Emerging ¹⁸F labeling strategies for peptide-based PET tracers: a review of recent technological advances

Positron emission tomography (PET) imaging has emerged as a powerful, noninvasive molecular imaging technique that is extensively used for the diagnosis and investigation of various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. Among available radionuclides, ¹⁸F is the most frequently used for PET probe synthesis owing to its favorable physical properties, such as an optimal half-life, low positron energy, and high β⁺ purity, which make it particularly suitable for high-resolution in vivo imaging. Recent advances in peptide-based PET tracers have demonstrated significant potential for tumor imaging due to their small molecular size, high receptor-binding affinity, favorable pharmacokinetics, and low immunogenicity. However, direct labeling of peptides with ¹⁸F via C-F bond formation remains challenging, as it typically requires harsh reaction conditions that are incompatible with the chemical stability of most peptides. To address these limitations, several novel ¹⁸F-radiolabeling strategies have been developed, significantly improving labeling efficiency while expanding the clinical applicability of peptide-based radiotracers. These strategies can be broadly classified into three categories: direct labeling via heteroatom-F bond formation, indirect labeling using prosthetic groups, and bioorthogonal chemistry labeling strategy. This review provides a comprehensive overview of these emerging ¹⁸F-labeling strategies for peptides, highlighting their advantages, limitations, and potential for future clinical applications, particularly in cancer imaging and personalized medicine.