{"title":"一种新的靶向APJ受体的基于apelin的PET放射性示踪剂的设计和临床前评估，用于血管生成的分子成像","authors":"Béatrice Louis, Vincent Nail, Oriane Nachar, Ahlem Bouhlel, Anaïs Moyon, Laure Balasse, Stéphanie Simoncini, Adrien Chabert, Samantha Fernandez, Pauline Brige, Guillaume Hache, Aura Tintaru, Clément Morgat, Françoise Dignat-George, Philippe Garrigue, Benjamin Guillet","doi":"10.1007/s10456-023-09875-8","DOIUrl":null,"url":null,"abstract":"<div><p>APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([<sup>68</sup>Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [<sup>67</sup>Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [<sup>68</sup>Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [<sup>68</sup>Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [<sup>68</sup>Ga]Ga-AP747 and [<sup>68</sup>Ga]Ga-RGD<sub>2</sub> small animal PET/CT. [<sup>68</sup>Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [<sup>68</sup>Ga]Ga-RGD<sub>2</sub>. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [<sup>68</sup>Ga]Ga-AP747 PET signal was more than twice higher than that of [<sup>68</sup>Ga]Ga-RGD<sub>2</sub> on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [<sup>68</sup>Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [<sup>68</sup>Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [<sup>68</sup>Ga]Ga-RGD<sub>2</sub>.\n</p></div>","PeriodicalId":7886,"journal":{"name":"Angiogenesis","volume":"26 3","pages":"463 - 475"},"PeriodicalIF":9.2000,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10456-023-09875-8.pdf","citationCount":"2","resultStr":"{\"title\":\"Design and preclinical evaluation of a novel apelin-based PET radiotracer targeting APJ receptor for molecular imaging of angiogenesis\",\"authors\":\"Béatrice Louis, Vincent Nail, Oriane Nachar, Ahlem Bouhlel, Anaïs Moyon, Laure Balasse, Stéphanie Simoncini, Adrien Chabert, Samantha Fernandez, Pauline Brige, Guillaume Hache, Aura Tintaru, Clément Morgat, Françoise Dignat-George, Philippe Garrigue, Benjamin Guillet\",\"doi\":\"10.1007/s10456-023-09875-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([<sup>68</sup>Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [<sup>67</sup>Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [<sup>68</sup>Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [<sup>68</sup>Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [<sup>68</sup>Ga]Ga-AP747 and [<sup>68</sup>Ga]Ga-RGD<sub>2</sub> small animal PET/CT. [<sup>68</sup>Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [<sup>68</sup>Ga]Ga-RGD<sub>2</sub>. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [<sup>68</sup>Ga]Ga-AP747 PET signal was more than twice higher than that of [<sup>68</sup>Ga]Ga-RGD<sub>2</sub> on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [<sup>68</sup>Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [<sup>68</sup>Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [<sup>68</sup>Ga]Ga-RGD<sub>2</sub>.\\n</p></div>\",\"PeriodicalId\":7886,\"journal\":{\"name\":\"Angiogenesis\",\"volume\":\"26 3\",\"pages\":\"463 - 475\"},\"PeriodicalIF\":9.2000,\"publicationDate\":\"2023-03-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://link.springer.com/content/pdf/10.1007/s10456-023-09875-8.pdf\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Angiogenesis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10456-023-09875-8\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PERIPHERAL VASCULAR DISEASE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Angiogenesis","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s10456-023-09875-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PERIPHERAL VASCULAR DISEASE","Score":null,"Total":0}
Design and preclinical evaluation of a novel apelin-based PET radiotracer targeting APJ receptor for molecular imaging of angiogenesis
APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([68Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [67Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [68Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [68Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [68Ga]Ga-AP747 and [68Ga]Ga-RGD2 small animal PET/CT. [68Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [68Ga]Ga-RGD2. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [68Ga]Ga-AP747 PET signal was more than twice higher than that of [68Ga]Ga-RGD2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [68Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [68Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [68Ga]Ga-RGD2.
期刊介绍：
Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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