Development and first-in-human study of PSMA-targeted PET tracers with improved pharmacokinetic properties

Area of Science:

• Radiochemistry and Nuclear Medicine
• Oncology
• Molecular Imaging

Background:

• Development of novel radiotracers is crucial for enhancing the diagnostic accuracy of prostate cancer (PCa).
• Existing tracers like [⁶⁸Ga]Ga-PSMA-617 and [⁶⁸Ga]Ga-PSMA-11 have limitations in tumor-to-kidney ratio and urinary system accumulation.
• Minimizing radiation toxicity to the urinary system is a key objective in developing new PCa imaging agents.

Purpose of the Study:

• To synthesize and evaluate novel ⁶⁸Ga-labeled tracers based on [⁶⁸Ga]Ga-PSMA-617.
• To augment the tumor-to-kidney ratio and reduce activity accumulation in the bladder.
• To ultimately minimize radiation toxicity to the urinary system in PCa patients.

Main Methods:

• Four novel radiotracers were synthesized by introducing quinoline, phenylalanine, and decanoic acid groups to enhance lipophilicity.
• In vitro binding affinity assays (saturation and competition) were performed on LNCaP cells.
• In vivo studies included metabolic analysis, Positron Emission Tomography (PET)/Computed Tomography (CT) imaging, and biodistribution experiments in LNCaP tumor-bearing mice, followed by a first-in-human study.

Main Results:

• Four tracers were synthesized with high radiochemical purity (>95%) and molar activity (20.0-25.5 GBq/μmol).
• [⁶⁸Ga]Ga-TWS02 exhibited low nanomolar binding affinity (K_i < 10 nM) and superior tumor-to-kidney (0.93) and tumor-to-muscle (107.62) ratios compared to reference tracers.
• First-in-human studies confirmed [⁶⁸Ga]Ga-TWS02's ability to detect PCa lesions with reduced urinary system accumulation and potential for bladder invasion detection.

Conclusions:

• The structural modifications successfully modulated binding affinity and pharmacokinetic properties of the PSMA-based tracers.
• [⁶⁸Ga]Ga-TWS02 demonstrates excellent performance for PCa diagnosis, offering clear imaging and reduced toxicity.
• TWS02, when chelated with DOTA, is also suitable for therapeutic applications with ¹⁷⁷Lu and ²²⁵Ac, potentially for PCa treatment.