[ 68 Ga]Ga-DOTA-CEND1: A Novel PET Cyclic Peptide Tracer for Noninvasive Imaging of Neuropilin-1 Expression in Pan-Tumors

As a transmembrane glycoprotein overexpressed in various tumors, neuropilin-1 (NRP-1) is involved in tumor progression, angiogenesis, and immune evasion. This study developed a novel PET cyclic peptide radiotracer [ 68 Ga]Ga-DOTA-CEND1 for NRP-1 detection specifically and sensitively across multiple tumor types, potentially guiding personalized NRP-1 therapeutic regimens. NRP-1 expression was assessed and confirmed through immunohistochemical analysis of tissue microarrays, Western blot, immunohistochemistry, and immunofluorescence staining. The biochemical properties of the probe were investigated through radiochemical purity, lipid–water partition coefficient, pharmacokinetics, in vivo and in vitro stabilities, and biosafety studies. To determine diagnostic sensitivity and clinical applicability, cellular uptake assays, micro positron-emission tomography/computed tomography (PET/CT), blocking studies, and ex vivo biodistribution were performed in four NRP-1 positive tumor models (fibrosarcoma, TNBC, NSCLC, and pancreatic tumor) and one NRP-1-negative model (cervical tumor). [ 68 Ga]Ga-DOTA-CEND1 demonstrated >95% radiochemical purity, optimal pharmacokinetics, favorable hydrophilicity, robust in vivo and in vitro stability, and an ideal biosafety profile. Micro PET/CT at 1 h postinjection revealed significantly higher tumor uptake in NRP-1 positive tumor models than in the NRP-1 negative tumor model, while coinjection with nonradioactive CEND-1 significantly reduced tumor uptake, and tumor-to-muscle ratios aligned with NRP-1 expression levels, confirming the specificity and sensitivity of the radiotracer. As the first PET cyclic peptide radiotracer, [ 68 Ga]Ga-DOTA-CEND1 holds great potential for noninvasively detecting NRP-1 expression across tumor types, optimizing NRP-1 targeted therapy, and evaluating therapeutic responses.