高肾脏和唾液腺摄取是以赖氨酸-尿素-谷氨酸（Lys-urea-Glu）药效团为基础的针对前列腺特异性膜抗原（PSMA）的放射性配体的常见特征。在本研究中，我们研究了赖氨酸-尿素-2-氨基己二酸（Lys-urea-Aad）、赖氨酸-尿素-S-羧甲基半胱氨酸（Lys-urea-Cmc）和赖氨酸-尿素-O-羧甲基丝氨酸（Lys-urea-Cms）药效团衍生的放射性配体（带有/不带有白蛋白结合剂），以确定其是否能保持优良的PSMA靶向能力，但最小化对肾脏和唾液腺的摄取。方法：通过将之前报道的Lys-urea-Aad衍生物HTK03149中的Aad替换为Cmc和Cms，得到HTK03177和HTK03187。由HTK03149、HTK03177和HTK03187衍生出HTK03170、HTK04048和HTK04028，相应地结合了一种白蛋白结合基团，4-(对甲氧基苯基)丁酸。利用表达PSMA的LNCaP前列腺癌细胞和[18F]DCFPyL作为放射性配体进行体外竞争结合试验。使用标记有68Ga的HTK03177和HTK03187以及标记有177Lu的HTK03170、HTK04048和HTK04028进行LNCaP肿瘤载体小鼠的成像和生物分布研究。使用[177Lu]Lu-HTK03170进行LNCaP肿瘤载体小鼠的放射性配体治疗研究，并与[177Lu]Lu-PSMA-617进行比较。结果：Ga-HTK03177、Ga-HTK03187、Lu-HTK03170、Lu-HTK04048和Lu-HTK04028的计算Ki(PSMA)值分别为5.0±2.4、10.6±2.0、1.6±0.4、1.4±1.0和13.9±3.2nM。注射后1小时的PET成像和生物分布研究显示，[68Ga]Ga-HTK03177和[68Ga]Ga-HTK03187在LNCaP肿瘤载体中摄取高（24.7±6.85和21.1±3.62%ID/g），但在肾脏（7.76±1.00和2.83±0.45%ID/g）和唾液腺（0.22±0.02和0.16±0.02%ID/g）等正常器官/组织中摄取最小。SPECT成像和生物分布研究显示，177Lu标记的HTK03170、HTK04048和HTK04028在注射后4-24小时达到峰值，大约为43-65%ID/g，并且随时间相对稳定。它们在肾脏（≤17.4%ID/g）和唾液腺（≤2.92%ID/g）的峰值平均摄取量较低，并且随时间持续减少。放射性配体治疗研究表明，与[177Lu]Lu-PSMA-617（37 MBq）相比，1/4剂量的[177Lu]Lu-HTK03170（9.3 MBq）导致更好的中位生存期（63 vs 90天）。结论：我们的数据表明，赖氨酸-尿素-2-氨基己二酸、赖氨酸-尿素-S-羧甲基半胱氨酸和赖氨酸-尿素-O-羧甲基丝氨酸是设计PSMA靶向放射性配体的有前途的药效团，特别适用于放射治疗应用，以减少对肾脏和唾液腺的毒性。©作者。

High kidney and salivary gland uptake is a common feature of prostate-specific membrane antigen (PSMA)-targeted radioligands derived from the lysine-urea-glutamic acid (Lys-urea-Glu) pharmacophore. In this study we investigated if radioligands derived from lysine-urea-2-aminoadipic acid (Lys-urea-Aad), lysine-urea-S-carboxylmethylcysteine (Lys-urea-Cmc) and lysine-urea-O-carboxylmethylserine (Lys-urea-Cms) pharmacophores with/without an albumin binder could retain good PSMA-targeting capability but with minimized kidney and salivary gland uptake. Methods: HTK03177 and HTK03187 were obtained by replacing Aad in the previously reported Lys-urea-Aad-derived HTK03149 with Cmc and Cms, respectively. HTK03170, HTK04048 and HTK04028 were derived from HTK03149, HTK03177 and HTK03187, respectively, with the conjugation of an albumin-binding moiety, 4-(p-methoxyphenyl)butyric acid. In vitro competition binding assays were conducted using PSMA-expressing LNCaP prostate cancer cells and [18F]DCFPyL as the radioligand. Imaging and biodistribution studies of 68Ga-labeled HTK03177 and HTK03187, and 177Lu-labeled HTK03170, HTK04048 and HTK04028 were performed in LNCaP tumor-bearing mice. Radioligand therapy study of [177Lu]Lu-HTK03170 was carried out in LNCaP tumor-bearing mice and [177Lu]Lu-PSMA-617 was used for comparison. Results: The calculated Ki(PSMA) values of Ga-HTK03177, Ga-HTK03187, Lu-HTK03170, Lu-HTK04048 and Lu-HTK04028 were 5.0±2.4, 10.6±2.0, 1.6±0.4, 1.4±1.0 and 13.9±3.2 nM, respectively. PET Imaging and biodistribution studies at 1 h post-injection showed that both [68Ga]Ga-HTK03177 and [68Ga]Ga-HTK03187 had high uptake in LNCaP tumor xenografts (24.7±6.85 and 21.1±3.62 %ID/g, respectively) but minimal uptake in normal organs/tissues including kidneys (7.76±1.00 and 2.83±0.45 %ID/g, respectively) and salivary glands (0.22±0.02 and 0.16±0.02 %ID/g, respectively). SPECT imaging and biodistribution studies showed that the LNCaP tumor uptake of 177Lu-labeled HTK03170, HTK04048 and HTK04028 peaked at 4-24 h post-injection at ~43-65 %ID/g and was relatively sustained over time. Their peaked average uptake in kidneys (≤ 17.4 %ID/g) and salivary glands (≤ 2.92 %ID/g) was lower and continuously reduced over time. Radioligand therapy study showed that compared with [177Lu]Lu-PSMA-617 (37 MBq), a quarter dose of [177Lu]Lu-HTK03170 (9.3 MBq) led to a better median survival (63 vs 90 days). Conclusions: Our data demonstrate that that Lys-urea-Aad, Lys-urea-Cmc and Lys-urea-Cms are promising pharmacophores for the design of PSMA-targeted radioligands especially for radiotherapeutic applications to minimize toxicity to kidneys and salivary glands.© The author(s).