Jia-Zhe Lin, Maria Kominia, Janine Doorduin, Erik F J de Vries
{"title":"抗癌候选药物[11C]曲美布汀在大鼠胶质瘤模型中的PET成像。","authors":"Jia-Zhe Lin, Maria Kominia, Janine Doorduin, Erik F J de Vries","doi":"10.1016/j.nucmedbio.2024.108985","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Preclinical studies suggest that trimebutine could be a potential treatment for glioblastoma. The aim of this study was to investigate the distribution, kinetics and tumor accumulation of [<sup>11</sup>C]trimebutine.</p><p><strong>Method: </strong>A proliferation assay and cell scratch healing assay were performed to confirm the antitumor effects of trimebutine on C6 glioma cells in-vitro. Trimebutine was subsequently labeled with <sup>11</sup>C. The distribution and kinetics of [<sup>11</sup>C]trimebutine in health rats and rats with an orthotopic C6 glioma were evaluated by ex-vivo gamma counting and positron emission tomography, respectively. Blocking experiments with an excess of unlabeled trimebutine or the μ-opioid receptor ligand cyprodime were employed to determine if trimebutine exhibits saturable binding in the brain. In addition, plasma stability of the tracer was assessed.</p><p><strong>Results: </strong>The proliferation assay and cell scratch healing assay confirmed that trimebutine has anti-tumor effects in-vitro. [<sup>11</sup>C]Trimebutine with a radiochemical purity >98 % was synthesized in 15 ± 5 % radiochemical yield. In peripheral organs, the highest accumulation of the tracer was detected in excretion organs. In the brain, the highest tracer uptake was observed in the brainstem and the lowest in the hypothalamus, although differences between regions were small. PET imaging showed rapid brain uptake of [<sup>11</sup>C]trimebutine, followed by a gradual washout. Administration of an intravenous dose of trimebutine (10 mg/kg) significantly decreased the uptake in all brain regions (p < 0.05), except midbrain. Likewise, administration of cyprodime (2 mg/kg) significantly reduced [<sup>11</sup>C]trimebutine uptake in the brain (p < 0.01). However, uptake of [<sup>11</sup>C]trimebutine in the tumor was not significantly different from its brain uptake in rats bearing an orthotopic C6 glioma. The percentage of intact [<sup>11</sup>C]trimebutine at 60 min post injection was only 1.7 ± 0.6 %.</p><p><strong>Conclusion: </strong>Trimebutine exhibits inhibitory effects on the growth and migration of glioma cells in a dose- and time-dependent manner. [<sup>11</sup>C]Trimebutine was able to penetrate the blood-brain barrier in rats and tracer uptake could be significantly reduced by administration of a μ-opioid receptor antagonist. However, [<sup>11</sup>C]trimebutine failed to selectively accumulate in orthotopic C6 glioma, which could be caused by low expression levels of the drug target in these tumors, or by fast metabolism of the tracer.</p>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"142-143 ","pages":"108985"},"PeriodicalIF":3.6000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PET imaging of the anticancer drug candidate [<sup>11</sup>C]trimebutine in a rat glioma model.\",\"authors\":\"Jia-Zhe Lin, Maria Kominia, Janine Doorduin, Erik F J de Vries\",\"doi\":\"10.1016/j.nucmedbio.2024.108985\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Preclinical studies suggest that trimebutine could be a potential treatment for glioblastoma. The aim of this study was to investigate the distribution, kinetics and tumor accumulation of [<sup>11</sup>C]trimebutine.</p><p><strong>Method: </strong>A proliferation assay and cell scratch healing assay were performed to confirm the antitumor effects of trimebutine on C6 glioma cells in-vitro. Trimebutine was subsequently labeled with <sup>11</sup>C. The distribution and kinetics of [<sup>11</sup>C]trimebutine in health rats and rats with an orthotopic C6 glioma were evaluated by ex-vivo gamma counting and positron emission tomography, respectively. Blocking experiments with an excess of unlabeled trimebutine or the μ-opioid receptor ligand cyprodime were employed to determine if trimebutine exhibits saturable binding in the brain. In addition, plasma stability of the tracer was assessed.