Huang Steve S, DiFilippo Frank P, Lindner Daniel J, Heston Warren D
Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, USA.
Department of Radiology, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ, 85259, USA.
EJNMMI Radiopharm Chem. 2024 Jan 30;9(1):7. doi: 10.1186/s41181-024-00237-3.
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 [Ga]Ga-PSMA-11. The purpose of this study was to investigate if [Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [Ga]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, [Ga]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, [Ga]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 [Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [Ga]Ga-PSMA-11 activity in these two organs during the first hour.
Biodistribution and micro-PET imaging of [Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [Ga]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.
当前一代放射性标记的靶向前列腺特异性膜抗原（PSMA）的治疗药物受到唾液腺显著摄取的限制，这会因辐射暴露导致剂量限制性口干症。JB - 1498是一种基于尿素的小分子，带有一个高度带负电荷的连接子，靶向前列腺特异性膜抗原（PSMA）。先前对具有相同带负电荷连接子的类似示踪剂的研究表明，与[镓]Ga - PSMA - 11相比，其正常器官/软组织本底摄取较低。本研究的目的是调查与[镓]Ga - PSMA - 11相比，[镓]Ga - JB - 1498在小鼠中唾液腺摄取是否减少。
在小鼠肿瘤模型中，JB - 1498对PSMA结合和肿瘤摄取表现出高亲和力。在一项低摩尔活度的初始生物分布研究中，[镓]Ga - JB - 1498的唾液腺摄取为0.13±0.01%ID/g。在第二项针对非荷瘤小鼠的高摩尔活度生物分布研究中，静脉注射后1小时，[镓]Ga - JB1498的唾液腺摄取为0.39±0.24%ID/g，肾脏摄取为10.12±1.73%ID/g。这种唾液腺摄取显著低于已发表的[镓]Ga - PSMA - 11的摄取。微型PET在视觉上证实了生物分布研究的结果。动态微型PET成像显示，与这两个器官在第一个小时内[镓]Ga - PSMA - 11活性逐渐增加相比，[镓]Ga - JB1498在唾液腺和肾脏中的活性逐渐降低。
与[镓]Ga - PSMA - 11相比，[镓]Ga - JB - 1498的生物分布和微型PET成像显示其唾液腺摄取显著降低，且在小鼠肾脏和唾液腺中的药代动力学行为不同。我们的研究结果表明，构建具有高度带负电荷连接子的PSMA靶向分子是一种在诊疗应用中减少GCP - II/PSMA配体唾液腺摄取的有前景的策略。
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