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[F]FB - A20FMDV2作为使用正电子发射断层扫描测量啮齿动物肺部αβ整合素占有率的选择性标志物的临床前评估。

Preclinical evaluation of [F]FB-A20FMDV2 as a selective marker for measuring αβ integrin occupancy using positron emission tomography in rodent lung.

作者信息

Onega Mayca, Parker Christine A, Coello Christopher, Rizzo Gaia, Keat Nicholas, Ramada-Magalhaes Joaquim, Moz Sara, Tang Sac-Pham, Plisson Christophe, Wells Lisa, Ashworth Sharon, Slack Robert J, Vitulli Giovanni, Wilson Frederick J, Gunn Roger, Lukey Pauline T, Passchier Jan

机构信息

Imanova Ltd trading as Invicro, Burlington Danes Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.

GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Hertfordshire, SG1 2NY, UK.

出版信息

Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):958-966. doi: 10.1007/s00259-019-04653-5. Epub 2020 Jan 3.

DOI:10.1007/s00259-019-04653-5
PMID:31897589
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7075836/
Abstract

PURPOSE

Integrin αβ belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αβ in rodent lung to support human translational studies.

METHODS

The synthesis of [F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αβ antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software.

RESULTS

[F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [F]FB-A20FMDV2 with a molar activity of up to 150 GBq/μmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30-60 min post-administration of [F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 μSv/MBq.

CONCLUSION

[F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvβ6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.

摘要

目的

整合素αβ属于整合素家族的RGD亚群，其表达水平是某些类型癌症和肺纤维化的预后及诊疗因素。本文描述了源自口蹄疫病毒的合成20氨基酸肽A20FMDV2（NAVPNLRGDLQVLAQKVART）的GMP放射性标记，并表征了[F]FB - A20FMDV2作为一种高亲和力、特异性和选择性PET放射性配体，用于定量和可视化啮齿动物肺中的αβ，以支持人体转化研究。

方法

[F]FB - A20FMDV2的合成采用全自动且符合GMP标准的流程。使用Sprague - Dawley大鼠进行同源（未标记的FB - A20FMDV2）和异源（抗αβ抗体8G6）阻断研究。为了生成剂量学估计值，生成组织滞留时间，并使用器官水平内部剂量评估/指数建模（OLINDA/EXM）软件计算相关的组织暴露量和有效剂量。

结果

[F]FB - A20FMDV2的合成在180分钟内完成，提供了约800 MBq的[F]FB - A20FMDV2，摩尔活度高达150 GBq/μmol，放射化学纯度高（>97%）。静脉注射给大鼠后，[F]FB - A20FMDV2迅速代谢，在30分钟时完整的放射性示踪剂占大鼠血浆中总放射性的5%。对于大鼠的同源和异源阻断，在注射[F]FB - A20FMDV2后30 - 60分钟，同源和异源阻断的肺与心SUV比值分别降低了38.9±6.9%和56±19.2%。使用OLINDA/EXM进行的啮齿动物生物分布和剂量学计算得出人体全身有效剂量为33.5 μSv/MBq。

结论

[F]FB - A20FMDV2是一种特异性和选择性PET配体，用于测量肺中与药物相关的αvβ6整合素占有率。从啮齿动物数据外推得到的有效剂量与用氟 - 18标记的化合物的典型值一致，并结合了新型全自动且符合GMP标准的合成方法，可用于转化研究中的临床应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/165b7e672872/259_2019_4653_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/456c37278869/259_2019_4653_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/c9e3dca3596f/259_2019_4653_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/068721186d2f/259_2019_4653_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/f948ddfdab27/259_2019_4653_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/275f585c27df/259_2019_4653_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/165b7e672872/259_2019_4653_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/456c37278869/259_2019_4653_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/c9e3dca3596f/259_2019_4653_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/068721186d2f/259_2019_4653_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/f948ddfdab27/259_2019_4653_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/275f585c27df/259_2019_4653_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4b60/7075836/165b7e672872/259_2019_4653_Fig5_HTML.jpg

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