Gallium Dotatate Ga-68

GPCRs, as key signal transduction molecules on the cell surface, regulate various physiological processes and constitute one-third of the targets for clinical drug applications. Based on structural similarities, GPCRs are divided into several families, including A, B, C, etc. Although most drugs targeting GPCRs are small molecules, many GPCRs have endogenous ligands that are peptides containing fewer than 50 amino acids. According to the pharmacology guidelines of the International Union of Basic and Clinical Pharmacology (IUPHAR), about one-third (64 types) of class A GPCRs bind to endogenous peptides; 20 types of class B GPCRs are activated by 15 endogenous peptides, and these receptors are classified according to the ligands they recognize into families such as calcitonin, corticotropin-releasing factor, glucagon, parathyroid hormone (although it has 84 amino acids, it is still typically considered a peptide), vasoactive intestinal peptide (VIP), or pituitary adenylate cyclase-activating peptide (PACAP), etc. Typically, endogenous peptides can bind to GPCRs on the cell surface, bridging paracrine and autocrine signaling and regulating the downstream signaling pathways of GPCRs. Peptides are one of the largest and oldest categories of intercellular chemical messengers. The pioneering development of using these naturally occurring peptides as therapeutic drugs dates back to the application of insulin in the 1920s. Insulin primarily acts on tyrosine kinase receptors, and the development of this therapy has made full use of the outstanding pharmacokinetic properties of peptides: high affinity, selectivity, and potency. Consistent with the observed effects of insulin, most other peptide therapies are well-tolerated with fewer side effects. However, naturally occurring peptides are generally not suitable as effective therapeutic drugs. The development of peptide drugs is limited by factors such as poor pharmacokinetic properties (short half-life, rapid degradation, high clearance), as well as insufficient oral bioavailability due to low intestinal stability and poor permeability. Therefore, to make most peptides effective drugs, strategies that address these issues need to be developed. Peptide-based therapeutic drugs are experiencing a resurgence. Emerging innovative strategies include extending the half-life, stabilizing peptide chains, and enhancing resistance to proteolytic degradation, all of which significantly improve pharmacokinetic properties and oral bioavailability. A prime example of these strategies might be the development of glucagon-like peptide-1 (GLP-1) receptor agonists, which possess enhanced resistance to proteolytic degradation and reduced renal clearance. Numerous successful market products and a large array of novel approaches in preclinical stages (such as peptide stabilization, cyclization, and glycosylation) stem from these efforts. This success has also spurred the development of multifunctional peptides that combine agonist activities against two or more GPCRs within the same peptide, based on relatively high sequence homology and similar binding sites. Complementary pharmacokinetic strategies are expanding the variety of drugs acting on specific GPCRs. Approved peptide therapeutic drugsMost of the peptide drugs targeting GPCRs that have been approved for clinical use or are under development function as agonists, used to substitute for or enhance the low levels of endogenous peptides. The following figure summarizes peptide drugs targeting GPCRs. Within class A GPCRs, representative receptor targets include the μ and κ opioid receptors (abbreviated as MOR and KOR, respectively) for pain relief; oxytocin and vasopressin receptors for inducing labor; as well as apelin and angiotensin receptors for the treatment of cardiovascular diseases; and somatostatin receptors for treating acromegaly and Cushing's disease, among others. Peptide therapies targeting Class B receptors include GLP-1 receptor agonists for the treatment of Type 2 Diabetes (T2D), GLP-2 receptor agonists for the treatment of Short Bowel Syndrome, as well as other synthetic or modified peptide hormones. Currently, a few peptide antagonists have entered clinical trials, most of which target Class A GPCRs. For example, antagonists that block the action of Gonadotropin-Releasing Hormone (such as degarelix and abarelix) are used for cancer treatment. Synthesis of Endogenous Peptide AnalogsThe marketed synthetic endogenous peptide drugs targeting Class A and Class B GPCRs include those targeting the angiotensin receptor, melanocortin receptor, thyrotropin-releasing hormone receptor, vasopressin receptor, oxytocin receptor, calcitonin receptor, glucagon receptor, parathyroid hormone receptor, among others. According to statistics, peptide drugs targeting