Xie Chengde, Peng Lei, Nie Hui, Yang Tianhong, Wu Renbo, Zhang Dake, Wen Fuhua, Chen Junyu, Xue Lingyu, Zhang Xiangsong, Zha Zhihao, Wang Jianjun
MOE Key Laboratory of Resources and EnvironmentalSystems Optimization, College of Environmental Scienceand Engineering, North China Electric Power University, Beijing, 102206, People's Republic of China.
Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-Sen University, 58# Zhongshan Er Road, Guangzhou, 510080, Guangdong Province, People's Republic of China.
EJNMMI Res. 2025 May 1;15(1):52. doi: 10.1186/s13550-025-01230-w.
Fibroblast activation protein (FAP) targeting radiotracers have emerged as promising agents for cancer imaging and therapy. Recent advancements have focused on optimizing these agents for better tumor targeting and enhanced theranostic efficacy. In this study, we introduced a novel heterodimeric radioligand labeled with gallium-68, which targets FAP. We aimed to evaluate its in vitro and in vivo performance, comparing its efficacy with monomeric FAPI derivatives.
The heterodimeric ligand BiFAPI was synthesized by conjugating a cyclic peptide with a quinoline-based motif via a DOTA chelator. [ Ga]Ga-BiFAPI demonstrated high radiochemical purity (> 95%) and exceptional stability in physiological conditions, as well as in both PBS and serum. In vitro studies revealed that the binding affinity of BiFAPI was comparable to that of FAP2286 and FAPI-04. Notably, [ Ga]Ga-BiFAPI exhibited superior cellular uptake, with rapid internalization and slower efflux rates. Micro-PET/CT imaging in tumor-bearing mice demonstrated significantly higher tumor uptake than [ Ga]Ga-FAP2286 and [ Ga]Ga-FAPI-04. Co-injection with a FAP inhibitor reduced tumor uptake, confirming the tracer's FAP specificity. In vitro autoradiography, immunohistochemistry, and Western blotting confirmed the correlation between radioactive tracer accumulation and FAP-positive regions. Biodistribution studies revealed high tumor-to-blood ratios and rapid clearance from non-target tissues, further supporting the tracer's favorable pharmacokinetics.
[ Ga]Ga-BiFAPI demonstrated superior tumor-targeting properties, higher tumor uptake, and favorable pharmacokinetics compared to [ Ga]Ga-FAP2286 and [ Ga]Ga-FAPI-04. Its promising performance in preclinical models positioned it as a potentially valuable agent for FAP-targeted PET imaging and cancer theranostics.
靶向成纤维细胞活化蛋白（FAP）的放射性示踪剂已成为癌症成像和治疗的有前景的药物。最近的进展集中在优化这些药物以实现更好的肿瘤靶向性和增强的诊疗效果。在本研究中，我们引入了一种新型的用镓-68标记的异二聚体放射性配体，其靶向FAP。我们旨在评估其体外和体内性能，并将其疗效与单体FAPI衍生物进行比较。
通过DOTA螯合剂将环肽与喹啉基基序偶联，合成了异二聚体配体BiFAPI。[⁶⁸Ga]Ga-BiFAPI显示出高放射化学纯度（>95%），在生理条件下以及在PBS和血清中均具有出色的稳定性。体外研究表明，BiFAPI的结合亲和力与FAP2286和FAPI-04相当。值得注意的是，[⁶⁸Ga]Ga-BiFAPI表现出优异的细胞摄取，具有快速内化和较慢的流出率。荷瘤小鼠的微型PET/CT成像显示，其肿瘤摄取明显高于[⁶⁸Ga]Ga-FAP2286和[⁶⁸Ga]Ga-FAPI-04。与FAP抑制剂共同注射可降低肿瘤摄取，证实了该示踪剂对FAP的特异性。体外放射自显影、免疫组织化学和蛋白质印迹证实了放射性示踪剂积累与FAP阳性区域之间的相关性。生物分布研究显示肿瘤与血液的比率高，且从非靶组织中快速清除，进一步支持了该示踪剂良好的药代动力学。
与[⁶⁸Ga]Ga-FAP2286和[⁶⁸Ga]Ga-FAPI-04相比，[⁶⁸Ga]Ga-BiFAPI表现出优异的肿瘤靶向特性、更高的肿瘤摄取和良好的药代动力学。其在临床前模型中的良好性能使其成为FAP靶向PET成像和癌症诊疗的潜在有价值的药物。
