Synthesis and evaluation of indium-111-labeled imidazothiadiazole sulfonamide derivative for single photon emission computed tomography imaging targeting carbonic anhydrase-IX
Synthesis and evaluation of indium-111-labeled imidazothiadiazole sulfonamide derivative for single photon emission computed tomography imaging targeting carbonic anhydrase-IX
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DOI：
10.1016/j.bmcl.2020.127255
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发表时间：
2020-07-15
影响因子：
2.7
通讯作者：
Ono, Masahiro
中科院分区：
文献类型：
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作者：
Iikuni, Shimpei;Okada, Yuya;Ono, Masahiro
碳酸酐酶-IX（CA-IX）是在许多类型的实体瘤的缺氧区域中过表达的锌酶;因此，CA-IX的体内成像可能有助于癌症诊断。在这项研究中，我们新设计并合成了一种基于咪唑并噻二唑磺酰胺（IS）支架与螯合部分DO 3A（[111 In] DO 3A-IS 1）结合的111 In标记的CA-IX显像剂，并评估其对CA-IX高表达肿瘤显像的实用性。在醋酸盐缓冲液中，用111 InCl 3与[111 In] DO 3A-IS 1反应，成功地合成了[111 In] DO 3A-IS 1，放化产率为76%。体外试验显示，[111 In] DO 3A-IS 1在鼠血浆中具有显著的稳定性，与CA-IX高表达（HT-29）细胞（118 ± 21%初始剂量/mg蛋白）的结合大于与CA-IX低表达（MDA-MB-231）细胞（1.4 ± 0.3%初始剂量/mg蛋白）的结合。此外，在动物体内生物分布测定中，[111 In] DO 3A-IS 1在HT-29肿瘤中显示出显著的蓄积（在注射后24小时为8.71 ± 1.41%注射剂量/g）。此外，在单光子发射计算机断层扫描（SPECT）研究中，与MDA-MB-231肿瘤相比，[111 In] DO 3A-IS 1可清晰和选择性地显示HT-29肿瘤。这些结果表明，[111 In] DO 3A-IS 1可以作为一个有用的SPECT显像剂与新的支架靶向CA-IX。
Carbonic anhydrase-IX (CA-IX) is a zinc enzyme overexpressed in the hypoxic regions of many types of solid tumors; therefore,in vivoimaging of CA-IX may contribute to cancer diagnosis. In this study, we newly designed and synthesized an111In-labeled CA-IX imaging agent based on an imidazothiadiazole sulfonamide (IS) scaffold conjugated with a chelating moiety, DO3A ([111In]DO3A-IS1), and evaluated its utility for imaging of CA-IX high-expressing tumors. [111In]DO3A-IS1 was successfully synthesized at a 76% radiochemical yield by reacting its precursor with111InCl3in acetate buffer. Inin vitroassays, [111In]DO3A-IS1 showed marked stability in murine plasma and greater binding to CA-IX high-expressing (HT-29) cells (118 ± 21% initial dose/mg protein) than CA-IX low-expressing (MDA-MB-231) cells (1.4 ± 0.3% initial dose/mg protein). Moreover, in anin vivobiodistribution assay, [111In]DO3A-IS1 showed marked accumulation in the HT-29 tumor (8.71 ± 1.41% injected dose/g at 24 h postinjection). In addition, in a single photon emission computed tomography (SPECT) study, [111In]DO3A-IS1 clearly and selectively visualized the HT-29 tumor as compared with the MDA-MB-231 tumor. These results indicate that [111In]DO3A-IS1 may serve as a useful SPECT imaging agent with the novel scaffold targeting CA-IX.