Class A GPCRs are mainly high-affinity (pKi=8.4) and high-efficacy (pEC50=8.5) agonists. However, they typically exhibit a very short plasma half-life following intravenous administration, with a median value of about 5.3 minutes. This reflects their rapid degradation by peptidases or their higher rate of excretion, particularly through the kidneys. Theoretically, the levels of peptide drugs are expected to decrease to less than 1% of the original dose within 6 half-lives, which is approximately 32 minutes. Lastly, endogenous peptides usually have a low rate of binding to plasma proteins, ensuring that most peptides in circulation are unbound and can directly interact with and activate the corresponding receptors. However, unbound peptides are also highly susceptible to renal clearance and cleavage by serum or tissue proteases, both of which can reduce the plasma half-life. For all Class B GPCRs, the pharmacokinetic and pharmacodynamic median values of their endogenous ligands are similar to those of Class A receptor peptides: high efficacy (pEC50=9.9), accompanied by a short plasma half-life (15 minutes) and a low volume of distribution (approximately 9.9 L). It is worth mentioning that the short plasma half-lives of at least two classes of peptides have been utilized for clinical benefit. The peptide drug with the shortest plasma half-life is Angiotensin II. Synthetic analogs of this Angiotensin II are used to treat critically ill patients with distributive shock due to sepsis, where abnormal distribution of blood to the smallest vessels leads to insufficient systemic blood supply, potentially resulting in death. This drug binds to the AT1 receptors on vascular smooth muscle, and after intravenous administration, it effectively raises blood pressure within a median time of 5 minutes. Its short half-life (less than 1 minute) ensures that the possibility of hypertensive crisis due to overdose is minimal. Similarly, oxytocin, which was sequenced and synthesized in the 1950s, is used to induce labor and immediately enhance contractions upon intravenous administration, but its effects wear off within an hour, reflecting its short half-life of several minutes. Modified peptidesTaking Semaglutide as an example, modifications and redesigns have significantly extended its half-life (approximately 168 hours). This extension is achieved by using a fatty acid linker, which allows the molecule to form non-covalent reversible interactions with albumin, thereby reducing renal excretion. Simultaneously, alpha-aminobutyric acid has been introduced at position 8 of Semaglutide to reduce metabolism mediated by Dipeptidyl Peptidase-4 (DPP-4). Additionally, Albiglutide and Dulaglutide utilize different protein linking strategies. These two GLP-1 receptor agonists are covalently linked to large molecules (albumin and the Fc fragment of human IgG4, respectively). In Albiglutide, the GLP-1 sequence at position 8 is also modified by substituting glycine with alanine near the DPP-4 cleavage site to reduce metabolism. Another exemplary case is Lutathera ([177Lu]-dotatate) used for the treatment of neuroendocrine tumors, representing a recent example of peptide receptor radionuclide therapy. In this compound, the peptide dotatate, an agonist of the somatostatin receptor, is labeled with lutetium [177]. After the peptide binds to somatostatin receptors highly expressed on tumor surfaces, the radiation emitted causes tumor cell death, while the limited range of the particles minimally affects the surrounding healthy tissue due to their short penetration depth. Peptide Design Optimization StrategiesRecent approvals of peptide drugs have shown trends such as high sustained target efficacy combined with increased plasma half-lives, reduced enzymatic metabolism, and decreased renal clearance. For example, degarelix is a synthetic derivative of GnRH that blocks the binding of endogenous peptides to pituitary receptors and is used to treat prostate cancer. After subcutaneous injection, degarelix forms a drug depot at the injection site, with the drug slowly releasing into the bloodstream, producing a plasma half-life of 42-70 days. Clearance is unaffected, primarily through hepatic-biliary hydrolysis and renal excretion of unchanged drug. Additionally, lanreotide is a somatostatin agonist that functions mainly by binding to SST2 and SST5 receptors, used to inhibit growth hormone release to treat acromegaly; it also forms a drug depot at the injection site with a 22-day plasma half-life and includes non-natural amino acids. Peptides, being charged and hydrophilic molecules, typically lack oral bioavailability. Decades after the synthetic modification of peptides, most peptide drugs still possess the intrinsic drawback of low membrane permeability, which limits their oral bioavailability and tissue