-PSMA showed high accumulation in tumor similar to that of [125I]I-NpG-D-PSMA.
Conclusions
[211At]At-NpG-D-PSMA showed high in vivo stability against deastatination and high tumor accumulation. [211At]At-NpG-D-PSMA should be considered as a potential new TAT for mCRPC.
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