Synthesis and Preclinical Evaluation of Peptide Dimer‐Based PET Tracers for Imaging VEGFR‐2 Expression in Tumors

ABSTRACTThe vascular endothelial growth factor A (VEGF‐A)/VEGF receptor 2 (VEGFR‐2) signaling pathway is pivotal in regulating angiogenesis. We have synthesized a linear peptide‐based VEGFR‐2–targeted positron emission tomography (PET) tracer, but its target affinity and in vivo stability need further improvement. In this study, we developed two novel 64Cu‐labeled VEGFR‐2–targeted PET dimer tracer [64Cu]VEGF2215 and [64Cu]VEGF2216 modified with a pegylated linear and branched linker, respectively, to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. Both tracers exhibited a radiochemical yield of over 95% and showed a high affinity for VEGFR‐2 in U87MG cells. PET/CT imaging experiments indicated that [64Cu]VEGF2215 exhibited a time‐dependent accumulation in the U87MG tumor, with a maximum uptake of 4.95 ± 1.26 %ID/g at 24 h post‐injection. In comparison, [64Cu]VEGF2216 showed a consistently lower tumor uptake, peaking at only 3.07 ± 0.35 %ID/g. Blocking and biodistribution experiments further confirmed the specificity of [64Cu]VEGF2215 for VEGFR‐2. The favorable properties of [64Cu]VEGF2215, including efficient synthesis, high tumor uptake, and rapid clearance from most normal organs, suggest it is a promising PET tracer for VEGFR‐2‐positive tumors.