distribution, including distribution to the CNS. Emisphere's use of a pharmacologically inactive small molecule enhancer, N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC), co-formulated with Semaglutide, results in the oral drug semaglutide having increased transcellular permeability and about 4% bioavailability. Experimental methods to enhance brain permeability include linking the drug neurotensin to the brain barrier-penetrating peptide angiopep-2, thus increasing the blood-brain barrier crossing capability by approximately tenfold through receptor-mediated transcytosis. This approach is sufficient to reverse pain behaviors in animal models of neuropathic and bone cancer pain. Cyclization helps in resistance to metabolism, and its hydrophobicity enhances absorption by intestinal cells. Despite very low bioavailability via the oral route (0.08%-0.16%), this is sufficient to achieve clinically effective plasma concentrations. Desmopressin is one example of an orally administered peptide drug, showcasing the potential of engineering peptides to possess oral activity. The new generation of peptide drugs often incorporates unnatural amino acid residues, such as D-amino acids, N-methyl amino acids, or residues with unnatural side chains. Chemical modifications—non-amino acid monomers added to peptides during synthesis—are also becoming increasingly important. These modifications include N-terminal modifications, C-terminal capping, fatty acids, and polyethylene glycol (PEG) groups. Among 49 peptide drugs approved for targeting GPCRs studied by researchers, 22 contain only natural amino acids, 3 contain at least one unnatural amino acid, 3 have at least one chemical modification, and 21 contain both chemical modifications and unnatural amino acids. Classic Case: Development of GLP-1 Agonist Peptides Exenatide is the first clinically-approved GLP-1 receptor agonist. In 1992, scientists identified a novel peptide hormone, exendin-4, from the saliva of the Heloderma suspectum. Exendin-4 shares many pharmacological properties with GLP-1: enhancing insulin secretion and reducing plasma glucose levels. However, unlike GLP-1, exendin-4 is resistant to enzymatic cleavage and inactivation by DPP4. As exenatide, it was approved in 2005 as an adjunct therapy for Type 2 Diabetes (T2D) and as a monotherapy in 2009. Although exenatide is widely used in the treatment of T2D, its short plasma half-life requires frequent (twice daily) subcutaneous injections, which limits its efficacy, leads to poor patient compliance, and increases the risk of additional side effects such as injection site infections. Following the success of exenatide, researchers have adopted multiple strategies to increase the plasma stability and half-life of GLP-1 receptor agonists, to reduce renal clearance, and to enhance oral bioavailability. These strategies are generally divided into two approaches. One approach focuses on extending the plasma half-life of exenatide, which led to the development of once-weekly Exenatide (QW) and lixisenatide. Exenatide QW involves reformulating exenatide into microspheres composed of the biodegradable polymer poly(D,L-lactide-co-glycolide), thus extending the dosing interval to once weekly. In lixisenatide, modifications to the exenatide sequence, including the addition of a lysine tail at the C-terminus, confer resistance to DPP4 enzyme cleavage and prolong the plasma half-life. The second strategy focuses on modifying the natural GLP-1 peptide, resulting in the production of liraglutide, albiglutide, dulaglutide, and the recently approved semaglutide. Liraglutide, approved in 2009, is a human GLP-1 receptor agonist based on the natural GLP-1 peptide, with an amino acid substitution (Lys34Arg) and a C16 palmitic acid side chain attached via a glutamyl spacer at position 26. These modifications increase its binding to serum albumin, significantly reducing renal clearance and DPP4 enzyme cleavage. The modified GLP-1 is released from albumin at a slow, steady rate, resulting in slower degradation and reduced renal clearance compared to the mature endogenous form of GLP-1, GLP-17-37. Semaglutide, approved in 2017, incorporates the non-natural amino acid α-aminoisobutyric acid at position 8 to reduce DPP4 enzyme cleavage, and contains a substituted C18 dicarboxylic fatty acid at Lys26 that provides strong albumin binding. Both albiglutide and dulaglutide are peptide fusion protein variants. Each carries protection against DPP4 enzyme cleavage due to a substitution at position 8, and both include two GLP-1 molecules, either fused to human serum albumin (albiglutide) or covalently linked via a small peptide connector to the human IgG4-Fc heavy chain (dulaglutide), to increase the molecule's half-life through recycling and/or interaction with the neonatal Fc receptor (FcRn) or by increasing molecular weight. Reference: https://www.nature.com/articles/s41573-020-0062-z

