AUTOMATED SYNTHESIS AND IN VITRO STUDIES OF [68GA]GA-FAPI-46 IN HOSPITAL RADIOPHARMACY

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Early evidence appointed fibroblast activation protein (FAP), a type II transmembrane serine protease, as highly expressed in the stroma of various tumor entities, designating FAP as the next target for cancer studies in nuclear medicine. Several radiolabeled fibroblast activation protein inhibitors (FAPI) are currently in development and investigation as potential PET imaging agents for different neoplasms, with the potential for future theranostic applications. The aim of this study was to implement the efficient and convenient automated synthesis of [68Ga]Ga-FAPI-46 from ABX, using Modular Lab Pharm Tracer and the generator Gallia Pharm® from Eckert & Ziegler, for clinical applications in nuclear medicine services, as well as to evaluate routine quality control parameters such as radiochemical yield and purity, radiochemical stability, and sterility tests in accordance with the GMP rules. The synthesis was conducted in automated module, employing disposable cassettes in an adapted synthesis template with high purity raw materials and reagents. [68Ga]GaCl3 was percolated through resin and eluted with 0.5 mL of 5.5 M HCl in saline into a reaction vial containing 50 μg of FAPI-46 in 1.5 mL of 0.1 M acetate buffer (pH = 4.5) and 100 µL of ethanol. The solution was heated at 95°C for 10 min. The resulting product was purified through a Sep-Pak C18 cartridge, which was pre-conditioned with ethanol and 0.9% saline, and eluted with 0.4 mL of 70% ethanol. The final product was diluted with 0.9% saline and filtered through a Millipore 0.22 µm filter. Radiochemical yield (RCY) was assessed by determining the activity retained in the module in relation to the final product. Radiochemical purity (RCP) of [68Ga]Ga-FAPI-46 was analyzed by ascending chromatography using either ITLC-SG strip and 0.1 M ammonium acetate and methanol (1:1) solution or TLC and 1 M sodium citrate (pH = 5.5), and Sep-Pak C18 cartridge. Radiochemical stability was assessed through UHPLC analysis. Microbiological, pyrogenic, and filter tests were conducted on all batches. Additionally, in-vitro studies were carried out to assess Log P and serum protein binding for [68Ga]Ga-FAPI-46. The automated synthesis produced [68Ga]Ga-FAPI-46 with an activity of 684 ± 67 MBq, a RCY of 88.4 ± 2.6%, and pH = 4.5 (n = 8). The RCP was determined as 97.32 ± 1.92% by ascending chromatography and 97.74 ± 2.12% by Sep-Pak C18 cartridge. The RCP remained above 97% for more than 120 min as analyzed by UHPLC, showing high radiochemical stability. Microbiological assays demonstrated that the final product was obtained as a sterile and pyrogen free solution. The filter test passed for all batches. The Log P was determined as -3.57 ± 0.15 (n = 10), showing the hydrophilic characteristics of [68Ga]Ga-FAPI-46 with a serum protein binding of 52.11 ± 1.49% (n = 6). The [68Ga]Ga-FAPI-46 was synthesized with consistently high RCY and RCP, exhibiting reproducibility, yielding a sterile and pyrogen free final solution, that means an efficient way for routine syntheses in nuclear medicine services confirmed by clinical application in six patients.

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