Octreotide Analogs

Reflecting recent work in the Papini lab

Somatostatin, SS, is a cyclic tetradecapeptide able to inhibit the release of growth hormone, GH, mainly through the binding to two G‐protein coupled receptor, GPCR, subtypes, SSTR₂ and SSTR₅. These receptors are overexpressed in approximately 90% of carcinoid tumors. However, the clinical use of somatostatin is limited by its short half‐life in vivo.

In order to overcome this severe drawback, a huge number of analogs have been prepared, leading to the development of Octreotide, which is currently used in the clinic, among other applications, to treat various neuroendocrine tumors and, radiolabeled by, for example, ¹¹¹In, ¹¹C, and ⁶⁸Ga, for imaging SS‐secreting tumors. Despite the success of Octreotide, there is an unmet need for the development of novel, more stable and selective Octreotide‐derived radiotherapeutics.

To this end, the Cu(I)‐catalyzed azide‐alkyne 1,3‐dipolar Huisgen's cycloaddition, the prototypic click reaction, presents a promising opportunity to replace the susceptible disulfide bridge with a durable [1,2,3]triazolyl containing bridge and to introduce conformational constraints increasing specific receptor binding.

Researchers in the Papini Group, published in Peptide Science, report the design and synthesis of a series of i‐to‐i + 5 1,4‐ and 4,1‐disubstituted [1,2,3]triazolyl‐bridged cyclopeptides derived from the Octreotide scaffold and their detailed conformational analysis via NMR spectroscopy.