Gastric Cancer (GC), also known simply as GC, is one of the most lethal malignancies worldwide, with over one hundred million new cases reported in 2022, leading to the death of 783,000 individuals. Globally, the incidence and mortality rates of gastric cancer have been on the decline in most regions over the past few decades. This considerable change is largely attributed to economic development and improved practices in food preservation associated with refrigeration technology during food transport and storage. In 2020, it was estimated that there were 1.1 million cases of stomach cancer diagnosed globally, with 720,000 in males and 370,000 in females. Stomach cancer ranks among the top three most common cancers in 19 countries worldwide and is the most common cancer in four countries: Bhutan, Kyrgyzstan, Cape Verde, and Tajikistan. Sixty percent of all stomach cancer cases occur in East Asia, with China alone accounting for 43.9% of cases. The incidence of stomach cancer is higher in males, with 66% of all cases occurring in men. There are significant differences in the incidence rates across different regions; in several African countries, the incidence rate is less than 5 cases per 100,000 person-years in males, whereas in East Asian countries, it exceeds 30 cases per 100,000 person-years. This indicates that factors such as gender, region, and level of economic development have a significant impact on the incidence of stomach cancer. Moreover, in high-incidence areas such as East Asia, especially China, the prevention and control of stomach cancer represent a considerable challenge. In 2020, it was estimated that there were 1.1 million cases of stomach cancer diagnosed globally, with 720,000 in males and 370,000 in females. Stomach cancer ranks among the top three most common cancers in 19 countries worldwide and is the most common cancer in four countries: Bhutan, Kyrgyzstan, Cape Verde, and Tajikistan. Sixty percent of all stomach cancer cases occur in East Asia, with China alone accounting for 43.9% of cases. The incidence of stomach cancer is higher in males, with 66% of all cases occurring in men. There are significant differences in the incidence rates across different regions; in several African countries, the incidence rate is less than 5 cases per 100,000 person-years in males, whereas in East Asian countries, it exceeds 30 cases per 100,000 person-years. This indicates that factors such as gender, region, and level of economic development have a significant impact on the incidence of stomach cancer. Moreover, in high-incidence areas such as East Asia, especially China, the prevention and control of stomach cancer represent a considerable challenge. From: DOI: 10.1016/j.eclinm.2022.101404However, unlike the previously reported continuous decline in the overall incidence rate across all age groups, recent reports indicate an increase in the incidence of gastric cancer among young adults (under the age of 50), particularly a noticeable growth in the incidence of non-cardia tumors among the more affluent population. Gastric cancer can be roughly divided into two major anatomical sub-sites: although the majority of gastric cancers occur in the distal part of the stomach (non-cardia), globally, about 18% of gastric cancers originate in the cardia, which is the region adjacent to the gastroesophageal junction. Both anatomical locations of gastric cancer have overlapping risk factors, such as smoking, heavy alcohol consumption, and consumption of pickled foods; however, they also have their distinct etiologies. Cardia gastric cancer is often associated with gastroesophageal reflux disease and obesity, while approximately 90% of non-cardia gastric cancers can be attributed to Helicobacter pylori (H. pylori) infection. This implies that prevention and treatment strategies for different types of gastric cancer may need to be distinct, especially considering the rising incidence rates in young populations and the etiological differences between cardia and non-cardia gastric cancers. From: DOI: 10.1016/ S0140-6736(16)30354-3Timeline of Significant Discoveries and Key Advances in the Treatment of Gastric Cancer: In recent years, targeted therapies against specific molecular targets have been introduced into clinical practice, such as the anti-HER2 antibody trastuzumab and the anti-VEGFR-2 antibody ramucirumab. Claudin 18.2 is also a significant target for gastric cancer treatment, as the gene is associated with specific molecular subtypes involved in the development and progression of gastric cancer. This gene and its interaction pathways serve as potential targets for the development of new personalized treatment strategies. The G protein-coupled receptor (GPCR) signaling pathway is one of those pathways. Abnormal activation of GPCRs and G proteins can promote the progression of gastric cancer. Activated GPCRs/G proteins may serve as effective biomarkers for early diagnosis, prognostic prediction, and clinical therapeutic targets. This indicates that through the detection and intervention of these receptors and their aberrant activation states, it is possible to achieve early detection, accurate prognostic assessment, and targeted treatment of gastric cancer, thereby improving patient survival rates and quality of life. GPCR and Gastric CancerAs early as 1986, a study by Young et al. was the first to link G protein-coupled receptors (GPCRs) with tumorigenic activity. They demonstrated through experiments that the Mas proto-oncogene could confer tumorigenicity to NIH 3T3 cells in vivo in nude mice. Mas encodes a typical GPCR and, unlike most oncogenes, does not carry activating oncogenic mutations. Instead, tumorigenicity is caused by its overexpression and the abundance of ligands in the circulation system or locally produced ligands. There is now a substantial body of evidence suggesting that various wild-type GPCRs, acting under the influence of excessive circulating agonists or agonists produced within the tumor microenvironment, can induce oncogenic transformation and drive tumor progression. Specific neuropeptides, particularly neurotransmitters and intestinal hormones, play an autocrine and paracrine role in various cancers. These neuropeptides include Gastrin-Releasing Peptide (GRP), Endothelin, Bradykinin, Neuromedin B, Neuropeptide Y, Gastrin, Cholecystokinin, Arginine Vasopressin, and Angiotensin II, among others. Each, upon binding to their respective GPCRs, triggers sustained activation, thereby stimulating proliferation in a variety of cell types and playing a crucial role in many malignant human cancers, such as small cell lung carcinoma, pancreatic cancer, head and neck squamous cell carcinoma, prostate cancer, and gastric cancer. From: DOI: 10.3390/cancers15030736Progress in the development of new drugs for gastric cancer targeting GPCR-class receptorsAccording to statistics from the Synapse database, there are currently nearly 1000 research and development pipelines for gastric cancer globally, of which 38 are GPCR (G protein-coupled receptor) type target pipelines. Popular pipeline targets include SSTR, EP2R, EP4R, CCR8, CCKR, SMO, NTSR1, A2bR, CCR7, among others. The leading indications related to gastric cancer include gastric cancer, gastro-enteropancreatic neuroendocrine tumors, gastroesophageal junction tumors, and Her2-negative gastric cancer, among others. The principal types of therapeutic agents include radiopharmaceuticals, peptide conjugates, radionuclide-conjugated drugs, synthetic peptides, monoclonal antibodies, and fusion proteins. In the field of clinical research, the major regions for clinical studies on gastric medications are the United States, China, Japan, Europe, Australia, and others. Several drugs are currently in the late stages of clinical trials (Phase 2, Phase 2/3, Phase 3, etc.). Representative investigational drugs include: Representative Pipeline: (177Lu) Lutetium-DOTATATE and SSTRs ReceptorLutetium-177 Dotatate (LU-177 Lutetium Dotatate, also known as Lutathera) is a radiopharmaceutical developed by Advanced Accelerator Applications. It is primarily used for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This medicinal product is formed by the conjugation of the somatostatin analogue Dotatate with the radioactive isotope Lutetium-177. Dotatate is a compound that can specifically bind to somatostatin receptors (SSTRs) that are overexpressed on neuroendocrine tumor cells. Lutetium-177 is a beta-emitting radioisotope. When combined with Dotatate, the resultant Lutetium-177 Dotatate can accurately target and accumulate within tumor cells that express high levels of somatostatin receptors. The radioactive decay of Lutetium-177 releases beta radiation, which destroys the cancer cells, thereby achieving a localized radiation therapy effect. Somatostatin is a peptide hormone composed of 14 amino acid residues and features a single disulfide bond. This hormone is capable of inhibiting the secretion of growth hormone, insulin, glucagon, gastrin, cholecystokinin, and thyrotropin, but due to its extremely short half-life in the body (less than 3 minutes), its value in therapy is limited. Research has identified the β-turn pharmacophore of somatostatin, which has become the lead sequence for the development of analogs with greater biological stability and potency. Based on this, octreotide was developed and approved for the treatment of acromegaly, adenomas, and pancreatic, breast, and prostate tumors. Subsequent research has spurred the development of selective receptor