Wang Ran, Jin Wenbin, Luo Yang, Hong Haiyan, Zhao Ruiyue, Li Linlin, Yan Li, Qiao Jinping, Ploessl Karl, Zhu Lin, Kung Hank F
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
Department of Nuclear Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China.
Mol Pharm. 2024 Jul 1;21(7):3256-3267. doi: 10.1021/acs.molpharmaceut.4c00020. Epub 2024 Jun 10.
Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [Ga]Ga-P16-093, containing a Ga(III) chelator, ,'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-,'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log = 22.18) or lutetium-177 (log = 21.85). The aim of this study is to evaluate AAZTA-Gly--(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, ) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, , was effectively accomplished. Labeling with either [Ga]GaCl or [Lu]LuCl in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [Ga]Ga- or [Lu]Lu- with high yields and excellent radiochemical purities. Results of binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [Ga]Ga-P16-093 and [Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 μM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [Ga]Ga- and [Lu]Lu- displayed excellent uptake and retention in the tumor. Results indicate that [Ga]Ga/[Lu]Lu- (Ga]Ga/[Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.
前列腺特异性膜抗原（PSMA）在前列腺癌细胞中过表达，可作为成像和放射性配体治疗（RLT）的靶点。此前，含有镓（III）螯合剂，'-双[2-羟基-5-（羧乙基）苄基]乙二胺-'-二乙酸（HBED-CC）的[Ga]Ga-P16-093显示出优异的PSMA靶向特性，并在前列腺癌患者诊断中表现出高肿瘤摄取和滞留。最近，[Lu]Lu-PSMA-617已被美国食品药品监督管理局（FDA）批准用于治疗前列腺癌患者。以AAZTA（6-氨基-6-甲基全氢-1,4-二氮杂环庚烷四乙酸）作为螯合剂的PSMA-093衍生物被设计为与诊断和治疗放射性金属（如镓-68（log = 22.18）或镥-177（log = 21.85））形成复合物的替代剂。本研究的目的是评估导致镓-68/镥-177诊疗对的AAZTA-Gly--（甲基羧基）-Tyr-Phe-Lys-NH-CO-NH-Glu（命名为AZ-093，）作为潜在的PSMA靶向剂。所需前体AZ-093的合成有效完成。在50°C的醋酸钠缓冲溶液（pH 4-5）中，用[Ga]GaCl或[Lu]LuCl标记5至15分钟，可高产率且放射化学纯度优异地产生[Ga]Ga-或[Lu]Lu-。结合研究、细胞摄取和滞留（使用PSMA阳性前列腺癌细胞系22Rv1-FOLH1-oe）的结果分别与[Ga]Ga-P16-093和[Lu]Lu-PSMA-617相当。在有或没有竞争性阻断剂（2μM“冷”PSMA-11）的情况下测定特异性细胞摄取。在37°C下，PSMA阳性细胞中的细胞结合和内化在2小时内呈时间依赖性增加。细胞摄取被“冷”PSMA-11完全阻断，表明它们在竞争相同的PSMA结合位点。在植入PSMA阳性肿瘤细胞的小鼠模型中，[Ga]Ga-和[Lu]Lu-在肿瘤中均表现出优异的摄取和滞留。结果表明，[Ga]Ga/[Lu]Lu-（[Ga]Ga/[Lu]Lu-AZ-093）作为前列腺癌诊断和放疗的PSMA靶向剂具有潜在用途。
