Imma Carbo-Bague , Shefali Saini , Shelbie J. Cingoranelli , Patrick R.W.J. Davey , Marianna Tosato , Suzanne E. Lapi , Caterina F. Ramogida
{"title":"评估一种新型六价 1,2-羟基吡啶酮基无环螯合物 HOPO-O6-C4，用于 43Sc/47Sc、68Ga 和 45Ti 放射性药物","authors":"Imma Carbo-Bague , Shefali Saini , Shelbie J. Cingoranelli , Patrick R.W.J. Davey , Marianna Tosato , Suzanne E. Lapi , Caterina F. Ramogida","doi":"10.1016/j.nucmedbio.2023.108872","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><p>Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in <sup>68</sup>Ga and increasing availability of new radiometals such as <sup>43</sup>Sc/<sup>47</sup>Sc and <sup>45</sup>Ti, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O<sub>6</sub>-C4 and its in vitro and in vivo evaluation with the above mentioned radiometals.</p></div><div><h3>Methods</h3><p>To investigate the affinity of HOPO-O<sub>6</sub>-C4, macroscopic studies were performed with Sc<sup>3+</sup>, and Ga<sup>3+</sup> followed by DFT structural optimization of the Sc<sup>3+</sup>, Ga<sup>3+</sup> and Ti<sup>4+</sup> complexes. Further tracer studies with <sup>43</sup>Sc (and <sup>47</sup>Sc), <sup>45</sup>Ti, and <sup>68</sup>Ga were performed to determine the potential for positron emission tomography (PET) imaging with these complexes. In vitro stability studies followed by in vivo imaging and biodistribution studies were performed to understand the kinetic stability of the resultant radiometal-complexes of HOPO-O<sub>6</sub>-C4.</p></div><div><h3>Results</h3><p>Promising radiolabeling results with HOPO-O<sub>6</sub>-C4 were obtained with <sup>43</sup>Sc, <sup>47</sup>Sc, <sup>45</sup>Ti, and <sup>68</sup>Ga radionuclides; rapid radiolabeling was observed at 37 °C and pH 7 in under 30-min. Apparent molar activity measurements were performed for radiolabeling of HOPO-O<sub>6</sub>-C4 with <sup>43</sup>Sc (4.9 ± 0.26 GBq/μmol), <sup>47</sup>Sc (1.58 ± 0.01 GBq/μmol), <sup>45</sup>Ti (11.5 ± 1.6 GBq/μmol) and <sup>68</sup>Ga (5.74 ± 0.7 GBq/μmol), respectively. Preclinical in vivo imaging studies resulted in promising results with [<sup>68</sup>Ga]Ga-HOPO-O<sub>6</sub>-C4 indicating a rapid clearance through hepatic excretion route and no decomplexation whereas [<sup>43</sup>Sc]Sc-HOPO-O<sub>6</sub>-C4, [<sup>47</sup>Sc]Sc-HOPO-O<sub>6</sub>-C4 and [<sup>45</sup>Ti]Ti-HOPO-O<sub>6</sub>-C4 showed modest and significant evidence of decomplexation, respectively.</p></div><div><h3>Conclusions</h3><p>The tris-1,2-HOPO chelator HOPO-O<sub>6</sub>-C4 is a promising scaffold for elaboration into a <sup>68</sup>Ga- based radiopharmaceutical.</p></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"128 ","pages":"Article 108872"},"PeriodicalIF":3.6000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969805123006005/pdfft?md5=7dfc517b2bee6fa2a22a6c9b5e0ee960&pid=1-s2.0-S0969805123006005-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Evaluation of a novel hexadentate 1,2-hydroxypyridinone-based acyclic chelate, HOPO-O6-C4, for 43Sc/47Sc, 68Ga, and 45Ti radiopharmaceuticals\",\"authors\":\"Imma Carbo-Bague , Shefali Saini , Shelbie J. Cingoranelli , Patrick R.W.J. Davey , Marianna Tosato , Suzanne E. Lapi , Caterina F. Ramogida\",\"doi\":\"10.1016/j.nucmedbio.2023.108872\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Introduction</h3><p>Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in <sup>68</sup>Ga and increasing availability of new radiometals such as <sup>43</sup>Sc/<sup>47</sup>Sc and <sup>45</sup>Ti, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O<sub>6</sub>-C4 and its in vitro and in vivo evaluation with the above mentioned radiometals.