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Effects of Linker Modification on Tumor-to-Kidney Contrast of 68Ga-Labeled PSMA-Targeted Imaging Probes
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-19 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00499 Hsiou-Ting Kuo 1 , Jinhe Pan 1 , Zhengxing Zhang 1 , Joseph Lau 1 , Helen Merkens 1 , Chengcheng Zhang 1 , Nadine Colpo 1 , Kuo-Shyan Lin 1, 2, 3 , François Bénard 1, 2, 3
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-19 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00499 Hsiou-Ting Kuo 1 , Jinhe Pan 1 , Zhengxing Zhang 1 , Joseph Lau 1 , Helen Merkens 1 , Chengcheng Zhang 1 , Nadine Colpo 1 , Kuo-Shyan Lin 1, 2, 3 , François Bénard 1, 2, 3
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68Ga-PSMA-11 is currently the most popular prostate-specific membrane antigen (PSMA) radioligand used in the clinic to detect prostate cancer and metastases. However, the high uptake of 68Ga-PSMA-11 in kidneys can create halo-artifacts resulting in lower detection sensitivity for lesions adjacent to the kidneys. In this study, we developed two 68Ga-labeled PSMA-targeted tracers, 68Ga-HTK01166 and 68Ga-HTK01167, based on 68Ga-PSMA-617 with the goal of improving tumor-to-kidney ratio compared to 68Ga-PSMA-11. The 2-naphthylalanine (2-Nal) in PSMA-617 was replaced with 2-indanylglycine (Igl) or 3,3-diphenylalanine (Dip) to synthesize HTK01166 and HTK01167, respectively. Binding affinities (Ki) of Ga-PSMA-11, Ga-PSMA-617, Ga-HTK01166, and Ga-HTK01167 to PSMA were 3.13 ± 0.40, 1.23 ± 0.08, 5.74 ± 2.48, and 25.7 ± 9.84 nM, respectively, as determined by in vitro competition binding assays. 68Ga labeling was performed in HEPES buffer with microwave heating, and 68Ga-labeled PSMA-11, PSMA-617, HTK01166, and HTK01167 were obtained in 46–69% average decay-corrected radiochemical yield with >99% radiochemical purity and 62.9–152 GBq/μmol average specific activity. PET imaging and biodistribution studies were performed in mice bearing PSMA-expressing LNCap prostate cancer xenografts. All tracers enabled clear visualization of tumors in PET images with excellent tumor-to-background contrast. The uptake values (%ID/g) for tumor and kidneys at 1 h postinjection were 8.91 ± 0.86 and 204 ± 70.6 for 68Ga-PSMA-11, 16.7 ± 2.30 and 29.2 ± 5.14 for 68Ga-PSMA-617, 14.1 ± 4.40 and 147 ± 59.6 for 68Ga-HTK01166, and 7.79 ± 1.65 and 4.30 ± 1.80 for 68Ga-HTK01167. The tumor-to-kidney ratios for 68Ga-labeled PSMA-11, PSMA-617, HTK01166, and HTK01167 were 0.05 ± 0.02, 0.63 ± 0.10, 0.10 ± 0.02, and 1.98 ± 0.63, respectively. Compared with 68Ga-PSMA-617, 68Ga-HTK01166 showed comparable tumor uptake and almost 5-fold higher kidney uptake, whereas 68Ga-HTK01167 exhibited lower tumor and kidney uptake. Compared with 68Ga-PSMA-11, 68Ga-HTK01167 had similar tumor uptake and tumor-to-blood contrast ratio (23.8 ± 6.71 vs 20.4 ± 4.98) but higher tumor-to-background contrast ratios for other background organs especially for kidneys. Our data indicate that substitution of 2-Nal in PSMA-617 with other lipophilic amino acid can modulate PSMA binding affinity and their pharmacokinetics in vivo.
