Baranski Ann-Christin, Schäfer Martin, Bauder-Wüst Ulrike, Wacker Anja, Schmidt Jana, Liolios Christos, Mier Walter, Haberkorn Uwe, Eisenhut Michael, Kopka Klaus, Eder Matthias
Department of Nuclear Medicine, University of Heidelberg , Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Division of Radiopharmaceutical Development, German Cancer Consortium (DKTK) Freiburg, Department of Nuclear Medicine, Faculty of Medicine, Medical Center - University of Freiburg , Hugstetter Straße 55, 79106 Freiburg, Germany.
Bioconjug Chem. 2017 Sep 20;28(9):2485-2492. doi: 10.1021/acs.bioconjchem.7b00458. Epub 2017 Aug 24.
Ga-Glu-urea-Lys-(Ahx)-HBED-CC (Ga-PSMA-11) represents a successful radiopharmaceutical for PET/CT imaging of prostate cancer. Further optimization of the tumor-to-background contrast might significantly enhance the sensitivity of PET/CT imaging and the probability of detecting recurrent prostate cancer at low PSA values. This study describes the advantage of histidine (H)/glutamic acid (E) and tryptophan (W)/glutamic acid (E) containing linkers on the pharmacokinetic properties of Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper(I)-catalyzed azide-alkyne cycloaddition. Their Ga complexes were compared to the clinical reference Ga-PSMA-11 with respect to cell binding, effective internalization, and tumor targeting properties in LNCaP-bearing balb/c nu/nu mice. The introduction of (HE) (i = 1-3) or (WE) (i = 1-3) into PSMA-11 resulted in a significantly changed biodistribution profile. The uptake values in kidneys, spleen, liver, and other background organs were reduced for (HE) while the tumor uptake was not affected. For (HE) the tumor uptake was significantly increased. The introduction of tryptophan-containing linkers also modulated the organ distribution profile. The results clearly indicate that histidine is of essential impact in order to improve the tumor-to-organ contrast. Hence, the histidine/glutamic acid linker modifications considerably improved the pharmacokinetic properties of Ga-PSMA-11 leading to a reduced uptake in dose limiting organs and a significantly enhanced tumor-to-background contrast. Glu-urea-Lys-(HE)-HBED-CC represents a promising Ga complex ligand for PET/CT-imaging of prostate cancer.
镓-谷氨酸-尿素-赖氨酸-（己酰化赖氨酸）-HBED-CC（镓-PSMA-11）是一种成功用于前列腺癌PET/CT成像的放射性药物。进一步优化肿瘤与背景的对比度可能会显著提高PET/CT成像的灵敏度以及在低前列腺特异性抗原（PSA）值时检测复发性前列腺癌的概率。本研究描述了含组氨酸（H）/谷氨酸（E）和色氨酸（W）/谷氨酸（E）的连接子对镓-PSMA-11药代动力学性质的影响。通过基于标准Fmoc的固相合成与铜（I）催化的叠氮化物-炔烃环加成相结合的方法获得示踪剂。将它们的镓配合物与临床参考镓-PSMA-11在携带LNCaP的balb/c裸鼠中的细胞结合、有效内化和肿瘤靶向特性方面进行了比较。将（HE）（i = 1 - 3）或（WE）（i = 1 - 3）引入PSMA-11导致生物分布曲线发生显著变化。对于（HE），肾脏、脾脏、肝脏和其他背景器官的摄取值降低，而肿瘤摄取不受影响。对于（HE），肿瘤摄取显著增加。引入含色氨酸的连接子也调节了器官分布曲线。结果清楚地表明，组氨酸对于改善肿瘤与器官的对比度至关重要。因此，组氨酸/谷氨酸连接子修饰显著改善了镓-PSMA-11的药代动力学性质，导致剂量限制器官的摄取减少以及肿瘤与背景的对比度显著增强。谷氨酸-尿素-赖氨酸-（HE）-HBED-CC是一种有前景的用于前列腺癌PET/CT成像的镓配合物配体。
