Zhang Qingyu, Hu Zhoumi, Zhao Haitao, Du Fuqiang, Lv Chun, Peng Tukang, Zhang Yukai, Zhang Bowu, Liu Jianjun, Wang Cheng
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China; MOE Key Lab of Resource Chemistry, Joint International Research Laboratory of Resource Chemistry of Ministry of Education, Shanghai Key Laboratory of Rare Earth Functional Materials, and Shanghai Frontiers Science Centre of Biomimetic Catalysis, Shanghai Normal University, Shanghai 200234, China.
Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 210000, China.
Bioorg Chem. 2025 Jun 15;160:108445. doi: 10.1016/j.bioorg.2025.108445. Epub 2025 Apr 10.
This study aimed to develop and evaluate two novel F-labeled radiopharmaceuticals, [F]AlF-NOTA-De-FAPI and [F]AlF-NOTA-Glu-FAPI, for Positron Emission Tomography (PET) imaging of tumors expressing fibroblast activation protein. Molecular docking simulations predicted the binding affinities of NOTA-De-FAPI and NOTA-Glu-FAPI with FAP. The radiotracers were synthesized and evaluated for radiochemical yield, purity, and molar activity. Surface plasmon resonance analysis measured binding kinetics. In vitro and in vivo stability and distribution coefficients were assessed. PET/CT imaging and ex vivo biodistribution studies were conducted in U87MG tumor-bearing mice. A pilot clinical study compared [F]AlF-NOTA-De-FAPI with [Ga]Ga-DOTA-FAPI-04 and [F]FDG in a liver cancer patient. Molecular docking simulations showed that NOTA-De-FAPI had a slightly higher binding affinity for FAP. The radiotracers were synthesized with high purity and molar activity. SPR analysis confirmed higher binding affinity of NOTA-De-FAPI (K = 86.35 pM) compared to NOTA-Glu-FAPI (K = 187 pM). In PET/CT imaging, [F]AlF-NOTA-De-FAPI demonstrated higher tumor uptake in U87MG tumor-bearing mice, with a peak SUV of 2.71 ± 0.39 at 1 h post-injection. Ex vivo biodistribution studies showed that [F]AlF-NOTA-De-FAPI had a tumor uptake of 9.16 ± 0.49 %ID/g at 1 h post-injection, significantly higher than [F]AlF-NOTA-Glu-FAPI (6.60 ± 0.82 %ID/g). In the clinical study, [F]AlF-NOTA-De-FAPI showed strong uptake in the primary tumor but exhibited higher physiological uptake in salivary glands, thyroid, and pancreas compared to [Ga]Ga-DOTA-FAPI-04. [F]AlF-NOTA-De-FAPI demonstrated potential as a FAP-targeting tracer with high specific uptake and favorable tumor-to-normal tissue ratios in preclinical models. However, clinical evaluation revealed limitations, such as high physiological uptake in certain glands and lower tumor uptake compared to [Ga]Ga-DOTA-FAPI-04. Further optimization and clinical validation are needed.
本研究旨在开发并评估两种新型的F标记放射性药物，即[F]AlF-NOTA-De-FAPI和[F]AlF-NOTA-Glu-FAPI，用于对表达成纤维细胞活化蛋白的肿瘤进行正电子发射断层扫描（PET）成像。分子对接模拟预测了NOTA-De-FAPI和NOTA-Glu-FAPI与FAP的结合亲和力。合成了放射性示踪剂，并对其放射性化学产率、纯度和摩尔活度进行了评估。表面等离子体共振分析测定了结合动力学。评估了体外和体内稳定性以及分布系数。在荷U87MG肿瘤小鼠中进行了PET/CT成像和离体生物分布研究。一项初步临床研究在一名肝癌患者中比较了[F]AlF-NOTA-De-FAPI与[Ga]Ga-DOTA-FAPI-04和[F]FDG。分子对接模拟表明，NOTA-De-FAPI对FAP的结合亲和力略高。合成的放射性示踪剂具有高纯度和摩尔活度。SPR分析证实，与NOTA-Glu-FAPI（K = 187 pM）相比，NOTA-De-FAPI具有更高的结合亲和力（K = 86.35 pM）。在PET/CT成像中，[F]AlF-NOTA-De-FAPI在荷U87MG肿瘤小鼠中显示出更高的肿瘤摄取，注射后1小时的SUV峰值为2.71±0.39。离体生物分布研究表明，[F]AlF-NOTA-De-FAPI在注射后1小时的肿瘤摄取为9.16±0.49 %ID/g，显著高于[F]AlF-NOTA-Glu-FAPI（6.60±0.82 %ID/g）。在临床研究中，[F]AlF-NOTA-De-FAPI在原发性肿瘤中显示出强烈摄取，但与[Ga]Ga-DOTA-FAPI-04相比，在唾液腺、甲状腺和胰腺中表现出更高的生理性摄取。[F]AlF-NOTA-De-FAPI在临床前模型中显示出作为FAP靶向示踪剂的潜力，具有高特异性摄取和良好的肿瘤与正常组织比值。然而，临床评估揭示了一些局限性，如在某些腺体中的高生理性摄取以及与[Ga]Ga-DOTA-FAPI-04相比更低的肿瘤摄取。需要进一步优化和临床验证。
