Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Uppsala University, 752 37 Uppsala, Sweden.
Int J Mol Sci. 2024 Mar 23;25(7):3615. doi: 10.3390/ijms25073615.
Previously, we designed the EuK-based PSMA ligand BQ0413 with an maE chelator for labeling with technetium-99m. It showed efficient tumor targeting, but our preclinical data and preliminary clinical results indicated that the renal excretion levels need to be decreased. We hypothesized that this could be achieved by a decrease in the ligand's total negative charge, achieved by substituting negatively charged glutamate residues in the chelator with glycine. The purpose of this study was to evaluate the tumor targeting and biodistribution of two new PSMA inhibitors, BQ0411 and BQ0412, compared to BQ0413. Conjugates were radiolabeled with Tc-99m and characterized in vitro, using PC3-pip cells, and in vivo, using NMRI and PC3-pip tumor-bearing mice. [Tc]Tc-BQ0411 and [Tc]Tc-BQ0412 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity. The biodistribution pattern for the new conjugates was characterized by rapid excretion. The tumor uptake for [Tc]Tc-BQ0411 was 1.6-fold higher compared to [Tc]Tc-BQ0412 and [Tc]Tc-BQ0413. [Tc]Tc-BQ0413 has demonstrated predominantly renal excretion, while the new conjugates underwent both renal and hepatobiliary excretion. In this study, we have demonstrated that in such small targeting ligands as PSMA-binding EuK-based pseudopeptides, the structural blocks that do not participate in binding could have a crucial role in tumor targeting and biodistribution. The presence of a glycine-based coupling linker in BQ0411 and BQ0413 seems to optimize biodistribution. In conclusion, the substitution of amino acids in the chelating sequence is a promising method to alter the biodistribution of [Tc]Tc-labeled small-molecule PSMA inhibitors. Further improvement of the biodistribution properties of BQ0413 is needed.
先前，我们设计了基于 EuK 的 PSMA 配体 BQ0413，并在其中加入了 maE 螯合剂，以便用锝-99m 进行标记。它显示出了高效的肿瘤靶向能力，但我们的临床前数据和初步临床结果表明，其肾排泄水平需要降低。我们假设，通过降低配体的总负电荷，可以实现这一点，方法是用甘氨酸取代螯合剂中的带负电荷的谷氨酸残基。本研究旨在评估两种新型 PSMA 抑制剂 BQ0411 和 BQ0412 的肿瘤靶向和生物分布情况，并与 BQ0413 进行比较。使用 PC3-pip 细胞在体外和 NMRI 和 PC3-pip 荷瘤小鼠在体内，对放射性标记的[Tc]Tc-BQ0411 和[Tc]Tc-BQ0412 进行了研究。[Tc]Tc-BQ0411 和[Tc]Tc-BQ0412 与 PC3-pip 细胞的 PSMA 特异性结合具有皮摩尔亲和力。新结合物的生物分布模式以快速排泄为特征。与[Tc]Tc-BQ0412 和[Tc]Tc-BQ0413 相比，[Tc]Tc-BQ0411 对肿瘤的摄取率提高了 1.6 倍。[Tc]Tc-BQ0413 主要通过肾脏排泄，而新结合物则通过肾脏和肝胆排泄。在这项研究中，我们已经证明，在 PSMA 结合的 EuK 基假肽等小型靶向配体中，不参与结合的结构块在肿瘤靶向和生物分布中可能具有关键作用。BQ0411 和 BQ0413 中存在基于甘氨酸的偶联连接子似乎优化了生物分布。总之，在螯合序列中取代氨基酸是改变[Tc]Tc 标记的小分子 PSMA 抑制剂生物分布的一种很有前途的方法。需要进一步改善 BQ0413 的生物分布特性。
