Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
J Med Chem. 2024 May 9;67(9):7068-7087. doi: 10.1021/acs.jmedchem.3c02402. Epub 2024 Apr 24.
Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-called FAPIs are among the most promising representatives. FAPIs typically have a relatively high molecular weight and contain very polar, multicharged chelator moieties. While this is not limiting the application of FAPIs in oncology, more druglike FAPIs could be required to optimally study diseases characterized by denser, less permeable tissue. In response, we designed the first druglike F-labeled FAPIs. We report target potencies, biodistribution, and pharmacokinetics and demonstrate FAP-dependent uptake in murine tumor xenografts. Finally, this paper puts forward compound as a highly promising, druglike FAPI for F-PET imaging. This molecule is fit for additional studies in fibrosis and its preclinical profile warrants clinical investigation.
成纤维细胞激活蛋白（FAP）是组织重塑非常可靠的生物标志物。FAP 迄今为止主要在肿瘤学中进行研究，但人们对该酶在纤维化等其他疾病中的兴趣日益浓厚。最近，出现了针对 FAP 的诊断和治疗方法，其中所谓的 FAPI 是最有前途的代表之一。FAPI 通常具有相对较高的分子量，并含有非常极性的多电荷螯合部分。虽然这并没有限制 FAPI 在肿瘤学中的应用，但可能需要更多类似药物的 FAPI 来优化研究密度更高、渗透性更差的组织特征的疾病。有鉴于此，我们设计了第一个类似药物的 F 标记 FAPI。我们报告了靶标效力、生物分布和药代动力学，并在小鼠肿瘤异种移植中证明了 FAP 依赖性摄取。最后，本文提出化合物 作为一种很有前途的、类似药物的 F-PET 成像 FAPI。该分子适合进一步研究纤维化，其临床前特征值得临床研究。