antagonists, such as lanreotide, vapreotide, and pasireotide, and has introduced the fields of peptide imaging and peptide receptor radionuclide therapy. In these radionuclide therapies, radioactive elements such as ^111In, ^90Y, ^68Ga, or ^99mTc are linked to selective somatostatin analogs through chelating groups, leading to approved radiopharmaceutical formulations. These drugs can be used for tumor detection. In 2001, a preclinical animal model study on Lutetium Dotatate LU-177 was published in the International Journal of Cancer. It reported on the investigation of the biologic distribution of the drug in a rat model of pancreatic tumors, and these data were used to estimate the absorbed doses in normal human tissue. A 2004 study on the treatment effectiveness in patients with metastatic gastroenteropancreatic tumors positive for the somatostatin receptor revealed that, out of 50 patients treated with Lutetium Dotatate LU-177, disease stabilization was achieved in 24 patients, 19 patients experienced stable disease, the condition of 6 patients progressed, and 1 patient's disease status could not be assessed. The therapy significantly improved their overall health condition, quality of life, and scores for various functions and symptoms. In 2005, a clinical study on the use of Lutetium Dotatate LU-177 in 131 patients with metastatic or inoperable somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors was announced. After treatment with a maximum cumulative dose of 600 to 800 mCi of Lutetium Dotatate LU-177, 3 patients (2%) achieved complete remission, 32 patients (26%) had partial remission, 24 patients (19%) showed a minor response (tumor size reduction of 25% to 50%), 44 patients (35%) had stable disease, whereas 22 patients (18%) experienced disease progression. A high remission rate correlated positively with high uptake shown on pre-treatment somatostatin receptor imaging and fewer liver metastases. In contrast, patients with lower performance scores and extensive disease distribution had a significantly higher frequency of disease progression. Severe side effects were very rare, and the median time to disease progression was comparable to that with chemotherapy, with better effectiveness in patients with a limited tumor burden. An expanded clinical study published in 2008 further validated the safety and efficacy of Lutetium Dotatate LU-177. In a study involving 310 patients with gastroenteropancreatic neuroendocrine tumors, complete and partial tumor response rates were observed at 2% and 28%, respectively, with minor response rates (tumor size reduction of over 25% but less than 50%) at 16%. Compared with historical controls, this treatment method provided a survival benefit of 40 to 72 months from the point of diagnosis. From: DOI: 10.1200/JCO.2007.15.2553In 2017, results from a Phase 3 clinical study published in The New England Journal of Medicine indicated that, in a randomized, controlled trial involving 210 patients with gastroenteropancreatic neuroendocrine tumors, the experimental group (116 patients) receiving intravenous injections of 7.4 GBq dose of Lutetium Lu 177 Dotatate every 8 weeks for a total of four times, along with a concurrent intramuscular injection of 30 mg of long-acting octreotide every 4 weeks, had a significantly higher estimated progression-free survival rate at 20 months (65.2%) compared to the control group (10.8%), which consisted of 113 patients treated only with intramuscular injections of 60 mg of long-acting octreotide every 4 weeks. Additionally, the response rate for the Lutetium Lu 177 Dotatate group was 18%, markedly higher than the 3% observed in the control group. From: DOI: 10.1056/NEJMoa1607427Based on this, at the end of 2017, the U.S. FDA approved Lutetium Dotatate LU-177 for the treatment of patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Due to its targeted nature and relatively low systemic toxicity, this therapy has received widespread attention and application in the field of precision medicine. In October 2017, Novartis acquired the French innovative pharmaceutical company Advanced Accelerator Applications for $3.9 billion to build and expand its radioligand therapy platform. In 2018, Novartis invested an additional $2.1 billion to acquire the biopharmaceutical company Endocyte, securing several more radiopharmaceutical candidates. Through these acquisitions, Novartis has established and extended its radioligand therapy platform, comprising multiple marketed products: Lutathera (177Lu-DOTATATE) and 68Ga-Edotreotide, as well as several products in development: 177Lu-PSMA-617, 177Lu-PSMA-R2, 177Lu-NeoB, 177Lu-FF58, 225Ac-PSMA-617, etc. Furthermore, Lanreotide Acetate is a non-selective somatostatin receptor (SSTRs) antagonist that was first approved for marketing in 2002 for the treatment of acromegaly. Its investigational indications include gastroenteropancreatic neuroendocrine tumors. 