The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [68Ga]Ga-PSMA-11. The purpose of this study was to investigate if [68Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11. JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [68Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [68Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [68Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [68Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [68Ga]Ga-PSMA-11 activity in these two organs during the first hour. Biodistribution and micro-PET imaging of [68Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [68Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.

中文翻译：

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与 [68Ga]Ga-PSMA-11 相比，一种具有高负电荷连接体的新型 PSMA 靶向示踪剂显示小鼠唾液腺摄取减少

当前一代放射性标记的 PSMA 靶向治疗剂受到显着的唾液腺结合的限制，这会导致辐射暴露引起的剂量限制性口干症。JB-1498 是一种基于尿素的小分子，具有针对前列腺特异性膜抗原 (PSMA) 的高负电荷连接体。先前对具有相同带负电荷连接体的类似示踪剂的研究表明，与[68Ga]Ga-PSMA-11相比，正常器官/软组织背景摄取较低。本研究的目的是调查与 [68Ga]Ga-PSMA-11 相比，[68Ga]Ga-JB-1498 是否减少了小鼠唾液腺的摄取。JB-1498 在小鼠肿瘤模型中表现出对 PSMA 结合和肿瘤摄取的高亲和力。在一项低摩尔活性的初始生物分布研究中，[68Ga]Ga-JB-1498 表现出唾液腺摄取量为 0.13 ± 0.01%ID/g。在具有高摩尔活性的非荷瘤小鼠的第二项生物分布研究中，[68Ga]Ga-JB1498 在给药后一小时表现出唾液腺摄取量为 0.39 ± 0.24% ID/g，肾脏活性为 10.12 ± 1.73% ID/g静脉注射。这种唾液腺的摄取明显低于已发表的[68Ga]Ga-PSMA-11的摄取。Micro-PET 直观地证实了生物分布研究的结果。动态微型 PET 成像显示，唾液腺和肾脏中的 [68Ga]Ga-JB1498 活性逐渐降低，而在第一个小时内，这两个器官中的 [68Ga]Ga-PSMA-11 活性逐渐增加。与[68Ga]Ga-PSMA-11相比，[68Ga]Ga-JB-1498的生物分布和微型PET成像表明，小鼠的唾液腺摄取显着降低，并且在肾脏和唾液腺中具有不同的药代动力学行为。我们的研究结果表明，构建具有高负电荷连接体的 PSMA 靶向分子是一种有前途的策略，可减少治疗诊断应用中唾液腺对 GCP-II/PSMA 配体的摄取。