Development of carborane-based COX-2 inhibitors for theranostic approaches

本项目的目的是开发基于碳硼烷和金属碳硼烷的选择性环氧合酶-2(COX-2)抑制剂，并用碘(123I)或相应的放射性金属标记最有希望的衍生物，用于成像程序。碳硼烷是药物开发中公认的药物载体，具有显著的代谢稳定性、低毒性、高疏水性和三维芳香性。此外，它们还提供了使用与核医学相关的各种放射性核素进行放射性标记的极佳途径。重点介绍了以11-顶Nido-Carborate簇合物(C2B9)作为金属络合物的配体(如Nido Carborate(-2)，即所谓的二碳酸酯配体)或作为有机分子的取代基(如Nido Carborate(-1))的一些有机金属配合物的合成、表征和生物学评价。有两个工作包致力于开发合适的合成方法，将碘引入基于碳硼烷的环氧合酶-2抑制剂中，以及金属碳硼烷与环氧合酶-2抑制剂的组合。这些方法促进了碘或金属及其放射性对应物的引入。另一个工作包涉及合成的碘标记碳硼烷和金属碳硼烷的体外表征，以确定适合进行放射性标记研究的化合物。选定的候选人将在第四个工作包中用123I和放射性金属如99mTc、64Cu或89Zr进行放射性标记。在第五个工作包中，将在体外评估放射性标记的含碳硼烷的环氧合酶抑制剂在不同癌细胞系(环氧合酶-2过表达或不表达)中的特异性摄取，并在体内评价它们的生物分布、代谢稳定性和可视化环氧合酶-2过表达的肿瘤移植瘤的能力。该项目生产放射性标记的COX-2抑制剂，允许非侵入性和可重复地监测COX-2在疾病表现和进展期间以及靶向治疗期间的功能表达。这对放射治疗特别有希望，因为COX-2过度表达的肿瘤经常对放射治疗产生抵抗，因此早期了解患者的COX-2水平将允许个体化调整治疗计划。该项目的基本方向也为新型放射性标记碳硼烷和金属碳硼烷与其他目标载体的未来应用创造了一个平台。

The aim of this project is to develop selective cyclooxygenase-2 (COX-2) inhibitors based on carboranes and metallacarboranes and to label the most promising derivatives with iodine (123I) or corresponding radiometals for imaging procedures. Carboranes are recognized as pharmacophores in drug development with remarkable metabolic stability, low toxicity combined with high hydrophobicity and three-dimensional aromaticity. In addition, they offer excellent access for radiolabeling with various radionuclides relevant in nuclear medicine. The focus is on the synthesis, characterization and biological evaluation of a number of organometallic complexes in which 11-vertex nido carborate clusters (C2B9) are used as ligands in metal complexes (as nido carborate(-2), so-called dicarbollide ligand) or as substituents in organic molecules (as nido carborate(-1)). Two work packages are dedicated to the development of suitable synthetic approaches for the introduction of iodine into carborane-based COX-2 inhibitors and the combination of metallacarboranes with COX-2 inhibitors. These approaches facilitate the introduction of iodine or metals and their radioactive counterparts. Another work package deals with the in vitro characterization of the synthesized iodine-labeled carboranes and metallacarboranes in order to identify suitable compounds for radiolabeling studies. A selection of candidates will be radiolabeled in a fourth work package with 123I and radiometals like 99mTc, 64Cu or 89Zr. In a fifth work package, radiolabeled carborane-containing COX inhibitors will be evaluated in vitro for specific uptake in different cancer cell lines (COX-2 overexpressing or not) and in vivo for their biodistribution, metabolic stability and ability to visualize COX-2 overexpressing tumor xenografts. The project generates radiolabeled COX-2 inhibitors, which allow the non-invasive and repeatable monitoring of the functional expression of COX-2 during the manifestation and progression of diseases and during targeted therapy. This is particularly promising for radiotherapy, since COX-2-overexpressing tumors often develop resistance to radiotherapy, so that early information on the COX-2 levels of patients would allow individual adaptation of treatment plans. The basic orientation of this project also creates a platform for future applications of novel radiolabeled carboranes and metallacarboranes with other target vectors.