68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent

体内分布 尿素 前列腺癌 谷氨酸羧肽酶Ⅱ 配体(生物化学) 化学 药代动力学 体内 放射化学 核医学 核化学 癌症 体外 生物化学 药理学 医学 受体 内科学 生物技术 生物
作者
Xiaojiang Duan,Z. Cao,Hua Zhu,Chen Liu,Xiaojun Zhang,Jinming Zhang,Yanan Ren,Futao Liu,Xuekang Cai,Xiaoyi Guo,Zhen Xi,Martin G. Pomper,Zhi Yang,Yan Fan,Xing Yang
出处
期刊:European Journal of Nuclear Medicine and Molecular Imaging [Springer Science+Business Media]
卷期号:49 (3): 1030-1040 被引量:25
标识
DOI:10.1007/s00259-021-05486-x
摘要

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 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results.Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga 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 [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617.Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]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 [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake.The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study.ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.
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