</p><p><strong>Results: </strong>The proliferation assay and cell scratch healing assay confirmed that trimebutine has anti-tumor effects in-vitro. [<sup>11</sup>C]Trimebutine with a radiochemical purity >98 % was synthesized in 15 ± 5 % radiochemical yield. In peripheral organs, the highest accumulation of the tracer was detected in excretion organs. In the brain, the highest tracer uptake was observed in the brainstem and the lowest in the hypothalamus, although differences between regions were small. PET imaging showed rapid brain uptake of [<sup>11</sup>C]trimebutine, followed by a gradual washout. Administration of an intravenous dose of trimebutine (10 mg/kg) significantly decreased the uptake in all brain regions (p < 0.05), except midbrain. Likewise, administration of cyprodime (2 mg/kg) significantly reduced [<sup>11</sup>C]trimebutine uptake in the brain (p < 0.01). However, uptake of [<sup>11</sup>C]trimebutine in the tumor was not significantly different from its brain uptake in rats bearing an orthotopic C6 glioma. The percentage of intact [<sup>11</sup>C]trimebutine at 60 min post injection was only 1.7 ± 0.6 %.</p><p><strong>Conclusion: </strong>Trimebutine exhibits inhibitory effects on the growth and migration of glioma cells in a dose- and time-dependent manner. [<sup>11</sup>C]Trimebutine was able to penetrate the blood-brain barrier in rats and tracer uptake could be significantly reduced by administration of a μ-opioid receptor antagonist. However, [<sup>11</sup>C]trimebutine failed to selectively accumulate in orthotopic C6 glioma, which could be caused by low expression levels of the drug target in these tumors, or by fast metabolism of the tracer.</p>\",\"PeriodicalId\":19363,\"journal\":{\"name\":\"Nuclear medicine and biology\",\"volume\":\"142-143 \",\"pages\":\"108985\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-12-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nuclear medicine and biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.nucmedbio.2024.108985\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nuclear medicine and biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.nucmedbio.2024.108985","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
PET imaging of the anticancer drug candidate [11C]trimebutine in a rat glioma model.
Purpose: Preclinical studies suggest that trimebutine could be a potential treatment for glioblastoma. The aim of this study was to investigate the distribution, kinetics and tumor accumulation of [11C]trimebutine.
Method: A proliferation assay and cell scratch healing assay were performed to confirm the antitumor effects of trimebutine on C6 glioma cells in-vitro. Trimebutine was subsequently labeled with 11C. The distribution and kinetics of [11C]trimebutine in health rats and rats with an orthotopic C6 glioma were evaluated by ex-vivo gamma counting and positron emission tomography, respectively. Blocking experiments with an excess of unlabeled trimebutine or the μ-opioid receptor ligand cyprodime were employed to determine if trimebutine exhibits saturable binding in the brain. In addition, plasma stability of the tracer was assessed.
Results: The proliferation assay and cell scratch healing assay confirmed that trimebutine has anti-tumor effects in-vitro. [11C]Trimebutine with a radiochemical purity >98 % was synthesized in 15 ± 5 % radiochemical yield. In peripheral organs, the highest accumulation of the tracer was detected in excretion organs. In the brain, the highest tracer uptake was observed in the brainstem and the lowest in the hypothalamus, although differences between regions were small. PET imaging showed rapid brain uptake of [11C]trimebutine, followed by a gradual washout. Administration of an intravenous dose of trimebutine (10 mg/kg) significantly decreased the uptake in all brain regions (p < 0.05), except midbrain. Likewise, administration of cyprodime (2 mg/kg) significantly reduced [11C]trimebutine uptake in the brain (p < 0.01). However, uptake of [11C]trimebutine in the tumor was not significantly different from its brain uptake in rats bearing an orthotopic C6 glioma. The percentage of intact [11C]trimebutine at 60 min post injection was only 1.7 ± 0.6 %.
Conclusion: Trimebutine exhibits inhibitory effects on the growth and migration of glioma cells in a dose- and time-dependent manner. [11C]Trimebutine was able to penetrate the blood-brain barrier in rats and tracer uptake could be significantly reduced by administration of a μ-opioid receptor antagonist. However, [11C]trimebutine failed to selectively accumulate in orthotopic C6 glioma, which could be caused by low expression levels of the drug target in these tumors, or by fast metabolism of the tracer.
期刊介绍：
Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized.
These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field.
Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.
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