与[68Ga]Ga-PSMA-11相比，一种带有高负电荷连接体的新型 PSMA 靶向示踪剂在小鼠唾液腺中的吸收率有所下降。

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR EJNMMI Radiopharmacy and Chemistry Pub Date : 2024-01-30 DOI:10.1186/s41181-024-00237-3

Steve S. Huang, Frank P. DiFilippo, Daniel J. Lindner, Warren D. Heston

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引用次数: 0

摘要

背景：目前的放射性标记 PSMA 靶向治疗药物因唾液腺结合力突出而受到限制，从而导致辐射照射引起的剂量限制性口臭。JB-1498 是一种以尿素为基础的小分子，带有针对前列腺特异性膜抗原（PSMA）的高负电荷连接体。之前对具有相同负电荷连接体的类似示踪剂进行的研究表明，与[68Ga]Ga-PSMA-11相比，正常器官/软组织的本底摄取较低。本研究的目的是探讨与[68Ga]Ga-PSMA-11相比，[68Ga]Ga-JB-1498是否降低了小鼠唾液腺的摄取量：结果：JB-1498 在小鼠肿瘤模型中显示出与 PSMA 的高亲和力结合和肿瘤摄取。在低摩尔活性的初步生物分布研究中，[68Ga]Ga-JB-1498 的唾液腺摄取率为 0.13 ± 0.01%ID/g。在对无肿瘤小鼠进行的第二次生物分布研究中，[68Ga]Ga-JB-1498 的摩尔活性较高，静脉注射后一小时，[68Ga]Ga-JB-1498 的唾液腺摄取量为 0.39 ± 0.24% ID/g，肾脏活性为 10.12 ± 1.73% ID/g。唾液腺摄取量明显低于已公布的[68Ga]Ga-PSMA-11摄取量。显微-PET直观地证实了生物分布研究的结果。动态显微-PET成像显示，唾液腺和肾脏中的[68Ga]Ga-JB1498活性逐渐降低，而这两个器官中的[68Ga]Ga-PSMA-11活性在第一小时内逐渐升高：[68Ga]Ga-JB-1498的生物分布和显微PET成像显示，与[68Ga]Ga-PSMA-11相比，小鼠唾液腺摄取量显著减少，肾脏和唾液腺的药代动力学行为也不同。我们的研究结果表明，在治疗学应用中，构建带有高负电荷连接体的 PSMA 靶向分子是减少唾液腺对 GCP-II/PSMA 配体摄取的一种有前途的策略。

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A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11

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.

Conclusion

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.

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