</p></div><div><h3>Methods</h3><p>To investigate the affinity of HOPO-O<sub>6</sub>-C4, macroscopic studies were performed with Sc<sup>3+</sup>, and Ga<sup>3+</sup> followed by DFT structural optimization of the Sc<sup>3+</sup>, Ga<sup>3+</sup> and Ti<sup>4+</sup> complexes. Further tracer studies with <sup>43</sup>Sc (and <sup>47</sup>Sc), <sup>45</sup>Ti, and <sup>68</sup>Ga were performed to determine the potential for positron emission tomography (PET) imaging with these complexes. In vitro stability studies followed by in vivo imaging and biodistribution studies were performed to understand the kinetic stability of the resultant radiometal-complexes of HOPO-O<sub>6</sub>-C4.</p></div><div><h3>Results</h3><p>Promising radiolabeling results with HOPO-O<sub>6</sub>-C4 were obtained with <sup>43</sup>Sc, <sup>47</sup>Sc, <sup>45</sup>Ti, and <sup>68</sup>Ga radionuclides; rapid radiolabeling was observed at 37 °C and pH 7 in under 30-min. Apparent molar activity measurements were performed for radiolabeling of HOPO-O<sub>6</sub>-C4 with <sup>43</sup>Sc (4.9 ± 0.26 GBq/μmol), <sup>47</sup>Sc (1.58 ± 0.01 GBq/μmol), <sup>45</sup>Ti (11.5 ± 1.6 GBq/μmol) and <sup>68</sup>Ga (5.74 ± 0.7 GBq/μmol), respectively. Preclinical in vivo imaging studies resulted in promising results with [<sup>68</sup>Ga]Ga-HOPO-O<sub>6</sub>-C4 indicating a rapid clearance through hepatic excretion route and no decomplexation whereas [<sup>43</sup>Sc]Sc-HOPO-O<sub>6</sub>-C4, [<sup>47</sup>Sc]Sc-HOPO-O<sub>6</sub>-C4 and [<sup>45</sup>Ti]Ti-HOPO-O<sub>6</sub>-C4 showed modest and significant evidence of decomplexation, respectively.</p></div><div><h3>Conclusions</h3><p>The tris-1,2-HOPO chelator HOPO-O<sub>6</sub>-C4 is a promising scaffold for elaboration into a <sup>68</sup>Ga- based radiopharmaceutical.</p></div>\",\"PeriodicalId\":19363,\"journal\":{\"name\":\"Nuclear medicine and biology\",\"volume\":\"128 \",\"pages\":\"Article 108872\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0969805123006005/pdfft?md5=7dfc517b2bee6fa2a22a6c9b5e0ee960&pid=1-s2.0-S0969805123006005-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nuclear medicine and biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0969805123006005\",\"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://www.sciencedirect.com/science/article/pii/S0969805123006005","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}
Evaluation of a novel hexadentate 1,2-hydroxypyridinone-based acyclic chelate, HOPO-O6-C4, for 43Sc/47Sc, 68Ga, and 45Ti radiopharmaceuticals
Introduction
Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in 68Ga and increasing availability of new radiometals such as 43Sc/47Sc and 45Ti, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O6-C4 and its in vitro and in vivo evaluation with the above mentioned radiometals.
Methods
To investigate the affinity of HOPO-O6-C4, macroscopic studies were performed with Sc3+, and Ga3+ followed by DFT structural optimization of the Sc3+, Ga3+ and Ti4+ complexes. Further tracer studies with 43Sc (and 47Sc), 45Ti, and 68Ga were performed to determine the potential for positron emission tomography (PET) imaging with these complexes. In vitro stability studies followed by in vivo imaging and biodistribution studies were performed to understand the kinetic stability of the resultant radiometal-complexes of HOPO-O6-C4.
Results
Promising radiolabeling results with HOPO-O6-C4 were obtained with 43Sc, 47Sc, 45Ti, and 68Ga radionuclides; rapid radiolabeling was observed at 37 °C and pH 7 in under 30-min. Apparent molar activity measurements were performed for radiolabeling of HOPO-O6-C4 with 43Sc (4.9 ± 0.26 GBq/μmol), 47Sc (1.58 ± 0.01 GBq/μmol), 45Ti (11.5 ± 1.6 GBq/μmol) and 68Ga (5.74 ± 0.7 GBq/μmol), respectively. Preclinical in vivo imaging studies resulted in promising results with [68Ga]Ga-HOPO-O6-C4 indicating a rapid clearance through hepatic excretion route and no decomplexation whereas [43Sc]Sc-HOPO-O6-C4, [47Sc]Sc-HOPO-O6-C4 and [45Ti]Ti-HOPO-O6-C4 showed modest and significant evidence of decomplexation, respectively.
Conclusions
The tris-1,2-HOPO chelator HOPO-O6-C4 is a promising scaffold for elaboration into a 68Ga- based radiopharmaceutical.
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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