PSMA-1-DOTA: A New Ligand to Make Prostate Cancer Radioligand Therapy More Targeted

PSMA-targeted radioligand therapy (RLT) has transformed treatment for end-stage prostate cancer, offering strong tumor control in patients who have exhausted other options. However, these therapies frequently cause severe salivary gland damage, leading to debilitating dry mouth that often forces patients to stop treatment early. To overcome this, researchers at Case Western Reserve University developed PSMA-1-DOTA, a novel PSMA-targeting ligand designed for better binding and reduced off-target effects.

In preclinical tests, PSMA-1-DOTA showed about four times greater binding affinity to PSMA than established ligands like PSMA-11 and PSMA I&T. Mouse models with PC3pip tumor xenografts underwent microPET/CT imaging within the same week to compare 68Ga-labeled versions, revealing PSMA-1-DOTA had markedly lower uptake in salivary glands, lacrimal glands, and kidneys compared to 68Ga-PSMA-11 and 68Ga-PSMA I&T. Therapeutic studies then treated the same models with 177Lu-PSMA-1-DOTA or 177Lu-PSMA-617 (Pluvicto), confirming equivalent tumor growth inhibition without the toxicity concerns.

A key validation came from a compassionate-use PET scan in a patient with metastatic castration-resistant prostate cancer at Technical University of Munich, where 68Ga-PSMA-1-DOTA again demonstrated strong tumor targeting alongside minimal salivary gland uptake. This DOTA-chelated ligand can pair with alpha- or beta-emitting radionuclides, potentially widening the therapeutic window to make RLT viable earlier in treatment rather than as a last resort.

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