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 68Ga-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 68Ga-DFO-Nsucc-PSMA (68Ga-4) and 68Ga-DFO- pNCS-Bn-PSMA (68Ga-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of 68Ga-4 and 68Ga-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer 68Ga-HBED-CC-PSMA (68Ga-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 ( Kd values) were found to be predictive of pharmacokinetics in vivo. Compared to 68Ga-1, 68Ga-4 and 68Ga-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.

中文翻译：

---

针对前列腺特异性膜抗原的68Ga-去铁敏胺示踪剂的放射化学和临床前PET成像。

结合了基于尿素的Glu-NH-C（O）-NH-Lys组的放射性示踪剂由于其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）的作用而获得了突出的地位。在这里，评价了合成，放射性标记，和体外和体内表征的两个68Ga放射性标记的Glu-NH-C（O）-NH-Lys放射性示踪剂与去铁胺B（DFO）螯合物偶联。基于酰胺键和硫脲偶联化学的两个连接基团分别用于开发68Ga-DFO-Nsucc-PSMA（68Ga-4）和68Ga-DFO-pNCS-Bn-PSMA（68Ga-7）。放射性合成在室温下以高放射化学收率，化学/放射化学纯度和比活度进行。使用正电子发射断层扫描（PET）在患有皮下LNCaP肿瘤的小鼠中评估68Ga-4和68Ga-7的药代动力学分布。将数据与当前的临床基准放射性示踪剂68Ga-HBED-CC-PSMA（68Ga-1）进行比较（HBED = N，N'-双（2-羟基-5-（乙烯-β-羧基）苄基）乙二胺N，N '-二乙酸）。结果表明，靶标结合亲和力，蛋白质缔合，血池和背景器官清除特性以及对PSMA阳性病变的摄取在很大程度上取决于螯合物，接头和间隔基团的性质。发现蛋白质解离常数（Kd值）可预测体内的药代动力学。与68Ga-1相比，68Ga-4和68Ga-7导致肿瘤吸收减少，但血池清除率增加，在肾脏中的停留时间减少。