Abstract
Simple SummarySomatostatin receptors (SSTs) are of particular interest in oncology because these proteins are overexpressed on the cell membranes of different human malignancies, especially neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs). Radiolabeled short peptide analogs of the natural hormone somatostatin have been developed over the years to target SST-expressing tumors and are used for both imaging (diagnosis) and therapy. Today, this type of radiopharmaceutical plays a pivotal role in the management of NET and NEN patients. Despite their clinical success, new developments in recent years, in terms of peptide analogs and radionuclides, have shown certain advantages and hold promise for further improvement in both the diagnosis and therapy of SST-expressing tumors, even beyond NETs and NENs.Somatostatin receptors (SSTs) are recognized as favorable molecular targets in neuroendocrine tumors (NETs) and neuroendocrine neoplasms (NENs), with subtype 2 (SST2) being the predominantly and most frequently expressed. PET/CT imaging with 68Ga-labeled SST agonists, e.g., 68Ga-DOTA-TOC (SomaKit TOC®) or 68Ga-DOTA-TATE (NETSPOT®), plays an important role in staging and restaging these tumors and can identify patients who qualify and would potentially benefit from peptide receptor radionuclide therapy (PRRT) with the therapeutic counterparts 177Lu-DOTA-TOC or 177Lu-DOTA-TATE (Lutathera®). This is an important feature of SST targeting, as it allows a personalized treatment approach (theranostic approach). Today, new developments hold promise for enhancing diagnostic accuracy and therapeutic efficacy. Among them, the use of SST2 antagonists, such as JR11 and LM3, has shown certain advantages in improving image sensitivity and tumor radiation dose, and there is evidence that they may find application in other oncological indications beyond NETs and NENs. In addition, PRRT performed with more cytotoxic α-emitters, such as 225Ac, or β- and Auger electrons, such as 161Tb, presents higher efficacy. It remains to be seen if any of these new developments will overpower the established radiolabeled SST analogs and PRRT with β--emitters.
Highlights
The somatostatin family consists of two cyclic disulfide-bond-containing peptide hormones, one with 14 amino acids (SS-14, primary form in the brain) and one with 28 amino acids (SS-28, primary form in the gut)
The biologic actions of somatostatin are mediated by five somatostatin receptor subtypes (SST1-5), which belong to a distinct group within the G-protein-coupled receptor superfamily, known as 7-transmembrane receptors
The five subtypes (SST1-5) have approx. 50% identical amino acids, with homology being the most pronounced in the transmembrane regions, and they are subdivided into two subgroups: one consisting of SST2, SST3, and SST5, differing from the other subgroup, which consists of SST1 and SST4 in terms of amino acid homology and pharmacological profile [1]
Summary
The somatostatin family consists of two cyclic disulfide-bond-containing peptide hormones, one with 14 amino acids (SS-14, primary form in the brain) and one with 28 amino acids (SS-28, primary form in the gut). Radiopharmaceuticals targeting the SST play a pivotal role in the management of NEN and NET patients [6,7] These radiopharmaceuticals are mainly based on short peptide analogs of the natural hormone somatostatin, and their clinical success lies in the following factors: (a) the expression of SST in a high incidence and density on the surface of NET cells ( accessible) compared to their low expression in other tissues; (b) the development, over the years, of synthetic peptide analogs of somatostatin, which have been optimized in terms of in vivo stability, affinity, specificity, and pharmacokinetics; and (c) the advances in radiochemistry and chelation chemistry, which have allowed for the chemical tuning of these peptides for radiolabeling with various radionuclides for different medical applications in nuclear oncology. It presents (I) the radiolabeled SST agonists, including the key structural features of somatostatin that led to the currently established radiopharmaceuticals, their clinical applications, and the most recent advancements; (II) the radiolabeled SST antagonists, from their conceptualization and their structural design in comparison with the agonists to the clinical data and status of their development to date; (III) the current evidence for novel clinical indications of radiolabeled SST analogs, especially antagonists; and (IV) the perspectives of labeling with new radionuclides and of targeting somatostatin receptor subtypes other than SST2
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