Evaluation, optimization and labeling of substituted 1,3,4-oxadiazole derivatives as tracers for imaging of human telomerase reverse transcriptase (hTERT) activity in tumors
Nuclear Medicine, Radiotherapy, Radiobiology
Organic Molecular Chemistry - Synthesis and Characterisation
Final Report Abstract
It was the goal of the project to develop first (radio)tracers to image activity of the enzyme telomerase in cancer cell lines and to test tracers in vivo. The telomerase is an enzyme; its primary function is to maintain telomere length at the ends of alleles of linear chromosomes. Most cancers have ways to activate telomerase, which is inactive in somatic cells, to receive cell immortality and unregulated cell division. Most of the planned reference compounds and corresponding precursors for 18F-labeling as well as some additional tracer/precursor pairs were successfully synthesised. Radiosynthesis of the initially envisaged compounds failed, likely due to a benzylic fluorination being the dominant reaction pathway. Some 18F-labeled compounds were successfully prepared, even though they were not initially proposed. The project was heavily impacted by restrictions due to the CoViD-19 pandemic, especially the unavailability of PCR-based hTERT assays (which were a crucial part of the project in terms of assessing inhibitory potential of compounds) lead to some twisted sequential arrangements. For example, optimization of radiosynthesis was started without any knowledge of the inhibitory activity of compounds. When assays were available, it was found that none of the compounds (even the ones previously published as active by other groups) inhibited the proposed target. The only active compounds were the positive controls and a sulfonyl fluoride derivative, which is likely a broad-spectrum protease inhibitor. As none of the compounds showed dose-dependent inhibition, the planned animal experiments were not conducted. We are currently preparing a manuscript, which is discussing the results regarding new 1,3,4-oxadiazoles and their inhibitory potential and the non-reproducible results of other groups regarding oxadiazole-based compounds in terms of affinity towards the described target. The applicant still considers tracer-development towards hTERT imaging an interesting way to overcome disadvantages of metabolic tracers, which are in clinical application. However, highly selective and active inhibitors as the basis are very important. If further developments within the telomerase inhibitor research justify a restart of the tracer production, a new application will be considered.
