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

ABSTRACT 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 [ 18 F]PSB‐19427 ([ 18 F] 1 ) and [ 18 F]MRS‐4648 ([ 18 F] 2 ). Ex vivo imaging studies on human breast cancer tissues indicated specific binding of both radiotracers. Subsequent in vivo studies proved [ 18 F] 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 [ 18 F]FDG, [ 18 F] 1 was superior in visualizing TNBC, offering potential advantages over [ 18 F]FDG in terms of specificity and diagnostic accuracy. Thus, [ 18 F] 1 is a PET tracer with outstanding properties suitable for broad application in cancer diagnosis and personalized medicine.