School of Nuclear Science and Engineering, Tomsk Polytechnic University, Tomsk 634050, Russia.
Polytechnic Institute of Nuclear Technology, National Research and Innovation Agency, Yogyakarta 55281, Indonesia.
Int J Mol Sci. 2023 Jul 30;24(15):12206. doi: 10.3390/ijms241512206.
Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [I]PSMA-m-IB and [I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu) group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [I]PSMA-p-IB was higher than that of [I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [I]PSMA-p-IB showed less accumulation than [Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.
前列腺特异性膜抗原（PSMA）已被确定为开发治疗诊断试剂的靶标。在我们目前的工作中，我们描述了新型 N-[N-[(S)-1,3-二羧基丙基]氨基甲酰基]-(S)-L-赖氨酸（DCL）脲基 PSMA 抑制剂的设计和合成，这些抑制剂在赖氨酸 ε-氮原子上具有氯取代的芳基片段，在肽片段中包含两个 L-构型的苯丙氨酸残基的二肽作为连接子，以及 3-或 4-(三丁基锡基)苯甲酸作为它们结构中的 prosthetic group 用于放射性标记。用于比较和表征研究的标准化合物 [I]PSMA-m-IB 和 [I]PSMA-p-IB 首先使用两种替代合成方法合成。替代合成方法的一个重要优势是，首先将 prosthetic group（化合物的 NHS 激活酯）与多肽序列缀合，然后用放射性碘取代 Sn(Bu) 基团，从而使放射性核素在合成的最后一步引入，从而最大限度地减少放射性碘-123 在标记过程中的操作时间。所得到的 DCL 脲基 PSMA 抑制剂用碘-123 进行放射性标记。放射化学标记优化结果表明，[I]PSMA-p-IB 的放射化学产率高于 [I]PSMA-m-IB，分别为 74.9±1.0%和 49.4±1.2%。纯化后 [I]PSMA-p-IB 的放射化学纯度大于 99.50%。[I]PSMA-p-IB 的初步临床前评估表明，它在体外对 PC-3 PIP（表达 PSMA 的细胞）具有相当的亲和力和特异性结合。这种新的放射性配体 [I]PSMA-p-IB 的体内生物分布显示，与 [Lu]Lu-PSMA-617 相比，在几个正常器官（肝、肾和骨）中的积累较少。这些结果证明需要进一步的临床前开发，包括毒理学评估和荷瘤小鼠实验。
