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-(p-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.