Development of Novel

Area of Science:

• Nuclear Medicine
• Oncology
• Radiochemistry

Background:

• Prostate-specific membrane antigen (PSMA) is a key target for metastatic castration-resistant prostate cancer (mCRPC).
• Previous PSMA-targeting radiotheranostic agents like PSMA-DA1 showed promise.
• Enhancing tumor uptake is crucial for improving radiotheranostic efficacy.

Purpose of the Study:

• To design and evaluate a novel PSMA-targeted radiotheranostic agent, PSMA-NAT-DA1 (PNT-DA1), with enhanced tumor accumulation.
• To assess the diagnostic and therapeutic potential of PNT-DA1 in preclinical models of prostate cancer.

Main Methods:

• PSMA-NAT-DA1 (PNT-DA1) was synthesized by incorporating a lipophilic linker into PSMA-DA1.
• Radioligands [111In]In-PNT-DA1 and [225Ac]Ac-PNT-DA1 were prepared and characterized.
• PSMA binding affinity, tumor uptake, and imaging performance of [111In]In-PNT-DA1 were evaluated using SPECT/CT.
• Antitumor efficacy and toxicity of [225Ac]Ac-PNT-DA1 were assessed in preclinical models.

Main Results:

• [111In]In-PNT-DA1 exhibited significantly higher PSMA affinity (Kd = 8.20 nM) compared to [111In]In-PSMA-DA1 (Kd = 89.4 nM).
• [111In]In-PNT-DA1 demonstrated remarkable tumor accumulation (131.6% injected dose/g at 48 h) and clear tumor visualization.
• [225Ac]Ac-PNT-DA1 treatment resulted in significant tumor shrinkage with minimal toxicity.
• The antitumor efficacy of [225Ac]Ac-PNT-DA1 surpassed that of [225Ac]Ac-PSMA-DA1 and [225Ac]Ac-PSMA-617.

Conclusions:

• PSMA-NAT-DA1 (PNT-DA1) represents a promising advancement in PSMA-targeted radiotheranostics for prostate cancer.
• The enhanced affinity and tumor uptake of PNT-DA1 translate to superior diagnostic imaging and therapeutic outcomes.
• Combined diagnostic ([111In]In-PNT-DA1) and therapeutic ([225Ac]Ac-PNT-DA1) applications offer a potent strategy for managing mCRPC.