Gourni Eleni, Del Pozzo Luigi, Bartholomä Mark, Kiefer Yvonne, T Meyer Philipp, Maecke Helmut R, Holland Jason P
1 German Cancer Consortium (DKTK), Heidelberg, Germany.
2 Faculty of Medicine, Department of Nuclear Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.
Mol Imaging. 2017 Jan-Dec;16:1536012117737010. doi: 10.1177/1536012117737010.
Radiotracers incorporating the urea-based Glu-NH-C(O)-NH-Lys group have gained prominence due to their role in targeting prostate-specific membrane antigen (PSMA)-a clinical biomarker of prostate cancer. Here, the synthesis, radiolabeling, and in vitro and in vivo characterization of two Ga-radiolabeled Glu-NH-C(O)-NH-Lys radiotracers conjugated to the desferrioxamine B (DFO) chelate were evaluated. Two linker groups based on amide bond and thiourea coupling chemistries were employed to develop Ga-DFO-Nsucc-PSMA (Ga-4) and Ga-DFO- pNCS-Bn-PSMA (Ga-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of Ga-4 and Ga-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer Ga-HBED-CC-PSMA (Ga-1) (HBED = N,N'-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N'-diacetic acid). Results indicated that the target binding affinity, protein association, blood pool and background organ clearance properties, and uptake in PSMA-positive lesions are strongly dependent on the nature of the chelate, the linker, and the spacer groups. Protein dissociation constants ( K values) were found to be predictive of pharmacokinetics in vivo. Compared to Ga-1, Ga-4 and Ga-7 resulted in decreased tumor uptake but enhanced blood pool clearance and reduced residence time in the kidney. The study highlights the importance of maximizing protein binding affinity during radiotracer optimization.
由于含脲基Glu-NH-C(O)-NH-Lys基团的放射性示踪剂在靶向前列腺特异性膜抗原（PSMA）（一种前列腺癌的临床生物标志物）方面发挥的作用，它们已受到广泛关注。在此，对两种与去铁胺B（DFO）螯合物偶联的镓标记的Glu-NH-C(O)-NH-Lys放射性示踪剂的合成、放射性标记以及体外和体内特性进行了评估。分别采用基于酰胺键和硫脲偶联化学的两种连接基团来开发Ga-DFO-Nsucc-PSMA（Ga-4）和Ga-DFO-pNCS-Bn-PSMA（Ga-7）。放射性合成在室温下定量进行，具有高放射化学产率、化学/放射化学纯度和比活度。使用正电子发射断层扫描（PET）在荷皮下LNCaP肿瘤的小鼠中评估了Ga-4和Ga-7的药代动力学概况。将数据与当前临床基准放射性示踪剂Ga-HBED-CC-PSMA（Ga-1）（HBED = N,N'-双（2-羟基-5-（乙烯-β-羧基）苄基）乙二胺N,N'-二乙酸）进行比较。结果表明，靶向结合亲和力、蛋白质结合、血池和背景器官清除特性以及在PSMA阳性病变中的摄取强烈依赖于螯合物、连接基团和间隔基团的性质。发现蛋白质解离常数（K值）可预测体内药代动力学。与Ga-1相比，Ga-4和Ga-7导致肿瘤摄取减少，但血池清除增强且在肾脏中的停留时间缩短。该研究强调了在放射性示踪剂优化过程中最大化蛋白质结合亲和力的重要性。
