Preclinical Characterization of [68Ga]Ga/[177Lu]Lu-PSNT-AB: A Dual-Targeted Agent against PSMA and NTSR1 for Prostate Cancer Theranostics

Abstract Prostate-specific membrane antigen (PSMA) is a key biomarker for prostate cancer (PCa), while neurotensin receptor 1 (NTSR1) is positive in PSMA-negative PCa lesions. For comprehensive diagnosis and therapy of PCa, we synthesized dual-targeted PSNT-AB (combining PSMA-targeted EuK, NTSR1-targeted NT-20.3, albumin-binding 4-p-tolylbutyric acid and DOTA moieties) and prepared [68Ga]Ga/[177Lu]Lu-PSNT-AB. [68Ga]Ga-PSNT-AB possessed high affinity for PSMA-positive LNCaP and moderate affinity for NTSR1-positive PC-3 cells. Probes accumulated time-dependently in relevant cells, and [177Lu]Lu-PSNT-AB exerted potent cytotoxicity. Pharmacokinetics revealed prolonged blood half-lives for both probes. PET imaging revealed persistent [68Ga]Ga-PSNT-AB uptake in LNCaP, 22Rv1 and PC-3 tumors (10.29 ± 0.25% ID/g, 6.61 ± 0.30% ID/g, 3.74 ± 0.12% ID/g at 3 h post-injection). SPECT/CT showed sustained [177Lu]Lu-PSNT-AB retention in LNCaP tumors for at least 24 h. These results demonstrated that [68Ga]Ga/[177Lu]Lu-PSNT-AB are promising dual-targeted probes for PCa diagnosis and therapy, offering a potential strategy for comprehensive and effective precision management of PCa.