Mizuno Yuki, Uehara Tomoya, Jen Chun-Wei, Akizawa Hiromichi, Arano Yasushi
Laboratory of Molecular Imaging and Radiotherapy, Graduate School of Pharmaceutical Sciences, Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
Laboratory of Physical Chemistry, Showa Pharmaceutical University 3-3165 Higashi-Tamagawagakuen, Machida Tokyo 194-8543 Japan
RSC Adv. 2019 Aug 21;9(45):26126-26135. doi: 10.1039/c9ra04311j. eCollection 2019 Aug 19.
The presence of excess unlabeled ligands in the injectate hinders the target uptake of Tc-labeled targeting vectors. To address the issue, we previously developed a chemical design which provides a Tc-labeled trivalent RGD probe upon CN-βAla-Gly-Gly-c(RGDfK) (L) coordination to [Tc][Tc(CO)] core at pH 6.0. In this study, we extended our coordination mediated synthesis of the trivalent RGD probe to that of a tetravalent one. Our initial attempts reacting L with [Tc][Tc(CO)] core at pH 8.0 failed to provide [Tc][Tc(CO)(L)] due to the formation of multiple side products. A γ-aminobutylic acid (GABA) based isonitrile ligand CN-GABA-Gly-Gly-c(RGDfK) (L), on the other hand, avoided the side reaction and selectively provided [Tc][Tc(CO)(L)] (Tc-[L]) at pH 8.0. Tc-[L] exhibited higher binding affinity to integrin αβ than its unlabeled ligand, and visualized U87MG tumor without tedious post-labeling purification. These results indicate that the metal coordination-mediated syntheses of Tc-labeled multivalent probes have been successfully applied to a tetravalent one, which would allow a wider range of choices for designing novel Tc-labeled multivalent probes of high target uptake.
注射剂中存在过量未标记的配体会阻碍锝标记靶向载体的靶向摄取。为解决该问题，我们之前开发了一种化学设计，在pH 6.0条件下，当CN-βAla-Gly-Gly-c(RGDfK)（L）与[Tc][Tc(CO)]核心配位时可提供一种锝标记的三价RGD探针。在本研究中，我们将三价RGD探针的配位介导合成扩展至四价探针的合成。我们最初尝试在pH 8.0条件下使L与[Tc][Tc(CO)]核心反应，但由于形成多种副产物而未能得到[Tc][Tc(CO)(L)]。另一方面，一种基于γ-氨基丁酸（GABA）的异腈配体CN-GABA-Gly-Gly-c(RGDfK)（L）避免了副反应，并在pH 8.0条件下选择性地得到了[Tc][Tc(CO)(L)]（Tc-[L]）。Tc-[L]对整合素αβ的结合亲和力高于其未标记的配体，并且无需繁琐的标记后纯化即可实现U87MG肿瘤显像。这些结果表明，金属配位介导的锝标记多价探针合成已成功应用于四价探针，这将为设计具有高靶向摄取的新型锝标记多价探针提供更广泛的选择。
