Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Eur J Nucl Med Mol Imaging. 2022 Feb;49(3):1030-1040. doi: 10.1007/s00259-021-05486-x. Epub 2021 Aug 28.
Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized Ga-labeled ODAP-Urea-based ligand, [Ga]Ga-P137, and first-in-human results.
Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [Ga]Ga-P137 was performed in three patients head-to-head compared to [Ga]Ga-PSMA-617.
Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (K of 0.13 to 5.47 nM). [Ga]Ga-P137 was stable and hydrophilic. [Ga]Ga-P137 showed higher uptake than [Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [Ga]Ga-P137 was grossly equivalent to that of [Ga]Ga-PSMA-617 except for within the urinary tract, in which [Ga]Ga-P137 demonstrated lower uptake.
The optimized ODAP-Urea-based ligand [Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [Ga]Ga-PSMA-617, in a preliminary, first-in-human study.
ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.
前列腺特异性膜抗原（PSMA）是前列腺癌成像和治疗的有前途的靶点。最常用的支架包含谷氨酸-尿素（Glu-Urea）功能。我们最近开发了草酰二氨基丙酸-尿素（ODAP-Urea）PSMA 配体，试图改善现有药物的药代动力学特性。在这里，我们报告了一种优化的 Ga 标记的 ODAP-Urea 基配体 [Ga]Ga-P137 的合成及其在人体中的初步结果。
合成了 12 种 ODAP-Urea 基配体，并通过 Ga 在高放射化学产率和纯度下进行放射性标记。使用 NAALADase 测定法测定它们对 PSMA 的抑制能力。通过 microPET 在携带 22Rv1 前列腺肿瘤的小鼠中评估放射性配体。通过稳定性、细胞摄取和生物分布评估先导化合物 [Ga]Ga-P137。与 [Ga]Ga-PSMA-617 相比，对 3 名患者进行了 [Ga]Ga-P137 的 PET 成像头对头比较。
配体的收率为 11.1-44.4%，纯度>95%。它们对 PSMA 具有高亲和力（K 为 0.13 至 5.47 nM）。[Ga]Ga-P137 稳定且亲水性。[Ga]Ga-P137 在荷瘤小鼠中的摄取率高于 [Ga]Ga-PSMA-617，在 60 分钟时分别为 6.43±0.98%IA/g 和 3.41±1.31%IA/g。在人体研究中，[Ga]Ga-P137 的正常器官生物分布与 [Ga]Ga-PSMA-617 大致相当，除了在泌尿系统中，[Ga]Ga-P137 的摄取量较低。
优化的 ODAP-Urea 基配体 [Ga]Ga-P137 可在异种移植模型和人体中成像 PSMA，与初步的首次人体研究中基于 Glu-Urea 的配体 [Ga]Ga-PSMA-617 相比，膀胱蓄积较低。
ClinicalTrials.gov 标识符：NCT04560725，于 2020 年 9 月 23 日注册。https://clinicaltrials.gov/ct2/show/NCT04560725。
