Evaluation, optimization and labeling of substituted 1,3,4-oxadiazole derivatives as tracers for imaging of human telomerase reverse transcriptase (hTERT) activity in tumors

点击翻译按钮获取中文摘要

Human telomeres can be referred to as "end-caps" of chromosomes. They are composed of specific repeating nucleotide sequences and associated proteins.[1] The telomerase is consisting mainly of the (human) telomerase reverse transcriptase ((h)TERT) catalytic subunit and a telomeric RNA (TR or TERC) component. The primary function is the maintenance and therefore synthesis of telomere repeating units at the ends of alleles of linear chromosomes.[2,3] Once the telomeres reach a critical length, the corresponding cells enter replicative senescence or apoptosis is induced. Continuously dividing cells such as germ cells, stem cells and, most importantly, a vast majority of cancer cells (85-95%) depend on a high telomerase activity to ensure their survival. In contrast, telomerase activity is barely detectable in most adult somatic cells.[4–6] Given the above features suggests telomerase as a target for imaging of tumors. Despite the ideal properties of hTERT for development of imaging agents and numerous research efforts as well as examples of directed (radio)therapy[7,8] and indirect imaging[9–12], no small molecule inhibitor labeled for the use in diagnostic imaging modalities is known to date. Radiolabeling of these ligands for targeted, non-invasive imaging by positron emission tomography (PET) might be an especially attractive approach for tumors not accumulating or insufficiently accumulating clinically established metabolic tracers such as [18F]fluorodeoxyglucose (FDG) or [18F]fluorethyltyrosin (FET), in particular prostate-[13], breast-[14] and renal[15] cancers.[16] The potential hTERT tracers may add valuable information in cases where proliferation tracers (like 3'-deoxy-3'[18F]-fluorothymidine, [18F]FLT) exhibit certain limits.[17] Also non-tumor-specific FDG-uptake in inflamed tissue would not pose a problem when using the potential oxadiazole based imaging agents.[16,18–20]The class of 1,3,4-oxadiazole derivatives has been chosen to be developed as tracers for positron emission tomography. In a first approach two compounds will be prepared and suitable precursors will be labeled with [18F]fluorine, a positron emitting nuclide. After first distribution studies and in vitro tests a central decision on further research will determine further investigations on a very early stage of the proposed research, using the fluorescent properties of 1,3,4-oxadiazole derivatives as an indicator for late accumulation of the potential tracers. To be able to respond to long tracer accumulation times, different labeling strategies are taken into account. The potential final tracers will be fully evaluated in vitro and in vivo, using tumor models arising from hTERT expressing and non-expressing cell lines.