68Ga-Edotreotide is a non-selective SSTRs antagonist product developed by Advanced Accelerator Applications. It is a radioactive diagnostic agent used in PET scans to detect somatostatin receptor-positive neuroendocrine tumors in both adult and pediatric patients. Other related R&D pipelinesMisoprostol is a medication primarily used to reduce the risk of stomach ulcers in users of non-steroidal anti-inflammatory drugs (NSAIDs). Its mechanism of action involves stimulating prostaglandin receptors in the stomach, enhancing gastric protection against acidic substances, and reducing gastric acid secretion, thereby protecting the gastric mucosa from damage. Additionally, Misoprostol is used for various medical applications: in the field of gynecology, it can be used to manage early miscarriage, prevent postpartum hemorrhage, and perform abortion surgery during early pregnancy. When Misoprostol acts on prostaglandin receptors in the uterus and cervix, it increases the strength and frequency of uterine contractions and decreases cervical tension, thus playing a key role in the management of miscarriage. ONO-4578, developed by Ono Pharmaceutical, is a highly selective antagonist of the EP4 receptor and is currently being studied for its safety and efficacy as monotherapy and in combination with nivolumab in patients with advanced or metastatic solid tumors, including gastric cancer. Based on the results of a Phase 1 clinical study, ONO-4578 has demonstrated good tolerability and certain antitumor activity. YY-001 and HTL-0039732 are selective EP4 receptor antagonists developed by Shanghai Yu Yao and Sosei Group, respectively, and are currently involved in clinical studies for various solid tumors, including gastric cancer. BMS-986340 is an IgG1 subtype monoclonal antibody product targeting CCR8, originally researched and developed by BMS. This drug possesses enhanced non-fucosylated (NF) Fc region features. As the CCR8 receptor is a chemokine receptor expressed on the surface of regulatory T cells (Tregs) and participates in the regulation of the immune system, BMS-986340 has been engineered to specifically bind CCR8. Due to its non-fucosylated Fc segment, it enhances effector functions against target cells. This optimization enables BMS-986340 to effectively deplete regulatory T cells (Tregs), which may modulate the immune response for treating diseases associated with excessive immunosuppression or dysfunctional Tregs. Currently, clinical trials for various solid tumors, including gastric cancer, are underway involving BMS-986340. FPI-2059 is a small molecule radiopharmaceutical that targets the Neurotensin Receptor 1 (NTSR1). This receptor is overexpressed in a variety of solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer, head and neck squamous cell carcinoma, gastric cancer, Ewing sarcoma, and neuroendocrine-differentiated prostate cancer. FPI-2059 is developed based on compounds previously known as IPN-1087 and 3BP-227. These compounds have been studied as beta-emitting radiopharmaceuticals in researcher-initiated studies and phase I clinical trials. In 2021, Fusion Pharmaceuticals acquired this asset and transformed it into an alpha-emitting radiopharmaceutical, labeled with Actinium-225. Concurrently, FPI-2058 is a diagnostic analog of FPI-2059, replacing Actinium-225 with Indium-111 as the radioactive isotope for medical imaging and diagnostic purposes. This targeted radiopharmaceutical design aims to achieve precise targeted therapy and diagnosis for the aforementioned types of tumors. TT-4 is a selective A2B receptor antagonist developed by Tarus Therapeutics that is currently in phase 1/2 clinical development. The trial aims to evaluate its therapeutic effect in patients with various advanced solid tumors, including gastric cancer. 177Lu-PP-F11N is a radioactive drug complex that combines PP-F11N (a gastrin analog) with the beta-emitting radioactive isotope Lutetium-177. This drug exhibits potential antitumor activity and may be used as an agent for single-photon emission computerized tomography (SPECT) imaging. After intravenous injection, PP-F11N specifically binds to the Cholecystokinin-2 Receptor (CCK2R). This allows visualization of the tumor cells expressing the CCK-2 receptor using nuclear medicine imaging techniques. Additionally, the Lutetium-177 radioactive isotope delivers cytotoxic doses of beta-radiation to the tumor cells expressing the CCK-2 receptor, providing targeted destruction of these cells. As the CCK-2 receptor is widely expressed in various types of tumor cells, 177Lu-PP-F11N has the potential for the treatment of these specific types of tumors and offers targeted imaging for personalized, precise cancer diagnosis and therapy.