Prostate specific membrane antigen (PSMA) is an attractive target for molecular imaging of prostate cancer and several other solid tumors because of its overexpression in prostate carcinoma and tumor neovasculature, respectively. While currently most commonly used PSMA PET radioligands are Ga-labeled compounds, the short half-life and relatively low available radioactivity of gallium-68 have led to a steep increase in the development of F-labeled PSMA ligands. Several F-PSMA tracers such as [F]DCFPyL and [F]PSMA-1007 are already established in clinical practice, but there are still several drawbacks to be considered. Radiofluorination is often a multistep and time-consuming process requiring harsh labeling conditions. The limited sensitivity in the lower PSA ranges raises the need for improving the binding affinity of the ligands. Due to the metallic character of therapeutic radionuclides, there is very limited experience with F-PSMA tracers that can be applied for a theranostic approach. However, developments in the past few years have brought forward several improvements in these fields. These include the application of new radiosynthesis pathways for radiofluorination that reduces the process complexity, new approaches for the design of the pharmacophore, improving target interaction and the introduction of radiohybrid ligands, allowing labeling of the ligand with both diagnostic and therapeutic radionuclides. In this review, we will give an overview of these recent advancements of F-labeled PSMA PET radioligands.
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