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

PURPOSE: While PSMA-targeted radioligand therapy (RLT) has shown remarkable efficacy for treating end-stage prostate cancer, the α-emitting RLT often results in severe salivary gland toxicity, limiting its use. Various strategies to mitigate this side effect have been attempted with limited success. Accordingly, this study introduced a new PSMA-targeting ligand with more favorable binding characteristics than the existing ligands.

PROCEDURES: The binding affinity of PSMA-1-DOTA to PSMA was compared with that of PSMA-11 and PSMA I&T. Comparison of uptake in the salivary glands, kidneys and PC3pip tumor cells in the xenograft mouse models between [68 Ga]Ga-PSMA-1-DOTA, [68 Ga]Ga-PSMA-11 and [68 Ga]Ga-PSMA I&T was conducted with microPET/CT within the same week. The same mouse models were treated with [177Lu]Lu-PSMA-1-DOTA or [177Lu]Lu-PSMA-617. A compassionate use PET imaging study on a patient with metastatic castration-resistant prostate cancer was performed using [68 Ga]Ga-PSMA-1-DOTA.

RESULTS

The binding affinity of PSMA-1-DOTA to PSMA was found to be approximately four times greater than other PSMA-targeted ligands. Imaging with microPET/CT revealed significantly lower kidney, uptake and little salivary and lacrimal gland uptake with [68 Ga]Ga-PSMA-1-DOTA compared to other PSMA-radioligands. Preclinical efficacy studies demonstrated that [177Lu]Lu-PSMA-1-DOTA inhibited tumor growth comparable to that with [177Lu]Lu-PSMA-617, suggesting its potential to enhance the therapeutic window of targeted RLT by avoiding damage to the salivary glands. The compassionate use PET imaging confirmed the reduced salivary gland uptake of [68 Ga]Ga-PSMA-1-DOTA in the patient, indicating its potential utility as a targeting agent for RLT with α- or β-emitting radionuclides in patients with PSMA-positive prostate cancer.

CONCLUSION

PSMA-1-DOTA shows reduced uptake in salivary glands while effectively targeting PSMA-expressing tumors, thus potentially avoiding the side effects of xerostomia, and possibly moving PSMA-targeted RLT to a more frontline therapy for prostate cancer rather than the current use as a last resort.