Radiofluorination

Radiofluorination is the chemical process of introducing radioactive fluorine, most commonly the positron-emitting isotope fluorine-18, into organic molecules to create radiotracers for positron emission tomography (PET). Fluorine-18 has a half-life of about 109.8 minutes and decays by positron emission, enabling high-resolution PET imaging while allowing centralized production and distribution to PET facilities.

Fluorine-18 is produced in medical cyclotrons by irradiating enriched oxygen-18 water with protons via the 18O(p,n)18F reaction. The radionuclide is typically used as [18F]fluoride in aqueous solution. Labeling is carried out either by nucleophilic substitution, where [18F] fluoride displaces a suitable leaving group under phase-transfer catalysis or with cryptands, or by electrophilic fluorination using [18F]F2 gas or specialized reagents that enable milder conditions.

In practice, late-stage fluorination strategies are favored to install 18F close to the final tracer, maximizing specific activity and radiochemical yield. Common radiotracers include [18F]fluorodeoxyglucose ([18F]FDG), widely used in oncology and neurology, and a broad range of other agents such as [18F]FDOPA, [18F]FLT, and [18F]FMISO, among many receptor- or transporter-targeted compounds.

Applications and considerations: Radiofluorination enables PET imaging of metabolic activity, receptor binding, perfusion, and hypoxia. Radiotracers are produced in GMP-compliant radiopharmacies and require rapid synthesis, sterile filtration, and comprehensive quality control, including radiochemical purity, specific activity, residual solvent analysis, sterility, and pyrogen testing, along with appropriate radiation safety measures.

Challenges and future directions: The short half-life demands efficient automation and rapid workflows. Advances include automated synthesis platforms, copper- and nickel-mediated 18F fluorination of arenes, and late-stage fluorination strategies that expand the range of accessible tracers, while regulatory and safety frameworks govern production and use.