中文翻译：
接头修饰对68 Ga标记的PSMA靶向成像探针的肿瘤与肾脏对比的影响
68 Ga-PSMA-11是目前在临床上用于检测前列腺癌和转移的最流行的前列腺特异性膜抗原（PSMA）放射性配体。但是，肾脏对68 Ga-PSMA-11的高摄取会产生光晕伪像，从而导致对邻近肾脏的病变的检测灵敏度降低。在这项研究中，我们基于68 Ga-PSMA-617开发了两种以68 Ga标记的PSMA靶向示踪剂，即68 Ga-HTK01166和68 Ga-HTK01167，其目标是将肿瘤与肾脏的比率提高到68Ga-PSMA-11。用2-茚满基甘氨酸（Igl）或3,3-二苯丙氨酸（Dip）代替PSMA-617中的2-萘丙氨酸（2-Nal）以分别合成HTK01166和HTK01167。Ga-PSMA-11，Ga-PSMA-617，Ga-HTK01166和Ga-HTK01167与PSMA的结合亲和力（K i）分别为3.13±0.40、1.23±0.08、5.74±2.48和25.7±9.84 nM。通过体外竞争结合试验确定。在微波加热的HEPES缓冲液中进行68 Ga标记，然后68Ga标记的PSMA-11，PSMA-617，HTK01166和HTK01167的平均经衰变校正后的放射化学产率为46-69％，放射化学纯度大于99％，平均比活度为62.9-152 GBq /μmol。在携带表达PSMA的LNCap前列腺癌异种移植物的小鼠中进行了PET成像和生物分布研究。所有示踪剂均能在PET图像中清晰显示肿瘤，并具有出色的肿瘤与背景对比。注射后1 h肿瘤和肾脏的摄取值（％ID / g）对于68 Ga-PSMA-11分别为8.91±0.86和204±70.6，对于68 Ga-PSMA-617则为16.7±2.30和29.2±5.14，14.1 ± 4.40和147±59.6对68 Ga的HTK01166，和7.79±1.65和4.30±1.80 68 Ga的HTK01167。肿瘤与肾脏的比率为68Ga标记的PSMA-11，PSMA-617，HTK01166和HTK01167分别为0.05±0.02、0.63±0.10、0.10±0.02和1.98±0.63。与68 Ga-PSMA-617相比，68 Ga-HTK01166表现出相当的肿瘤摄取，肾脏摄取几乎提高了5倍，而68 Ga-HTK01167表现出较低的肿瘤和肾脏摄取。与68 Ga-PSMA-11相比，68 Ga-HTK01167具有相似的肿瘤吸收和肿瘤与血液的对比度（23.8±6.71 vs 20.4±4.98），但其他背景器官（尤其是肾脏）的肿瘤与背景的对比度更高。我们的数据表明，PSMA-617中的2-Nal被其他亲脂氨基酸取代可以调节PSMA结合亲和力及其体内药代动力学。
更新日期：2018-06-19
中文翻译：
接头修饰对68 Ga标记的PSMA靶向成像探针的肿瘤与肾脏对比的影响
68 Ga-PSMA-11是目前在临床上用于检测前列腺癌和转移的最流行的前列腺特异性膜抗原（PSMA）放射性配体。但是，肾脏对68 Ga-PSMA-11的高摄取会产生光晕伪像，从而导致对邻近肾脏的病变的检测灵敏度降低。在这项研究中，我们基于68 Ga-PSMA-617开发了两种以68 Ga标记的PSMA靶向示踪剂，即68 Ga-HTK01166和68 Ga-HTK01167，其目标是将肿瘤与肾脏的比率提高到68Ga-PSMA-11。用2-茚满基甘氨酸（Igl）或3,3-二苯丙氨酸（Dip）代替PSMA-617中的2-萘丙氨酸（2-Nal）以分别合成HTK01166和HTK01167。Ga-PSMA-11，Ga-PSMA-617，Ga-HTK01166和Ga-HTK01167与PSMA的结合亲和力（K i）分别为3.13±0.40、1.23±0.08、5.74±2.48和25.7±9.84 nM。通过体外竞争结合试验确定。在微波加热的HEPES缓冲液中进行68 Ga标记，然后68Ga标记的PSMA-11，PSMA-617，HTK01166和HTK01167的平均经衰变校正后的放射化学产率为46-69％，放射化学纯度大于99％，平均比活度为62.9-152 GBq /μmol。在携带表达PSMA的LNCap前列腺癌异种移植物的小鼠中进行了PET成像和生物分布研究。所有示踪剂均能在PET图像中清晰显示肿瘤，并具有出色的肿瘤与背景对比。注射后1 h肿瘤和肾脏的摄取值（％ID / g）对于68 Ga-PSMA-11分别为8.91±0.86和204±70.6，对于68 Ga-PSMA-617则为16.7±2.30和29.2±5.14，14.1 ± 4.40和147±59.6对68 Ga的HTK01166，和7.79±1.65和4.30±1.80 68 Ga的HTK01167。肿瘤与肾脏的比率为68Ga标记的PSMA-11，PSMA-617，HTK01166和HTK01167分别为0.05±0.02、0.63±0.10、0.10±0.02和1.98±0.63。与68 Ga-PSMA-617相比，68 Ga-HTK01166表现出相当的肿瘤摄取，肾脏摄取几乎提高了5倍，而68 Ga-HTK01167表现出较低的肿瘤和肾脏摄取。与68 Ga-PSMA-11相比，68 Ga-HTK01167具有相似的肿瘤吸收和肿瘤与血液的对比度（23.8±6.71 vs 20.4±4.98），但其他背景器官（尤其是肾脏）的肿瘤与背景的对比度更高。我们的数据表明，PSMA-617中的2-Nal被其他亲脂氨基酸取代可以调节PSMA结合亲和力及其体内药代动力学。
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