Adhikari Karuna, Grintsevich Sergei, de Groot Anke, Verhulst Emile, van Rymenant Yentl, Vangestel Christel, Lauwerys Louis, Miranda Alan, De Meester Ingrid, Van der Veken Pieter, Elvas Filipe
Molecular Imaging and Radiology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Bioconjug Chem. 2025 Aug 20;36(8):1887-1906. doi: 10.1021/acs.bioconjchem.5c00366. Epub 2025 Aug 11.
Fibroblast activation protein (FAP) is upregulated in cancer and fibrosis, making it an ideal target for imaging and therapy. Most FAP radioligands are large, highly polar, chelator-based molecules that suffer from limited tissue penetration and rapid tumor washout. In this study, we developed two covalently F-labeled, druglike FAP inhibitors, [F] and [F], featuring quaternary ammonium moieties linked via PEG chains to enhance tumor retention while maintaining high selectivity and favorable pharmacokinetics. Both radiotracers showed high affinity and specific uptake and . Compared to the clinically used [F]AlF-NOTA-FAPI-74, [F] and [F], exhibited significantly improved tumor retention at 6 h p.i. ([F]: 4.48 ± 0.34%IA/g; [F]: 6.70 ± 0.22%IA/g and [F]AlF-NOTA-FAPI-74:0.54 ± 0.08%IA/g). These findings highlight the importance of polarity tuning and the utility of quaternary ammonium groups for obtaining sustained tumor retention. They offer a valuable design strategy for novel radiotheranostic ligands that contain covalently bound radionuclides for imaging and treatment of FAP-positive tumors.
成纤维细胞活化蛋白（FAP）在癌症和纤维化中上调，使其成为成像和治疗的理想靶点。大多数FAP放射性配体是基于螯合剂的大分子，极性高，组织穿透力有限且肿瘤清除迅速。在本研究中，我们开发了两种共价氟标记的、类药物的FAP抑制剂，[F]和[F]，其具有通过聚乙二醇链连接的季铵部分，以增强肿瘤滞留，同时保持高选择性和良好的药代动力学。两种放射性示踪剂均显示出高亲和力和特异性摄取 以及 。与临床使用的[F]AlF-NOTA-FAPI-74相比，[F]和[F]在注射后6小时表现出显著改善的肿瘤滞留（[F]：4.48±0.34%IA/g；[F]：6.70±0.22%IA/g，[F]AlF-NOTA-FAPI-74：0.54±0.08%IA/g）。这些发现突出了极性调节的重要性以及季铵基团对于获得持续肿瘤滞留的效用。它们为含有共价结合放射性核素用于FAP阳性肿瘤成像和治疗的新型放射诊疗配体提供了有价值的设计策略。
