Development and Evaluation of Novel 68Ga/177Lu-Labeled PSMA Inhibitors with Enhanced Pharmacokinetics and Tumor Imaging for Prostate Cancer.

Prostate-specific membrane antigen (PSMA) has been a key target for diagnosing and treating prostate cancer, particularly in high-grade, metastatic, and therapy-resistant tumors. This study presents a series of novel 68Ga- and 177Lu-labeled PSMA inhibitors, derived from the previously developed [68Ga]Ga-Flu-1. We explored the impact of PEG chains, lipophilic macrocycles, and dimerization on their in vivo properties. The 68Ga- and 177Lu-labeled inhibitors were assessed for biodistribution and tumor targeting in PC3-PIP tumor xenografts, leading to the identification of several promising candidates based on imaging and tumor-specific uptake. Positron emission tomography (PET) imaging revealed that the poly(ethylene glycol)-modified [68Ga]Ga-BisPSMA-P4 demonstrated rapid tumor penetration and excellent tumor-to-background contrast. In comparative biodistribution studies, the naphthalene ring-modified [68Ga]Ga-BisPSMA-Nph-P4 showed higher tumor uptake (∼60% ID/g at 1 h postinjection) and rapid renal clearance (∼25% ID/g at 2 h postinjection). Additionally, [177Lu]Lu-BisPSMA-Nph-P4 displayed superior retention, with significant uptake on day 7, highlighting its potential as a novel PSMA inhibitor for prostate cancer diagnosis and treatment.