Fluorine‐18‐Labeled Nucleotide Analogs Targeting Ecto‐5'‐Nucleotidase (CD73) for Positron Emission Tomography Imaging of Solid Tumors

Ecto-5'-nucleotidase (CD73) is a potential new drug target for cancer immunotherapy. Its overexpression is associated with various aggressive cancers, including triple-negative breast cancer (TNBC) and pancreatic cancer, making it a promising target for diagnostic imaging. Besides antibodies, small-molecule CD73 inhibitors have been developed and are currently in clinical trials. This study aimed to develop and evaluate fluorine-18 labeled high-affinity CD73 inhibitors as tracers for the non-invasive positron emission tomography (PET) imaging of CD73 expression in cancer. Two CD73 inhibitors were selected for radiolabeling based on their high potency (K_i values of ca. 1 nM) and favorable pharmacokinetic properties, yielding [¹⁸F]PSB-19427 ([¹⁸F]1) and [¹⁸F]MRS-4648 ([¹⁸F]2). Ex vivo imaging studies on human breast cancer tissues indicated specific binding of both radiotracers. Subsequent in vivo studies proved [¹⁸F]1 to be superior due to its long elimination half-life and its accumulation in TNBC and pancreatic cancer tissues, suggesting its potential as a versatile PET tracer for imaging of various solid tumors. Compared to [¹⁸F]FDG, [¹⁸F]1 was superior in visualizing TNBC, offering potential advantages over [¹⁸F]FDG in terms of specificity and diagnostic accuracy. Thus, [¹⁸F]1 is a PET tracer with outstanding properties suitable for broad application in cancer diagnosis and personalized medicine.