Lei Wang, Hsiou-Ting Kuo, Zhengxing Zhang, Chengcheng Zhang, Chao-Cheng Chen, Devon Chapple, Ryan Wilson, Nadine Colpo, François Bénard, Kuo-Shyan Lin
{"title":"通过非天然氨基酸置换提高 68Ga 标记的 GRPR 靶向 TacBOMB2 衍生物的体内稳定性和肿瘤摄取率，用于正电子发射断层扫描的癌症成像","authors":"Lei Wang, Hsiou-Ting Kuo, Zhengxing Zhang, Chengcheng Zhang, Chao-Cheng Chen, Devon Chapple, Ryan Wilson, Nadine Colpo, François Bénard, Kuo-Shyan Lin","doi":"10.1186/s41181-024-00241-7","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [<sup>68</sup>Ga]Ga-TacBOMB2 (<sup>68</sup>Ga-DOTA-Pip-D-Phe<sup>6</sup>-Gln<sup>7</sup>-Trp<sup>8</sup>-Ala<sup>9</sup>-Val<sup>10</sup>-Gly<sup>11</sup>-His<sup>12</sup>-Leu<sup>13</sup>-Thz<sup>14</sup>-NH<sub>2</sub>).</p><h3>Results</h3><p>Unnatural amino acid substitutions were conducted for Gln<sup>7</sup>, Trp<sup>8</sup>, Ala<sup>9</sup>, Val<sup>10</sup>, Gly<sup>11</sup> and His<sup>12</sup>, either alone or in combination. Out of 25 unnatural amino acid substitutions, <i>tert</i>-Leu<sup>10</sup> (Tle<sup>10</sup>) and NMe-His<sup>12</sup> substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [<sup>68</sup>Ga]Ga-TacBOMB2, the Tle<sup>10</sup> and NMe-His<sup>12</sup> derived [<sup>68</sup>Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (K<sub>i</sub> = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection).</p><h3>Conclusions</h3><p>Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [<sup>68</sup>Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle<sup>10</sup>,NMe-His<sup>12</sup>,Thz<sup>14</sup>]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00241-7","citationCount":"0","resultStr":"{\"title\":\"Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography\",\"authors\":\"Lei Wang, Hsiou-Ting Kuo, Zhengxing Zhang, Chengcheng Zhang, Chao-Cheng Chen, Devon Chapple, Ryan Wilson, Nadine Colpo, François Bénard, Kuo-Shyan Lin\",\"doi\":\"10.1186/s41181-024-00241-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [<sup>68</sup>Ga]Ga-TacBOMB2 (<sup>68</sup>Ga-DOTA-Pip-D-Phe<sup>6</sup>-Gln<sup>7</sup>-Trp<sup>8</sup>-Ala<sup>9</sup>-Val<sup>10</sup>-Gly<sup>11</sup>-His<sup>12</sup>-Leu<sup>13</sup>-Thz<sup>14</sup>-NH<sub>2</sub>).</p><h3>Results</h3><p>Unnatural amino acid substitutions were conducted for Gln<sup>7</sup>, Trp<sup>8</sup>, Ala<sup>9</sup>, Val<sup>10</sup>, Gly<sup>11</sup> and His<sup>12</sup>, either alone or in combination. Out of 25 unnatural amino acid substitutions, <i>tert</i>-Leu<sup>10</sup> (Tle<sup>10</sup>) and NMe-His<sup>12</sup> substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [<sup>68</sup>Ga]Ga-TacBOMB2, the Tle<sup>10</sup> and NMe-His<sup>12</sup> derived [<sup>68</sup>Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (K<sub>i</sub> = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection).</p><h3>Conclusions</h3><p>Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [<sup>68</sup>Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle<sup>10</sup>,NMe-His<sup>12</sup>,Thz<sup>14</sup>]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.</p></div>\",\"PeriodicalId\":534,\"journal\":{\"name\":\"EJNMMI Radiopharmacy and Chemistry\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-02-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00241-7\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EJNMMI Radiopharmacy and Chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://link.springer.com/article/10.1186/s41181-024-00241-7\",\"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/s41181-024-00241-7","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, INORGANIC & NUCLEAR","Score":null,"Total":0}
Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography
Background
Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [68Ga]Ga-TacBOMB2 (68Ga-DOTA-Pip-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-Thz14-NH2).
Results
Unnatural amino acid substitutions were conducted for Gln7, Trp8, Ala9, Val10, Gly11 and His12, either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu10 (Tle10) and NMe-His12 substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [68Ga]Ga-TacBOMB2, the Tle10 and NMe-His12 derived [68Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (Ki = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection).
Conclusions
Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [68Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle10,NMe-His12,Thz14]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.
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