Wu Yitian, Zhang Xiaojun, Zhang Ying, Xu Baixuan, Tian Jiahe, Zhang Jinming
Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing 100853, China.
Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China.
Pharmaceuticals (Basel). 2022 Aug 14;15(8):1001. doi: 10.3390/ph15081001.
Prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals have become some of the most promising tools for the diagnosis and therapy prostate cancer (PCa). The structure of existing PSMA-targeted PET tracers still needs to be optimized to improve their pharmacokinetic properties and tumor-to-background ratio. In this study, we modified the structure of a well-studied PSMA tracer, and six novel tracers with variable hydrophilicity and pharmacokinetics were developed and evaluated both in vitro and in vivo. All of the novel tracers showed high hydrophilicity (log = -2.99 ± 0.33 to -3.49 ± 0.01), rapid clearance rates (elimination half-times = 15.55 to 35.97 min), and high affinity for PSMA (Ki = 8.11 ± 0.49 to 42.40 ± 2.11 nM) in vitro. Specific cell binding and micro-PET experiments showed that [Ga]Ga-PSMA-Q displayed the highest specific PSMA+ cell uptake (3.75 ± 0.35 IA%/10 at 60 min), tumor uptake (SUVmax = 0.97 ± 0.24 at 60 min p.i.), and tumor-to-muscle ratio (59.33 ± 5.72 at 60 min p.i.), while the tumor-to-muscle ratio was much higher than that of [Ga]Ga-PSMA-617. The results of this study validate the clinical potential of [Ga]Ga-PSMA-Q for PET imaging and further targeted therapy of prostate cancer.
前列腺特异性膜抗原（PSMA）靶向放射性药物已成为前列腺癌（PCa）诊断和治疗中最具前景的工具之一。现有PSMA靶向PET示踪剂的结构仍需优化，以改善其药代动力学性质和肿瘤与背景比值。在本研究中，我们对一种经过充分研究的PSMA示踪剂的结构进行了修饰，开发了六种具有不同亲水性和药代动力学的新型示踪剂，并在体外和体内进行了评估。所有新型示踪剂在体外均表现出高亲水性（log = -2.99 ± 0.33至-3.49 ± 0.01）、快速清除率（消除半衰期 = 15.55至35.97分钟）以及对PSMA的高亲和力（Ki = 8.11 ± 0.49至42.40 ± 2.11 nM）。特异性细胞结合和微型PET实验表明，[Ga]Ga-PSMA-Q在60分钟时显示出最高的特异性PSMA+细胞摄取（3.75 ± 0.35 IA%/10）、肿瘤摄取（注射后60分钟时SUVmax = 0.97 ± 0.24）和肿瘤与肌肉比值（注射后60分钟时为59.33 ± 5.72），而肿瘤与肌肉比值远高于[Ga]Ga-PSMA-617。本研究结果验证了[Ga]Ga-PSMA-Q在PET成像及前列腺癌进一步靶向治疗方面的临床潜力。
