Good practices for the automated production of F-SiFA radiopharmaceuticals.

Background: The positron emitting isotope fluorine-18 (F) possesses almost ideal physicochemical properties for the development of radiotracers for diagnostic molecular imaging employing positron emission tomography (PET). F in its nucleophilic anionic F form is usually prepared by bombarding an enriched O water target with protons of various energies between 5 and 20 MeV depending on the technical specifications of the cyclotron. Large thick-target yields between 5 and 14 GBq/µA can be obtained, enough to prepare large batches of radiotracers capable to serve a considerable contingent of patients (50 + per clinical batch). The overall yield of the radiotracer however depends on the efficiency of the F labeling chemistry. The Silicon Fluoride Acceptor chemistry (SiFA) has introduced a convenient and highly efficient way to provide clinical peptide-based F-radiotracers in a kit-like procedure matching the convenience of Tc radiopharmaceuticals.

Main Body: A radiotracer's clinical success primarily hinges on whether its synthesis can be automated. Due to its simplicity, the SiFA chemistry, which is based on isotopic exchange (F for F), does not only work in a manual setup but has been proven to be automatable, yielding large batches of F-radiotracers of high molar activity (A). The production of SiFA radiotracer can be centralized and the radiopharmaceutical be distributed via the "satellite" principle, where one production facility economically serves multiple clinical application sites. Clinically validated tracers such as [F]SiTATE and [F]Ga-rhPSMA-7/-7.3 have been synthesized in an automated synthesis unit under good manufacturing practice conditions and used in large patient cohorts. Communication of common guidelines and practices is warranted to further the dissemination of SiFA radiopharmaceuticals and to give easy access to this technology.

Conclusion: This current review highlights the most recent achievements in SiFA radiopharmaceutical automation geared towards large batch production for clinical application. Best practice advice and guidance towards a facilitated implementation of the SiFA technology into new and already operating PET tracer production facilities is provided. A brief outlook spotlights the future potential of SiFA radiochemistry within the landscape of non-canonical labeling chemistries.