Department of Chemistry , University of Zurich , Winterthurerstrasse 190 , CH-8057 Zurich , Switzerland.
Inorg Chem. 2019 Sep 16;58(18):12302-12310. doi: 10.1021/acs.inorgchem.9b01802. Epub 2019 Sep 6.
Photochemistry is a rich source of inspiration for developing alternative methods to functionalize proteins with drug molecules, fluorophores, and radioactive probes. Here, we report the synthesis and photochemical reactivity of a modified diethylenediamine pentaacetic acid chelate that was derivatized with a light-responsive aryl azide group (DTPA-PEG-ArN, compound ). The corresponding nonradioactive and radioactive Ga and In complexes of DTPA-PEG-ArN were synthesized and their physical and photochemical properties were studied to evaluate the potential of employing this ligand system in the photochemical synthesis of radiolabeled antibodies. Photodegradation kinetics revealed that irradiation with ultraviolet light (365 nm) induced rapid photoactivation of compound and the metal complexes Ga- and In-. Light-induced reactions were complete in <100 s, with measured first-order rate constants of 0.078 ± 0.045 s, 0.093 ± 0.009 s, and 0.117 ± 0.054 s ( = 2, per species) for compound , Ga-, and In-, respectively. Photochemically induced bioconjugation reactions between DTPA-PEG-ArN and the monoclonal antibody trastuzumab, as well as pre- and postconjugation Ga- and In-radiolabeling experiments, were performed using either a one-pot or two-step strategy. Both approaches yielded radiolabeled trastuzumab ([Ga]GaDTPA-azepin-trastuzumab) with average radiochemical conversions of 3.9 ± 1.0% ( = 4, one-pot), and 10.0 ± 1.0% ( = 3, two-step). One-pot radiolabeling reactions with [In]InCl produced the corresponding [In]InDTPA-azepin-trastuzumab radiotracer in a similar radiochemical conversion of 5.4 ± 0.8% ( = 3). Radiochemical conversions for the desired bimolecular coupling between the chelate and the protein were comparatively low. This observation is likely caused by the high photoinduced reactivity of the compounds and subsequent competition with background reactions. Nevertheless, access to DTPA-PEG-ArN increases the scope of photoradiochemical methods to include metal ions like In that form complexes with higher coordination numbers.
光化学为用药物分子、荧光团和放射性探针来修饰蛋白质提供了丰富的灵感来源。在这里，我们报告了一种改良的二亚乙基三胺五乙酸螯合物的合成和光化学反应性，该螯合物衍生自光响应的芳基叠氮基团（DTPA-PEG-ArN，化合物 ）。合成了相应的非放射性和放射性 Ga 和 In 配合物 DTPA-PEG-ArN，并研究了它们的物理和光化学性质，以评估该配体系统在光化学合成放射性标记抗体中的应用潜力。光降解动力学表明，用紫外线（365nm）照射诱导化合物 及其金属配合物 Ga-和 In-的快速光活化。光诱导反应在 <100s 内完成，对于化合物 、Ga-和 In-，测量的一级速率常数分别为 0.078 ± 0.045 s、0.093 ± 0.009 s 和 0.117 ± 0.054 s（ = 2，每种物质）。在使用一锅法或两步法进行 DTPA-PEG-ArN 与单克隆抗体曲妥珠单抗之间的光诱导生物偶联反应以及预偶联和后偶联 Ga-和 In-放射性标记实验中，都得到了放射性标记的曲妥珠单抗([Ga]GaDTPA-azepin-trastuzumab)，平均放射性化学转化率分别为 3.9 ± 1.0%（ = 4，一锅法）和 10.0 ± 1.0%（ = 3，两步法）。用 [In]InCl 进行的一锅法放射性标记反应得到了相应的 [In]InDTPA-azepin-trastuzumab 放射性示踪剂，放射性化学转化率为 5.4 ± 0.8%（ = 3）。期望的螯合物与蛋白质之间的双分子偶联的放射性化学转化率相对较低。这种观察结果可能是由于化合物的高光诱导反应性以及随后与背景反应的竞争所致。尽管如此，DTPA-PEG-ArN 的获得增加了光放射性化学方法的范围，包括与更高配位数形成配合物的 In 等金属离子。
