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Abstract

Development of somatostatin analogues (SSAs) plays a central role in the improvement of diagnostic and therapeutic tools in the treatment of neuroendocrine neoplasms (NENs). These analogues target the somatostatin receptors (sst) 1-5 which are often overexpressed on the outer membrane surface of many tumor cells. Poor selective modulation of a single sst receptor subtype by SSAs leads to a wide range of side effects, limiting their clinical impact. The high affinity of somatostatin (SST) and its analogues that bind to sst receptors results from a short subsequence (5-9 amino acids), usually within a rigid beta-turn motif. Tryptathionine bridges (Ttn) represent a privilege scaffold for the beta turn pharmacophore and contribute to high affinity, selectivity and significant metabolic stability of peptidic toxins. In the present thesis a trimmed somatostatin analogue, in which the disulfide bond found in octreotate was replaced by a tryptathionine bridge ((Ttn)-TATE), was made on solid phase. The resulting soluble (Ttn)-TATE displayed a high affinity in vitro for membrane solubilized sst2 receptor and for sst2 receptor expressed on whole Ar42J cells. Similar results were obtained from (Ttn)-TATE anchored on TentaGel microbeads. This work lays down the foundation for a one-bead-one-compound (OBOC) combinatorial tryptathionine peptidic library to isolate selective and avid binders of a desired sst receptor subtype and cellular phenotype outcome.