Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [⁶⁸Ga]Ga-PSMA-093 ([⁶⁸Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating ⁶⁸Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[⁶⁸Ga/¹⁷⁷Lu]-DOTAGA derivatives, (R)-[⁶⁸Ga/¹⁷⁷Lu]-13 and (S)-[⁶⁸Ga/¹⁷⁷Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[¹⁷⁷Lu]Lu-13 and (S)-[¹⁷⁷Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[¹⁷⁷Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding ⁶⁸Ga agents were comparable between structural isomers. The ^natGa and ^natLu equivalents showed high binding PSMA affinity (IC₅₀ = 24–111 nM), comparable to that of the parent agent, [^natGa]Ga-PSMA-093 (IC₅₀ = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [⁶⁸Ga/¹⁷⁷Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new ¹⁷⁷Lu-DOTAGA-based radionuclide therapy agents in the future.

中文翻译：

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68Ga 和 177Lu 标记的 (R)- vs (S)-DOTAGA 前列腺特异性膜抗原靶向衍生物的合成和评价

前列腺特异性膜抗原 (PSMA) 在前列腺癌细胞中过度表达，因此是前列腺癌诊断和放射性核素治疗的一个有吸引力的目标。最近，发表了使用新型 PSMA 靶向 PET 显像剂 [ ⁶⁸ Ga]Ga-PSMA-093 ([ ⁶⁸ Ga]Ga-HBED-CC- O-羧甲基-Tyr-CO-NH-Glu) 的临床研究结果，支持开发这种用于诊断前列腺癌的药物。在这项研究中，PSMA-093 中的 HBED-CC 螯合基团被立体选择性 ( R )- 或 ( S )-DOTAGA 取代。该螯合基团不仅用于螯合⁶⁸Ga 但也可用于络合其他放射性金属以进行放射性核素治疗。相应的光学纯 ( R )- 和 ( S )-[ ⁶⁸ Ga/ ¹⁷⁷ Lu]-DOTAGA 衍生物， ( R )-[ ⁶⁸ Ga/ ¹⁷⁷ Lu]- 13和 ( S )-[ ⁶⁸ Ga/ ¹⁷⁷ Lu]- 13、准备成功。对两种异构体之间的放射性标记、结合亲和力、细胞摄取和生物分布进行了比较。( R )-[ ¹⁷⁷ Lu]Lu- 13和 ( S ) - [¹⁷⁷ Lu]Lu- 13在 50 °C 表明复合物的形成速率是时间依赖性的，并且 ( S )-[ ¹⁷⁷ Lu]Lu- 13 的形成明显更快。相应的⁶⁸ Ga 试剂的复合物形成速率在结构异构体之间具有可比性。的^NAT Ga和^NAT路等同物表现出较高的结合亲和力PSMA（IC ₅₀ = 24-111纳米），比得上母体剂，[ ^NAT嘎] Ga的PSMA-093（IC ₅₀ = 34.0纳米）。在表达 PSMA 的 PC3-PIP 荷瘤小鼠中细胞摄取和生物分布研究的结果似乎表明标记的（R )- 和 ( S )- 异构体。这是第一次对PSMA 试剂的一对 [ ⁶⁸ Ga/ ¹⁷⁷ Lu]-( R )- 和 ( S )-DOTAGA 异构体进行评估。异构体之间的生物学研究结果显示没有明显差异；然而，在未来开发新的基于¹⁷⁷ Lu-DOTAGA 的放射性核素治疗剂时，应考虑 Lu 络合物形成速率的差异。