¹⁸F-Labeling of Arenes and Heteroarenes for Applications in Positron Emission Tomography

Diverse radiochemistry is an essential component of nuclear medicine; this includes imaging techniques such as positron emission tomography (PET). As such, PET can track diseases at an early stage of development, help patient care planning through personalized medicine and support drug discovery programs. Fluorine-18 is the most frequently used radioisotope in PET radiopharmaceuticals for both clinical and preclinical research. Its physical and nuclear characteristics (97% β+ decay, 109.8 min half-life, 635 keV positron energy) and high specific activity make it an attractive nuclide for labeling and molecular imaging. Arenes and heteroarenes are privileged candidates for 18F-incorporation as they are metabolically robust and therefore widely used by medicinal chemists and radiochemists alike. For many years, the range of (hetero)arenes amenable to 18F-fluorination was limited by the lack of chemically diverse precursors, and of radiochemical methods allowing 18F-incorporation in high selectivity and efficiency (radiochemical yield and purity, specific activity, and radio-scalability). The appearance of late-stage fluorination reactions catalyzed by transition metal or small organic molecules (organocatalysis) has encouraged much research on the use of these activation manifolds for 18F-fluorination. In this piece, we review all of the reactions known to date to install the 18F substituent and other key 18F-motifs (e.g., CF3, CHF2, OCF3, SCF3, OCHF2) of medicinal relevance onto (hetero)arenes. The field has changed significantly in the past five years, and the current trend suggests that the radiochemical space available for PET applications will expand rapidly in the near future