Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l-tyrosine and l-glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with 125I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC50 = 1-13 nM). In vitro cell uptake studies demonstrated that compounds containing an l-tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l-tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [125I]8 and [125I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [125I]19a/19b and [125I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [125I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2-3-fold lower uptake in the liver and blood than that observed for [125I]MIP-1095. [125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.

中文翻译：

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新型放射性碘标记的PSMA靶向配体的合成和评估，可用于前列腺癌的潜在放射治疗。

使用前列腺特异性膜抗原（PSMA）靶向配体的放射配体疗法（RLT）是治疗前列腺癌（PCa）及其转移的一种有吸引力的选择。我们在本文中报道了一系列放射性碘代的谷氨酸-脲-赖氨酸-苯丙氨酸衍生物作为新的PSMA配体，其中添加了1-酪氨酸和1-谷氨酸部分以增加亲水性，同时改善了体内靶向性能。合成了化合物8、15、19a / 19b和23a / 23b，并通过碘去锡基化对125 I进行了放射性标记。所有碘化化合物均表现出对PSMA的高结合亲和力（IC50 = 1-13 nM）。体外细胞摄取研究表明，含有L-酪氨酸接头部分（8、15和19a / 19b）的化合物比没有L-酪氨酸接头部分的MIP-1095和23a / 23b具有更高的内在化。对具有PC3-PIP和PC3异种移植物的小鼠的生物分布研究表明，具有较高亲脂性的[125I] 8和[125I] 15在肝脏和肠道中表现出较高的非特异性积累，而[125I] 19a / 19b和[125I] 23a / 23b含有其他谷氨酸部分的蛋白在肾脏和植入的PC3-PIP（PSMA +）肿瘤中显示出更高的积累。与[125I] MIP-1095相比，[125I] 23b显示出令人鼓舞的生物分布特征，具有良好的肿瘤保留能力，从肾脏快速清除并且在肝脏和血液中的摄取降低了2至3倍。[125 / 131I] 23b可以用作放射治疗前列腺过度表达PSMA的最佳PSMA配体。