Recent advances in radical C-H ¹⁹F/¹⁸F-fluorination and fluoroalkylation of native amino acids and peptides

Fluorinated amino acids and peptides play a pivotal role in drug discovery, chemical biology, and molecular imaging due to the unique influence of fluorine on molecular properties such as lipophilicity, metabolic stability, and biological activity. In parallel, 18F-labeled amino acids and peptides have become indispensable tools in positron emission tomography (PET), providing sensitive and quantitative imaging of biological processes in vivo. Traditional synthetic routes to access these fluorinated biomolecules often rely on prefunctionalized precursors or labor-intensive multistep approaches, limiting their applicability, particularly for late-stage modification. In recent years, direct radical C–H fluorination and fluoroalkylation strategies have emerged as powerful tools for the efficient and selective modification of native amino acids and peptides. These methods enable streamlined access to a wide range of fluorinated and radiolabeled derivatives, offering new opportunities for the rapid development of therapeutic candidates and PET tracers. This review summarizes recent advances in the direct radical C–H ¹⁹F/¹⁸F-fluorination and fluoroalkylation of native amino acids and peptides, highlighting key methodological breakthroughs, mechanistic insights, and representative applications. We further discuss the challenges that remain in the field and outline future directions aimed at expanding the chemical space and translational potential of these promising methodologies.