Somatostatin Analogs: Future Perspectives and Preclinical Studies-Pansomatostatins

Somatostatin (SS) is a native peptide hormone first isolated from ovine hypothalamic extracts and occurs either as a cyclic tetradecapeptide (SS-14) or as an N-terminally extended analog (SS-28). SS exerts numerous physiological actions by interacting with high-affinity receptors comprising five subtypes (sst1-5) found in the brain as well as in peripheral organs, like the pituitary, pancreas, gut, thyroid, adrenals, and kidneys, and the immune system. Although native SS-14 binds with nanomolar affinity to all sst1-5, it is unsuitable for drug development due to its poor metabolic stability. For such purposes, metabolically stabilized and sst2-prefering synthetic SS analogs have been developed, such as octreotide or lanreotide. After coupling to suitable chelators, these analogs can be labeled with medically useful radiometals for diagnostic imaging or radionuclide therapy. For example, after injection in patients, [111In-DTPA]octreotide localizes in primary and metastatic sst2 + lesions, which can be efficiently visualized with an imaging device. Despite the predominance of sst2 expression in many human tumors, coexpression of sst2 with other sst1-5 subtypes is frequent enough. Furthermore, a number of human tumors devoid of sst2 may instead express one or more of the other subtypes. These findings have stimulated the search for stable pansomatostatin-like analogs with the aim to broaden the clinical indications and/or to enhance the diagnostic/therapeutic efficacy of currently available sst2-preferring (radio)peptides. A number of Phe3-substituted octreotide analogs have been developed showing a broader affinity profile, such as DOTANOC and DOTABOC. Recently, the two multi-SS receptor ligands SOM230 and KE108 and their radiolabeled versions have been introduced and are currently evaluated in animal models for their applicability in the clinic. In addition to a pansomatostatin-like affinity, such analogs should display a preserved pharmacological profile and favorable in vivo pharmacokinetics before they can effectively replace the currently available sst2-prefering analogs.

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