Lin Jianguo, Gao Dingyao, Wang Shijie, Lv Gaochao, Wang Xiuting, Lu Chunmei, Peng Ying, Qiu Ling
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China.
Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
J Am Chem Soc. 2022 May 4;144(17):7667-7675. doi: 10.1021/jacs.1c12935. Epub 2022 Apr 22.
Target-enabled bioorthogonal reaction and self-assembly of a small-molecule probe into supramolecules have shown promise for molecular imaging. In this paper, we report a new stimuli-responsive bioorthogonal reaction scaffold () for controlling self-assembly by engineering the condensation reaction between 2-cyanobenzothiazole and cysteine. For probes with the scaffold, intramolecular cyclization took place soon after activation, which could efficiently outcompete free cysteine even at a low concentration and result in efficient aggregation in the target. Through integration with different enzyme-responsive substrates and an ammoniomethyl-trifluoroborate moiety (AmBF), two radioactive positron emission tomography (PET) tracers, [F] and [F], were designed, which showed high stability under physiological conditions and could produce clear PET signal in tumors to detect enzyme activity (e.g., caspase-3, γ-glutamyltranspeptidase) timely and accurately. Our results demonstrated that the scaffold could serve as a general molecular scaffold in the development of smart PET tracers for noninvasive imaging of enzyme activity, which could contribute to tumor detection and treatment efficacy evaluation.
基于靶点的生物正交反应以及小分子探针自组装形成超分子已在分子成像方面展现出前景。在本文中，我们报道了一种新型的刺激响应性生物正交反应支架（），通过设计2-氰基苯并噻唑与半胱氨酸之间的缩合反应来控制自组装。对于带有该支架的探针，激活后很快就会发生分子内环化，即使在低浓度下也能有效胜过游离半胱氨酸，并导致在靶点处有效聚集。通过与不同的酶响应底物和氨甲基三氟硼酸盐部分（AmBF）整合，设计了两种放射性正电子发射断层扫描（PET）示踪剂，[F]和[F]，它们在生理条件下显示出高稳定性，并且能够在肿瘤中产生清晰的PET信号，以及时、准确地检测酶活性（例如，半胱天冬酶-3、γ-谷氨酰转肽酶）。我们的结果表明，该支架可作为一种通用的分子支架，用于开发用于酶活性无创成像的智能PET示踪剂，这有助于肿瘤检测和治疗效果评估。
