Development, synthesis and evaluation of novel fluorescent Endothelin-B receptor probes

The endothelin (ET) signaling system is comprised of three endothelin peptides (ET-1, -2 and -3) and two corresponding endothelin-A and -B receptors (ET_AR and ET_BR), which belong to the G-protein coupled receptor (GPCR) superfamily. The endothelin axis, as this system is also referred to, contributes to the maintenance of vascular tone, functions as regulator of inflammation and proliferation and helps in balancing water homeostasis. In pathological settings, the ET axis is known to contribute to endothelial activation in cardiovascular diseases, to cell proliferation, chemoresistance and metastasis in cancer and to inflammation and fibrosis in renal disease. Antagonists of ET_AR and ET_BR, either subtype-specific compounds or substances with high affinity to both receptors, have been developed for more than 30 years. In the preclinical context, in vivo imaging of endothelin receptor expression has been utilized to assess ET-axis contribution to e.g. cancer or myocardial infarction. In this work, we present the development and synthesis of two novel ET_BR-specific fluorescent probes, based on the available antagonists BQ788 and IRL2500 and their preliminary evaluation in a breast cancer context.