Colin Didier J, Inkster James A H, Germain Stéphane, Seimbille Yann
MicroPET/SPECT/CT Imaging Laboratory, Centre for BioMedical Imaging (CIBM), University Hospital of Geneva, 1211 Geneva, Switzerland.
Cyclotron Unit, University Hospital of Geneva, 1211 Geneva, Switzerland.
EJNMMI Radiopharm Chem. 2017;1(1):16. doi: 10.1186/s41181-016-0019-z. Epub 2016 Oct 25.
αβ, αβ and αβ integrins are known to be involved in carcinogenesis and are overexpressed in many types of tumours compared to healthy tissues; thereby they have been selected as promising therapeutic targets. Positron emission tomography (PET) is providing a unique non-invasive screening assay to discriminate which patient is more prone to benefit from antiangiogenic therapies, and extensive research has been carried out to develop a clinical radiopharmaceutical that binds specifically to integrin receptors. We recently reported the synthesis of a new F-labelled RGD peptide prepared by 2-cyanobenzothiazole (CBT)/1,2-aminothiol conjugation. This study aims at characterising the preclinical biologic properties of this new tumour-targeting ligand, named [F]FPyPEGCBT-(RGDfK).The in vitro binding properties of [F]FPyPEGCBT-(RGDfK) were analysed by standard binding assay in U-87 MG and SKOV-3 cancer models and its selectivity towards integrins by siRNA depletions. Its preclinical potential was studied in mice bearing subcutaneous tumours by ex vivo biodistribution studies and in vivo microPET/CT imaging.
In vitro, FPyPEGCBT-(RGDfK) efficiently bound RGD-recognising integrins as compared to a control (RGDfV) peptide (IC = 30.8 × 10 M vs. 6.0 × 10 M). [F]FPyPEGCBT-(RGDfK) cell uptake was mediated by an active transport through binding to α, β and β but not to β subunits. In vivo, this new tracer demonstrated specific tumour uptake with %ID/g of 2.9 and 2.4 in U-87 MG and SKOV-3 tumours 1 h post injection. Tumour-to-muscle ratios of 4 were obtained 1 h after intravenous administration of the tracer allowing good visualisation of the tumours. However, unfavourable background accumulation and high hepatobiliary excretion were observed.
[F]FPyPEGCBT-(RGDfK) specifically detects tumours expressing RGD-recognising integrin receptors in preclinical studies. Further optimisation of this radioligand may yield candidates with improved imaging properties and would warrant the further use of this efficient labelling technique for alternative targeting vectors.
已知αβ、αβ和αβ整合素参与致癌过程，与健康组织相比，在多种肿瘤类型中过表达；因此，它们已被选为有前景的治疗靶点。正电子发射断层扫描（PET）提供了一种独特的非侵入性筛查方法，以区分哪些患者更可能从抗血管生成治疗中获益，并且已经开展了广泛的研究来开发一种能特异性结合整合素受体的临床放射性药物。我们最近报道了通过2-氰基苯并噻唑（CBT）/1,2-氨基硫醇共轭制备的一种新的F标记RGD肽的合成。本研究旨在表征这种名为[F]FPyPEGCBT-(RGDfK)的新型肿瘤靶向配体的临床前生物学特性。通过在U-87 MG和SKOV-3癌症模型中的标准结合试验分析了[F]FPyPEGCBT-(RGDfK)的体外结合特性，并通过siRNA缺失分析了其对整合素的选择性。通过离体生物分布研究和体内微型PET/CT成像在荷皮下肿瘤小鼠中研究了其临床前潜力。
在体外，与对照（RGDfV）肽相比，FPyPEGCBT-(RGDfK)能有效结合识别RGD的整合素（IC = 30.8×10 M对6.0×10 M）。[F]FPyPEGCBT-(RGDfK)的细胞摄取是通过与α、β和β亚基结合的主动转运介导的，而不是与β亚基结合。在体内，这种新的示踪剂在注射后1小时在U-87 MG和SKOV-3肿瘤中显示出特异性肿瘤摄取，%ID/g分别为2.9和2.4。静脉注射示踪剂1小时后，肿瘤与肌肉的比值为4，从而能够很好地可视化肿瘤。然而，观察到不利的背景积累和高肝胆排泄。
在临床前研究中，[F]FPyPEGCBT-(RGDfK)能特异性检测表达识别RGD整合素受体的肿瘤。对这种放射性配体的进一步优化可能会产生具有改善成像特性的候选物，并将保证进一步使用这种有效的标记技术用于替代靶向载体。
