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Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：当前一代放射性标记的PSMA靶向治疗剂受到显著唾液腺结合的限制，这导致辐射暴露导致的剂量限制性口干症。JB-1498是基于尿素的小分子,其具有靶向前列腺特异性膜抗原(PSMA)的高度带负电荷的接头。与[68Ga]Ga-PSMA-11相比,在具有相同带负电荷的接头的类似示踪剂上的先前工作证明了低的正常器官/软组织背景摄取。这项研究的目的是研究与[68Ga]Ga-PSMA-11相比，[68Ga]Ga-JB-1498是否降低了小鼠的唾液腺摄取。
结果：JB-1498在鼠肿瘤模型中表现出对PSMA结合和肿瘤摄取的高亲和力。在低摩尔活性的初始生物分布研究中，[68Ga]Ga-JB-1498显示0.13±0.01%ID/g的唾液腺摄取。在具有高磨牙活性的非荷瘤小鼠的第二次生物分布研究中，[68Ga]Ga-JB1498在IV注射后1小时显示0.39±0.24%ID/g的唾液腺摄取和10.12±1.73%ID/g的肾活性。这种唾液腺摄取显著低于公开的[68Ga]Ga-PSMA-11的摄取。Micro-PET在视觉上证实了生物分布研究的发现。动态微PET成像显示唾液腺和肾脏中[68Ga]Ga-JB1498活性逐渐降低，相比于在第一小时期间这两个器官中逐渐增加的[68Ga]Ga-PSMA-11活性。
结论：与[68Ga]Ga-PSMA-11相比，[68Ga]Ga-JB-1498的生物分布和微PET成像显示出显著降低的唾液腺摄取和小鼠肾脏和唾液腺的不同药代动力学行为。我们的发现表明，构建具有带高度负电荷的接头的PSMA靶向分子是一种有希望的策略，可以减少唾液腺在治疗应用中对GCP-II/PSMA配体的摄取。
结果：JB-1498在鼠肿瘤模型中表现出对PSMA结合和肿瘤摄取的高亲和力。在低摩尔活性的初始生物分布研究中，[68Ga]Ga-JB-1498显示0.13±0.01%ID/g的唾液腺摄取。在具有高磨牙活性的非荷瘤小鼠的第二次生物分布研究中，[68Ga]Ga-JB1498在IV注射后1小时显示0.39±0.24%ID/g的唾液腺摄取和10.12±1.73%ID/g的肾活性。这种唾液腺摄取显著低于公开的[68Ga]Ga-PSMA-11的摄取。Micro-PET在视觉上证实了生物分布研究的发现。动态微PET成像显示唾液腺和肾脏中[68Ga]Ga-JB1498活性逐渐降低，相比于在第一小时期间这两个器官中逐渐增加的[68Ga]Ga-PSMA-11活性。
结论：与[68Ga]Ga-PSMA-11相比，[68Ga]Ga-JB-1498的生物分布和微PET成像显示出显著降低的唾液腺摄取和小鼠肾脏和唾液腺的不同药代动力学行为。我们的发现表明，构建具有带高度负电荷的接头的PSMA靶向分子是一种有希望的策略，可以减少唾液腺在治疗应用中对GCP-II/PSMA配体的摄取。
