Department of Molecular Oncology , BC Cancer , Vancouver , BC V5Z 1L3 , Canada.
Department of Functional Imaging , BC Cancer , Vancouver , BC V5Z 4E6 , Canada.
Mol Pharm. 2018 Aug 6;15(8):3502-3511. doi: 10.1021/acs.molpharmaceut.8b00499. Epub 2018 Jul 3.
Ga-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 Ga-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 Ga-labeled PSMA-targeted tracers, Ga-HTK01166 and Ga-HTK01167, based on Ga-PSMA-617 with the goal of improving tumor-to-kidney ratio compared to Ga-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 ( K) 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. Ga labeling was performed in HEPES buffer with microwave heating, and Ga-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 Ga-PSMA-11, 16.7 ± 2.30 and 29.2 ± 5.14 for Ga-PSMA-617, 14.1 ± 4.40 and 147 ± 59.6 for Ga-HTK01166, and 7.79 ± 1.65 and 4.30 ± 1.80 for Ga-HTK01167. The tumor-to-kidney ratios for Ga-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 Ga-PSMA-617, Ga-HTK01166 showed comparable tumor uptake and almost 5-fold higher kidney uptake, whereas Ga-HTK01167 exhibited lower tumor and kidney uptake. Compared with Ga-PSMA-11, Ga-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.
镓-PSMA-11 是目前临床上最常用的前列腺特异性膜抗原（PSMA）放射性配体，用于检测前列腺癌及其转移灶。然而，Ga-PSMA-11 在肾脏中的高摄取会产生晕环伪影，导致对肾脏附近病灶的检测灵敏度降低。在这项研究中，我们基于 Ga-PSMA-617 开发了两种镓标记的 PSMA 靶向示踪剂，Ga-HTK01166 和 Ga-HTK01167，旨在提高与 Ga-PSMA-11 相比的肿瘤与肾脏的比值。用 2-吲哚基甘氨酸（Igl）或 3,3-二苯基丙氨酸（Dip）取代 PSMA-617 中的 2-萘基丙氨酸（2-Nal），分别合成 HTK01166 和 HTK01167。通过体外竞争结合实验测定，Ga-PSMA-11、Ga-PSMA-617、Ga-HTK01166 和 Ga-HTK01167 与 PSMA 的结合亲和力（K）分别为 3.13±0.40、1.23±0.08、5.74±2.48 和 25.7±9.84 nM。在 HEPES 缓冲液中进行 Ga 标记，采用微波加热，得到 Ga-PSMA-11、PSMA-617、HTK01166 和 HTK01167，其放射性化学产率为 46-69%，放射性化学纯度大于 99%，比活度为 62.9-152GBq/μmol。在表达 PSMA 的 LNCap 前列腺癌异种移植瘤小鼠中进行了 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，具有良好的肿瘤与背景对比度。注射后 1 小时，肿瘤和肾脏的摄取值（%ID/g）分别为 Ga-PSMA-11 的 8.91±0.86 和 204±70.6、Ga-PSMA-617 的 16.7±2.30 和 29.2±5.14、Ga-HTK01166 的 14.1±4.40 和 147±59.6，以及 Ga-HTK01167 的 7.79±1.65 和 4.30±1.80。与 Ga-PSMA-617 相比，Ga 标记的 PSMA-11、PSMA-617、HTK01166 和 HTK01167 的肿瘤与肾脏比值分别为 0.05±0.02、0.63±0.10、0.10±0.02 和 1.98±0.63。与 Ga-PSMA-617 相比，Ga-HTK01166 表现出相当的肿瘤摄取，肾脏摄取几乎高 5 倍，而 Ga-HTK01167 则表现出较低的肿瘤和肾脏摄取。与 Ga-PSMA-11 相比，Ga-HTK01167 具有相似的肿瘤摄取和肿瘤与血液的对比率（23.8±6.71 与 20.4±4.98），但对其他背景器官，特别是肾脏的肿瘤与背景的对比率更高。我们的数据表明，用其他亲脂性氨基酸替代 PSMA-617 中的 2-Nal 可以调节 PSMA 的结合亲和力及其体内药代动力学。
