SSTRs

Somatostatin receptors (SSTRs) are a family of five G protein-coupled receptors that mediate the effects of the neuropeptide somatostatin. The five subtypes, SSTR1 through SSTR5, have distinct tissue distribution and ligand affinities, with expression in the brain, pituitary, gastrointestinal tract, pancreas, and many tumors. SSTR2 is frequently prominent in neuroendocrine tumors and is a common therapeutic and diagnostic target, while other subtypes contribute to varied hormonal and neurological regulation.

All SSTRs are Gi/o-coupled GPCRs that inhibit adenylyl cyclase, reducing cyclic AMP levels. They influence ion channels by promoting potassium efflux and inhibiting voltage-gated calcium channels, thereby decreasing hormone and neurotransmitter secretion. Receptor signaling can also engage other pathways, including MAPK and PI3K cascades, contributing to antiproliferative and anti-secretory effects. Upon agonist binding, SSTRs may internalize, allowing continued signaling from endosomes and providing a mechanism for delivering radiolabeled ligands to tumors.

Endogenous ligands are somatostatin-14 and somatostatin-28. Clinically relevant ligands include synthetic analogs such as octreotide, lanreotide, and pasireotide, which vary in subtype selectivity. Radiolabeled somatostatin analogs, including Ga-68 DOTATATE, Ga-68 DOTATOC, and Ga-68 DOTANOC, are used for positron emission tomography imaging of somatostatin receptor–expressing tumors. Therapeutically, Lu-177 DOTATATE and related compounds enable targeted radiotherapy in certain neuroendocrine tumors.

SSTRs are integral to the management of neuroendocrine tumors and some pituitary disorders, providing both diagnostic imaging and targeted therapy options, while remaining an active area of research for broader anti-tumor and anti-secretory applications.