Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy

Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [177Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [177Lu]Lu-P17-079 ([177Lu]Lu-1) and [177Lu]Lu-P17-081 ([177Lu]Lu-2) were prepared. In vivo biodistribution studies of [177Lu]Lu-PSMA-617, [177Lu]Lu-1, and [177Lu]Lu-2 in mice bearing PC3-PIP (PSMA positive) tumor showed high uptake in PSMA-positive tumor (14.5, 14.7, and 11.3% ID/g at 1 h, respectively) and distinctively different bone uptakes (0.52, 6.52, and 5.82% ID/g at 1 h, respectively). PET imaging using [68Ga]Ga-P17-079 ([68Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [177Lu]Lu-P17-079 ([177Lu]Lu-1) is a promising candidate for further development as a hetero-bivalent radionuclide therapy agent targeting both PSMA expression and bone metastases for the treatment of prostate cancer.