Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting

体内分布 化学 多塔 谷氨酸羧肽酶Ⅱ 连接器 配体(生物化学) 体内 IC50型 前列腺癌 癌症研究 组合化学 生物化学 体外 癌症 螯合作用 受体 内科学 生物 有机化学 生物技术 操作系统 医学 计算机科学
作者
Seol Ju Moon,Mee Kyung Hong,Young Ju Kim,Yun Sang Lee,Dong Hoon Lee,June‐Key Chung,Jae Min Jeong
出处
期刊:Bioorganic & Medicinal Chemistry [Elsevier]
卷期号:26 (9): 2501-2507 被引量:11
标识
DOI:10.1016/j.bmc.2018.04.014
摘要

Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with 68Ga. NOTA-GUL and DOTA-GUL were synthesized and labeled with 68Ga using generator-eluted 68GaCl3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5. The stabilities of 68Ga-labeled compounds in human serum were tested at 37.5 °C. A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [125I]MIP-1072 (PSMA-specific binding agent) as a tracer. Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice. The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%). The IC50 of Ga-NOTA-GUL was 18.3 nM. In the biodistribution study, tumor uptake of 68Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68Ga-DOTA-GUL (4.66% ID/g) at 1 h. Tumor/muscle and tumor/blood uptake ratios of 68Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68Ga-DOTA-GUL (16.1 and 31.1, respectively). The tumor/kidney uptake ratio of 68Ga-NOTA-GUL was 3.4-fold higher than that of 68Ga-DOTA-GUL. 68Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand. In conclusion, we successfully synthesized 68Ga-NOTA-GUL and 68Ga-DOTA-GUL for prostate cancer imaging. 68Ga-NOTA-GUL showed better radiochemical and biodistribution results. 68Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical.
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