Somatostatin receptor antagonist

Somatostatin is a G protein-coupled receptor ligand. When the receptors are activated, it causes the cells where the receptors are expressed to decrease hormone secretion. Mainly, as a neuroendocrine inhibitor, it exerts its effects on gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), causing hormone secretions coupled to this pathway to be reduced. It can affect neurotransmission and memory formation within the central nervous system. Within human and animal models, it demonstrated its effects of preventing angiogenesis and reducing healthy and cancer cell proliferation. Within tumors, somatostatin receptors, mostly of the ssrt2 subtype, are expressed in most neuroendocrine tumors, breast tumors, some brain tumors, renal cell tumors, lymphomas and prostate tumors. == Radiolabel ==

The radiolabeled somatostatin receptor antagonists share the following structure: The antagonist has a peptide moiety. The nomenclature of the somatostatin receptor antagonists is also based on this order. The structure of somatostatin receptor antagonists are similar to that of the agonists. Some agonists were already approved by the FDA for clinical use, such as In-DTPA-octreotide and Ga-DOTATATE. Different subtype receptor antagonists were later developed. Research has mostly been done on the sstr2 receptor antagonist, as the sstr2 receptor is expressed on most tumors. ssrt2 selective antagonists that had even higher affinity were developed. These were LM3, JR10, and JR11, which make up the second generation. Compounds were developed with 3 macrocyclic chelators: DOTA, NODAGA, and CB-TE2A. as well as NODAGA Ga-NODAGA-based compounds were shown to have a higher binding affinity than its DOTA analogues. However, these somatostatin receptor antagonists showed a higher tumor uptake despite its lower affinity for ssrt receptors, Compounds containing one of the radionuclides of indium-111, lutetium-177, copper-64, yttrium-80 and gallium-68 have been made. A study indicated the gallium compound had the lowest affinity to the sstr2 receptor. while and Lu-DOTA-JR11 had similar research done as a therapeutic agent, The NODAGA chelator was used over DOTA in Gallium antagonists due to higher binding affinity, which is reverse that of the gallium-containing antagonists. Safety In general, somatostatin receptor antagonists were noted to be well tolerated. Somatostatin receptor antagonists can bind to the receptors without activating them , antagonizing the therapeutic inhibitory effects of SSA therapy. Slow intravenous injection might be used until further safety data becomes available. == Somatostatin receptor agonists versus antagonists in radiolabelling ==

Agonists of the somatostatin receptor had been long established as an imaging agent, with the first agonist Ga-DOTATOC coming out in 2001, which is based on a radiolabeled somatostatin receptor agonist drug octreotide, and further developments were based on its structure. Agonists share the characteristic of being uptaken into tumor cells, and degraded intracellularly. Antagonists, while not widely absorbed into the tumor cells, can bind to a wider range of receptors as they can bind to the receptors regardless if the receptors are activated or inactivated. A head-to-head study of the gallium-containing compounds, where the Ga-NODAGA-JR11 antagonist and Ga-DOTATOC agonist are directly compared, showed that Ga-NODAGA-JR11 had higher hepatic metastatic tumor detection rate and lesion sensitivity than Ga-DOTATOC. == Radiolabeled somatostatin receptor antagonists in Peptide Radionuclide Receptor Therapy (PRRT) ==

Somatostatin receptor antagonists are also being developed as therapeutic agents in peptide radionuclide receptor therapy (PRRT) due to the wider binding of antagonists compared to agonists. Moreover, another study finds out that radioactive atom, terbium-161 (161Tb), that can release short-ranged electrons, can combine with somatostatin receptor antagonists which localize at the cell membrane, giving an alternative solution, rather than the currently clinically used lutetium-somatostatin receptor agonist, which localize at the cytoplasm and nucleus. Moreover, Tb-antagonist in vitro shows 102-fold more potent than Lu-antagonist in inhibiting tumor cell growth and prolonging survival of mice, This result is further repeated and confirmed in vivo, showing the high potential and strengths of radiolabeled somatostatin receptor antagonists to treat neuroendocrine neoplasms. == Further potential ==

Other compounds other than radiolabelled somatostatin receptor antagonists have also been studied. Cyclosomatostatin is one such compound. Contrary to previously discussed compounds, cyclosomatostatin does not contain a radionuclide. It is a non-selective somatostatin receptor antagonist, inhibiting the effects of somatostatin on target cells in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS). However it acts as an agonist in SH-SY5Y neuroblastoma cells. This action makes up around 56% of total insulin action. Two animal tests were done, which shows that cyclosomatostatin can help prevent HDIR without correcting the hyperglycemic condition in the situation of hemorrhage and exogenous somatostatin infusion. Cyclosomatostatin may be related to other indications, including the potential of blocking the suppression of gastric emptying triggered by corticotropin-releasing hormone (CRH), the key regulator of the hypothalamic-pituitary-adrenal axis released to alter the body response caused by stress. Furthermore, cyclosomatostatin, even if used alone, may modulate neurotransmitter levels. It increases acetylcholine (ACh) release by reversing the inhibitory effect of a substance, DHP agonist Bay K 8844, to L-type voltage-sensitive Ca2+ calcium channel. ==References==