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

• Applicants: Professorin Dr. Evamarie Hey-Hawkins; Professor Dr. Jens Pietzsch
• Subject Area: Pharmacy ; Inorganic Molecular Chemistry - Synthesis and Characterisation ; Nuclear Medicine, Radiotherapy, Radiobiology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450570307

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.

• DFG Programme: Research Grants