Synthesis and evaluation of novel technetium-99m-hydroxamamide complex based on imidazothiadiazole sulfonamide targeting carbonic anhydrase-IX for tumor imaging
Synthesis and evaluation of novel technetium-99m-hydroxamamide complex based on imidazothiadiazole sulfonamide targeting carbonic anhydrase-IX for tumor imaging
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DOI：
10.1016/j.bmcl.2020.127596
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发表时间：
2020-11-15
影响因子：
2.7
通讯作者：
Ono, Masahiro
中科院分区：
文献类型：
--
作者：
Iikuni, Shimpei;Kitano, Anna;Ono, Masahiro
碳酸酐酶-IX（CA-IX）是用于检测与不良预后相关的肿瘤的有吸引力的靶标。我们之前报道了一种基于脲基磺酰胺作为CA-IX配体的[Tc-99 m]异羟肟胺复合物（[Tc-99 m] URB 2A），其在体外对CA-IX高表达细胞和体内肿瘤显示出良好的亲和力;然而，血池中的放射性保留表明成像的背景信号较高。为了改善[Tc-99 m] URB 2A的药代动力学，在本研究中，我们设计并合成了基于咪唑并噻二唑磺酰胺的[Tc-99 m] ISB 2，其在使用相应的111 In标记化合物的研究中表现出比脲基磺酰胺更大的CA-IX亲和力和更快的从血池中清除，并评估其用于CA-IX成像的实用性。在体外细胞结合试验中，[Tc-99 m] ISB 2与CA-IX高表达（HT-29）细胞显著结合;此外，其结合大于[Tc-99 m] URB 2A。在体内生物分布试验中，[Tc-99 m] ISB 2显示出比[Tc-99 m] URB 2A更快的血池清除率;然而，观察到HT-29肿瘤蓄积较低。[Tc-99 m] ISB 2的进一步结构修饰以提高其稳定性可能导致开发用于CA-IX成像的有用的[Tc-99 m]异羟肟胺络合物。
Carbonic anhydrase-IX (CA-IX) is an attractive target for detecting tumors associated with a poor prognosis. We previously reported a [Tc-99m]hydroxamamide complex based on ureidosulfonamide as a CA-IX ligand ([Tc-99m] URB2A), which showed a favorable affinity for CA-IX high-expressing cells in vitro and tumors in vivo; however, radioactivity retention in the blood pool suggested a high background signal on imaging. To improve the pharmacokinetics of [Tc-99m]URB2A, in this study, we designed and synthesized [Tc-99m]ISB2 based on imidazothiadiazole sulfonamide, which exhibited greater CA-IX affinity and faster clearance from the blood pool than ureidosulfonamide in studies using corresponding 111In-labeled compounds, and evaluated its utility for CA-IX imaging. In an in vitro cell binding assay, [Tc-99m]ISB2 markedly bound to CA-IX high-expressing (HT-29) cells; moreover, its binding was greater than that of [Tc-99m]URB2A. In an in vivo biodistribution assay, [Tc-99m]ISB2 showed faster clearance from the blood pool than [Tc-99m]URB2A; however, lower HT-29 tumor accumulation was observed. Further structural modification of [Tc-99m]ISB2 to improve its stability may lead to the development of a useful [Tc-99m]hydroxamamide complex for CA-IX imaging.