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（考克斯-2）抑制剂，并用碘（123 I）或相应的放射性金属标记最有前途的衍生物用于成像程序。碳硼烷具有良好的代谢稳定性、低毒性、高疏水性和三维芳香性，被认为是药物开发中的药效团。此外，它们还为核医学相关的各种放射性核素的放射性标记提供了良好的途径。重点是一些有机金属配合物的合成，表征和生物学评价，其中11-顶点nido carborate簇（C2B 9）用作金属配合物中的配体（如nido carborate（-2），所谓的dicarbolide配体）或作为有机分子中的取代基（如nido carborate（-1））。两个工作包致力于开发合适的合成方法，用于将碘引入基于碳硼烷的考克斯-2抑制剂和金属碳硼烷与考克斯-2抑制剂的组合。这些方法便于引入碘或金属及其放射性对应物。另一个工作包涉及合成的碘标记的碳硼烷和金属碳硼烷的体外表征，以确定合适的化合物进行放射性标记研究。在第四个工作包中，将用123 I和放射性金属（如99 mTc、64 Cu或89 Zr）对选定的候选物进行放射性标记。在第五个工作包中，将在体外评价放射性标记的含碳硼烷的考克斯抑制剂在不同癌细胞系（考克斯-2过表达或未过表达）中的特异性摄取，并在体内评价其生物分布、代谢稳定性和可视化考克斯-2过表达肿瘤异种移植物的能力。该项目产生放射性标记的考克斯-2抑制剂，其允许在疾病的表现和进展期间以及在靶向治疗期间对考克斯-2的功能表达进行非侵入性和可重复的监测。这对于放射治疗特别有希望，因为考克斯-2过表达的肿瘤通常对放射治疗产生抗性，因此关于患者考克斯-2水平的早期信息将允许个体适应治疗计划。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靶向载体的未来应用创造了平台。

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.