Yoichi Shimizu, Masato Ando, Hiroyuki Watanabe, Masahiro Ono
{"title":"基于羟酰胺螯合物的新型锝-99m 标记二价 PSMA 靶向探针用于诊断前列腺癌。","authors":"Yoichi Shimizu, Masato Ando, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1007/s12149-024-01959-9","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl–cystatin–urea–glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe “[<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub>” based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer.</p><h3>Methods</h3><p>Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [<sup>99m</sup>Tc]NaTcO<sub>4</sub> for 10 min at room temperature to obtain [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub>. [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60 min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15 min before adding [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub>. The biodistribution of [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120 min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10 mg/kg weight).</p><h3>Results</h3><p>[<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, <i>p</i> < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, <i>p</i> < 0.05). IC<sub>50</sub> of 2-PMPA was 245 ± 47 nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120 min after the administration of [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, <i>p</i> < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, <i>p</i> < 0.01).</p><h3>Conclusion</h3><p>[<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer.</p></div>","PeriodicalId":8007,"journal":{"name":"Annals of Nuclear Medicine","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Novel technetium-99m-labeled bivalent PSMA-targeting probe based on hydroxamamide chelate for diagnosis of prostate cancer\",\"authors\":\"Yoichi Shimizu, Masato Ando, Hiroyuki Watanabe, Masahiro Ono\",\"doi\":\"10.1007/s12149-024-01959-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl–cystatin–urea–glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe “[<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub>” based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer.</p><h3>Methods</h3><p>Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [<sup>99m</sup>Tc]NaTcO<sub>4</sub> for 10 min at room temperature to obtain [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub>. [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60 min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15 min before adding [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub>. The biodistribution of [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120 min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10 mg/kg weight).</p><h3>Results</h3><p>[<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, <i>p</i> < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, <i>p</i> < 0.05). IC<sub>50</sub> of 2-PMPA was 245 ± 47 nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120 min after the administration of [<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, <i>p</i> < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, <i>p</i> < 0.01).</p><h3>Conclusion</h3><p>[<sup>99m</sup>Tc]Tc-(Ham-SCUE)<sub>2</sub> has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer.</p></div>\",\"PeriodicalId\":8007,\"journal\":{\"name\":\"Annals of Nuclear Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-07-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Nuclear Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s12149-024-01959-9\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Nuclear Medicine","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s12149-024-01959-9","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
Novel technetium-99m-labeled bivalent PSMA-targeting probe based on hydroxamamide chelate for diagnosis of prostate cancer
Objective
Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl–cystatin–urea–glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe “[99mTc]Tc-(Ham-SCUE)2” based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer.
Methods
Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [99mTc]NaTcO4 for 10 min at room temperature to obtain [99mTc]Tc-(Ham-SCUE)2. [99mTc]Tc-(Ham-SCUE)2 was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60 min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15 min before adding [99mTc]Tc-(Ham-SCUE)2. The biodistribution of [99mTc]Tc-(Ham-SCUE)2 in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120 min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10 mg/kg weight).
Results
[99mTc]Tc-(Ham-SCUE)2 was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [99mTc]Tc-(Ham-SCUE)2 by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, p < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, p < 0.05). IC50 of 2-PMPA was 245 ± 47 nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120 min after the administration of [99mTc]Tc-(Ham-SCUE)2 (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, p < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, p < 0.01).
Conclusion
[99mTc]Tc-(Ham-SCUE)2 has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer.
期刊介绍：
Annals of Nuclear Medicine is an official journal of the Japanese Society of Nuclear Medicine. It develops the appropriate application of radioactive substances and stable nuclides in the field of medicine.
The journal promotes the exchange of ideas and information and research in nuclear medicine and includes the medical application of radionuclides and related subjects. It presents original articles, short communications, reviews and letters to the editor.
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