[en] BACKGROUND: Fibroblast activation protein inhibitor (FAPI)-based positron emission tomography (PET) radiopharmaceuticals have shown promise for imaging cancer-associated fibroblasts (CAFs), a key component of the tumor microenvironment. FAPI radiopharmaceuticals offer high tumor-to-background contrast and are not influenced by hyperglycemia. Among these, [18F]AlF-FAPI-74, labeled using the Al18F-method, offers logistical advantages over 68Ga-labeled radiopharmaceuticals, including a longer physical half-life and suitability for large-scale, centralized production. This study reports a fully automated, efficient, and GMP-compliant synthesis of [18F]AlF-FAPI-74 using the Trasis AllInOne® platform, alongside a refined isocratic radio-HPLC method that enhances fluorine-18 recovery and impurity resolution. Additionally, the impact of molar dose on [18F]AlF-FAPI-74 biodistribution is evaluated in a preclinical model and a clinical case-study highlighting the performance of [18F]AlF-FAPI-74 produced at high apparent molar activity is provided.
RESULTS: The automated GMP-compliant production was validated in three independent runs, with an average decay-corrected yield and apparent molar activity of 50 ± 10% and 1124 ± 254 GBq/µmol at the end of synthesis, respectively. Total synthesis time was 30 min. Quality control used validated analytical methods, including an optimized radio-HPLC protocol, ensuring regulatory compliance and batch consistency. [18F]AlF-FAPI-74 was produced with a radiochemical purity ≥ 95% and demonstrated excellent radiochemical stability in its final formulation for at least 10 h post-synthesis, at a concentration of 2019 MBq/mL. The in vitro binding kinetics of [18F]AlF-FAPI-74 were evaluated in a HEK293 cell line stably expressing human FAP, demonstrating rapid, specific uptake and internalization, along with high target affinity. In vivo biodistribution studies revealed a dose-dependent "molar amount effect," with doses > 30 nmol/kg yielding improved tumor-to-background ratios. This phenomenon was not observed in clinical imaging, where high molar activity supported excellent image contrast.
CONCLUSIONS: A robust, fully automated, and GMP-compliant production process for [18F]AlF-FAPI-74 is reported with high yield, purity, and stability, suitable for centralized production and distribution. The improved radio-HPLC method enhances quality control precision by accurately quantifying radiochemical and chemical purity. In vivo experiments confirmed fast tumor uptake of [18F]AlF-FAPI-74. While a clear mass effect on tumor-to-background ratios was observed in preclinical studies, high apparent molar activity resulted in excellent contrast in a clinical setting.
Disciplines :
Chemistry
Author, co-author :
Storms, Ward; Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium
Celen, Sofie; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
Maes, Justine; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
Serdons, Kim; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
Goffin, Karolien; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
De Groot, Tjibbe; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
Trump, Laura; Trasis, Ans, 4430, Belgium
Warnier, Corentin; Trasis, Ans, 4430, Belgium
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire
Gérardy, Romaric; Trasis, Ans, 4430, Belgium
Van Laere, Koen; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
Deroose, Christophe M; Nuclear Medicine, University Hospital Leuven, Leuven, 3000, Belgium
Kleynhans, Janke; Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium
Cleeren, Frederik ; Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 3000, Belgium. frederik.cleeren@kuleuven.be
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