PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer

Area of Science:

• Nuclear Medicine
• Oncology
• Radiopharmaceutical Chemistry

Background:

• Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is effective for advanced prostate cancer.
• Salivary gland toxicity is a major limitation of current α-emitting RLT.
• Existing PSMA-targeting ligands have suboptimal binding characteristics and toxicity profiles.

Purpose of the Study:

• To introduce and evaluate a novel PSMA-targeting ligand, PSMA-1-DOTA, with enhanced binding affinity and reduced salivary gland uptake.
• To compare the efficacy and toxicity of PSMA-1-DOTA with established PSMA-targeted agents.
• To assess the potential of PSMA-1-DOTA to improve the therapeutic window of PSMA-targeted RLT.

Main Methods:

• Binding affinity of PSMA-1-DOTA was compared to PSMA-11 and PSMA I&T.
• MicroPET/CT imaging in xenograft mouse models assessed uptake of [⁶⁸Ga]Ga-PSMA-1-DOTA, [⁶⁸Ga]Ga-PSMA-11, and [⁶⁸Ga]Ga-PSMA I&T in salivary glands, kidneys, and tumors.
• Therapeutic efficacy of [¹⁷⁷Lu]Lu-PSMA-1-DOTA was compared to [¹⁷⁷Lu]Lu-PSMA-617 in mouse models.
• A compassionate use PET imaging study in a prostate cancer patient was conducted using [⁶⁸Ga]Ga-PSMA-1-DOTA.

Main Results:

• PSMA-1-DOTA exhibited approximately four times greater binding affinity to PSMA than other ligands.
• [⁶⁸Ga]Ga-PSMA-1-DOTA showed significantly lower kidney uptake and minimal salivary/lacrimal gland uptake compared to controls.
• [¹⁷⁷Lu]Lu-PSMA-1-DOTA demonstrated comparable tumor growth inhibition to [¹⁷⁷Lu]Lu-PSMA-617.
• PET imaging in a patient confirmed reduced salivary gland uptake of [⁶⁸Ga]Ga-PSMA-1-DOTA.

Conclusions:

• PSMA-1-DOTA effectively targets PSMA-expressing tumors with reduced salivary gland uptake, potentially mitigating xerostomia.
• This novel ligand may enhance the therapeutic window for PSMA-targeted RLT.
• PSMA-1-DOTA holds promise for advancing PSMA-targeted RLT from a last-resort treatment to a more frontline therapy for prostate cancer.