A Novel Radiotracer for NTSR1-Targeted PET Imaging of Tumor: Preclinical and First-in-Human Studies

Neurotensin receptor 1 (NTSR1) is overexpressed in various cancers, making it an attractive target for tumor imaging and therapy. However, current NTSR1-targeting peptides derived from neurotensin (NT) analogs face challenges including rapid metabolic clearance and insufficient tumor uptake, limiting their clinical translation. To address this, we developed a novel probe, [⁶⁸Ga]Ga-DOTA-NT-20.3-IPBA, by conjugating the DOTA-NT-20.3 probe with an albumin-binding moiety (4-(<i>p</i>-iodophenyl)butyric acid [IPBA]). The resulting tracer exhibited enhanced lipophilicity and albumin-binding capacity, while maintaining reasonable in vitro stability, radiochemical yield, and purity (all >95%). In vitro and in vivo evaluations confirmed its high affinity and specificity for NTSR1. Clinical PET/CT imaging demonstrated significant tracer accumulation in lung adenocarcinoma, with a tumor-to-lung ratio of 7.89 ± 0.76 at 60 min postinjection and a favorable biodistribution profile. Collectively, [⁶⁸Ga]Ga-DOTA-NT-20.3-IPBA shows high potential as a PET tracer for NTSR1-expressing tumors and DOTA-NT-20.3-IPBA may be a promising candidate for future theranostic development.