PURPOSE Integrin αvβ6 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 [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvβ6 in rodent lung to support human translational studies. METHODS The synthesis of [18F]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-αvβ6 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 [18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/μmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]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 [18F]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 [18F]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.

中文翻译：

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临床前评估[18F] FB-A20FMDV2作为在啮齿动物肺中使用正电子发射断层显像技术测量αVβ6整联蛋白占用的选择标记。

目的整联蛋白αvβ6属于整联蛋白家族的RGD子集，其表达水平是某些类型的癌症和肺纤维化的预后和诊断学因素。本文描述了源自口蹄疫病毒的合成的20个氨基酸的肽A20FMDV2（NAVPNLRGDLQVLAQKVART）的GMP放射性标记，并表征了[18F] FB-A20FMDV2作为高亲和力，特异性和选择性PET放射性配体的用途用于啮齿动物肺中αvβ6的定量和可视化，以支持人类转化研究。方法[18F] FB-A20FMDV2的合成使用全自动且符合GMP的方法进行。使用Sprague-Dawley大鼠进行同源（未标记的FB-A20FMDV2）和异源（抗αvβ6抗体8G6）阻断研究。为了生成剂量估算，产生组织停留时间，并使用器官水平内部剂量评估/指数模型（OLINDA / EXM）软件计算相关的组织暴露和有效剂量。结果[18F] FB-A20FMDV2的合成在180分钟内完成，提供约800 MBq的[18F] FB-A20FMDV2，摩尔活性高达150 GBq /μmol，放射化学纯度高（> 97％）。静脉内给药于大鼠后，[18F] FB-A20FMDV2迅速被完整的放射性示踪剂代谢，占30分钟大鼠血浆中总放射性的5％。对于大鼠的同源和异源性阻滞，在给药[18F] FB-A20FMDV2后30-60分钟时，同源和异源性阻滞的肺心SUV比分别降低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计算可为人体提供33.5μSv/ MBq的全身有效剂量。结论[18F] FB-A20FMDV2代表一种特异性和选择性的PET配体，用于测量与药物相关的αvβ6整联蛋白在肺中的占有率。从啮齿类动物数据推断出的有效剂量与氟18标记的化合物的典型值相符，并与新型的完全自动化且符合GMP要求的合成方法结合使用，可用于翻译研究的临床应用。