Five Eleven Pharma Inc., Philadelphia, Pennsylvania 19104, United States.
College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
J Med Chem. 2023 Sep 14;66(17):12602-12613. doi: 10.1021/acs.jmedchem.3c01294. Epub 2023 Sep 5.
Prostate-specific membrane antigen (PSMA) is an excellent target for imaging and radionuclide therapy of prostate cancer. Recently, [Lu]Lu-PSMA-617 (Pluvicto) was approved by the FDA for radionuclide therapy. To develop hetero-bivalent agents targeting both PSMA and bone metastasis, [Lu]Lu-P17-079 ([Lu]Lu-1) and [Lu]Lu-P17-081 ([Lu]Lu-2) were prepared. In vivo biodistribution studies of [Lu]Lu-PSMA-617, [Lu]Lu-1, and [Lu]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 [Ga]Ga-P17-079 ([Ga]Ga-1) in the same mouse model displayed excellent images confirming the expected dual-targeting to PSMA-positive tumor and bone. Results suggest that [Lu]Lu-P17-079 ([Lu]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.
前列腺特异性膜抗原（PSMA）是成像和前列腺癌放射性核素治疗的极佳靶点。最近，[Lu]Lu-PSMA-617（Pluvicto）被 FDA 批准用于放射性核素治疗。为了开发针对 PSMA 和骨转移的双价靶向药物，制备了[Lu]Lu-P17-079([Lu]Lu-1)和[Lu]Lu-P17-081([Lu]Lu-2)。在 PSMA 阳性肿瘤小鼠体内的[Lu]Lu-PSMA-617、[Lu]Lu-1 和[Lu]Lu-2 的生物分布研究表明，它们在 PSMA 阳性肿瘤中有高摄取（分别在 1 h 时为 14.5、14.7 和 11.3% ID/g），且骨摄取明显不同（分别在 1 h 时为 0.52、6.52 和 5.82% ID/g）。在相同的小鼠模型中使用[Ga]Ga-P17-079([Ga]Ga-1)进行 PET 成像显示了优异的图像，证实了预期的对 PSMA 阳性肿瘤和骨的双靶向作用。结果表明，[Lu]Lu-P17-079([Lu]Lu-1)是进一步开发用于治疗前列腺癌的针对 PSMA 表达和骨转移的双价放射性核素治疗剂的有前途的候选物。
