An Improved ²¹¹At-Labeled Agent for PSMA-Targeted α-Therapy

Area of Science:

• Nuclear Medicine
• Radiopharmaceutical Therapy
• Oncology

Background:

• Alpha-particle emitters targeting prostate-specific membrane antigen (PSMA) are effective for prostate cancer treatment, especially in cases resistant to beta-particle therapy.
• Astatine-211 (211At), an alpha-emitter, offers potential for reduced toxicity compared to other alpha-emitting agents.
• Development of novel PSMA-targeted radiotracers is crucial for optimizing pharmacokinetic properties and therapeutic efficacy.

Purpose of the Study:

• To synthesize and evaluate a novel 211At-labeled radiotracer, 211At-3-Lu, for targeting PSMA in prostate cancer.
• To assess the pharmacokinetic profile, biodistribution, and therapeutic efficacy of 211At-3-Lu in preclinical models.
• To determine the toxicity profile of 211At-3-Lu through long-term studies.

Main Methods:

• Synthesis of 125I-labeled compounds to guide the selection of the optimal radiohalogen position and chelate composition.
• Evaluation of 211At-3-Lu in cell uptake and internalization assays using PSMA-expressing cells.
• Biodistribution studies in SCID mice bearing PSMA-positive tumors, followed by tumor growth control and long-term toxicity assessments.

Main Results:

• 211At-3-Lu demonstrated good radiochemical yield and high specific uptake in PSMA-positive cells.
• In vivo studies showed significant tumor uptake in PSMA+ PC3 PIP tumors with favorable tumor-to-organ ratios and minimal de-iodination.
• Therapeutic efficacy was observed with dose-dependent survival in flank and metastatic prostate cancer models, accompanied by minimal off-target toxicity.

Conclusions:

• The novel 211At-labeled radiotracer, 211At-3-Lu, exhibits promising efficacy in controlling prostate cancer growth.
• This agent demonstrates an acceptable toxicity profile, suggesting its potential for clinical application in prostate cancer management.
• 211At-3-Lu or similar analogs represent a viable option for targeted alpha-particle therapy in prostate cancer.