Drug effects on neuropeptides and their receptors: Big hopes but moderate success in the treatment of chronic pain.

Neuropeptides, including tachykinins, CGRP, and somatostatin, are localized in a peptidergic subgroup of nociceptive primary afferent neurons. Tachykinins and CGRP are pronociceptive, somatostatin is an antinociceptive mediator. Intensive drug research has been performed to develop tachykinin and CGRP antagonists, and somatostatin agonists as analgesics. CGRP receptor antagonists are efficacious and well-tolerated drugs in migraine. Monoclonal antibodies against CGRP or its receptor are used for the prophylactic treatment of migraine. Tachykinin NK1 receptor antagonists failed as analgesics but are used for chemotherapy-induced nausea and vomiting. New, orally active somatostatin 4 receptor agonists are promising drug candidates for treating various pain conditions.

(SiFA)SeFe: A Hydrophilic Silicon-Based Fluoride Acceptor Enabling Versatile Peptidic Radiohybrid Tracers.

The radiohybrid (rh) concept to design targeted (and chemically identical) radiotracers for imaging or radionuclide therapy of tumors has gained momentum. For this strategy, a new bifunctional Silicon-based Fluoride Acceptor (SiFA) moiety (SiFA)SeFe was synthesized, endowed with improved hydrophilicity and high versatility of integration into rh-compounds. Preliminary radiolabeling and stability studies under different conditions were conducted using model bioconjugate peptides. Further, three somatostatin receptor 2 (sstR2)-targeted rh-compounds ((SiFA)SeFe-rhTATE1-3, TATE = (Tyr3)-octreotate) were developed. Compound (SiFA)SeFe-rhTATE3, enables labeling with 18F for PET imaging or chelation of 177Lu for therapy. The rh-compounds possess comparable receptor binding affinity and in vitro performance as good as the clinically proven gold standards. SstR2-specificity was further shown for (SiFA)SeFe-rhTATE2 using the chicken chorioallantoic membrane (CAM) model. The biodistribution of two compounds in mice showed high accumulation in tumors and excretion via the kidneys, demonstrating the clinical applicability of the (SiFA)SeFe moiety.

Fish-hunting cone snail disrupts prey's glucose homeostasis with weaponized mimetics of somatostatin and insulin.

Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. Most venom components disrupt nervous, locomotor, and cardiovascular systems or cause tissue damage. The discovery that certain fish-hunting cone snails use weaponized insulins to induce hypoglycemic shock in prey highlights a unique example of toxins targeting glucose homeostasis. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective somatostatin receptor 2 (SSTR2) agonist that blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms with a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin's N-terminal tail closely mimics a glycosylated somatostatin from fish pancreas and is crucial for activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.

Expression of somatostatin receptors in canine and feline meningioma.

OBJECTIVES: The standard treatment for canine and feline meningiomas includes radiotherapy, surgical excision or combined therapy. However, new therapeutic approaches are required due to the possible recurrence or progression of meningiomas despite initial therapy. Adjunctive therapy with synthetic long-acting somatostatin (SST) analogues has been described in humans with SST-expressing tumours. The expression of SST receptors (SSTRs) by feline meningiomas is currently unknown, and there are little data about canine meningiomas. We hypothesized that SSTR is expressed by canine and feline meningiomas (S1). METHODS: Seven canines and 11 felines with histologically confirmed meningiomas underwent STTR screening. RNA expressions of SSTR1, SSTR2, SSTR3 and SSTR5 (canine) and SSTR1-SSTR 5 (feline) in fresh frozen and formalin-fixed and paraffin-embedded (FFPE) samples were investigated using real-time (RT)-qPCR. The expression of SSTR1 and SSTR2 in FFPE samples was evaluated using immunohistochemistry (IHC). The specificity of applied antibodies for canine and feline species was confirmed by western blotting. RESULTS: In canine meningiomas (n = 7), RNA expression of SSTR1, SSTR2 and SSTR5 was detected in all samples; SSTR3 RNA expression was detected in only 33% of samples. In feline meningiomas (n = 12), RNA expression of SSTR1, SSTR4, SSTR5 and SSTR2 was detected in 91%, 46%, 46% and 36% of samples, respectively; SSTR3 was not expressed. Overall, the detection rate was lower in FFPE samples. IHC revealed the expression of SSTR1 and SSTR2 in all samples from both species. However, it is important to exercise caution when interpreting IHC results due to the presence of diffuse background staining. CONCLUSIONS: SSTRs are widely expressed in canine and feline meningiomas, thereby encouraging further studies investigating SSTR expression to conduct trials about the effect of adjunctive therapy with long-acting SST-analogues.

[Nuclear medicine approaches in the diagnosis and treatment of neuroendocrine neoplasms]. / Nuklearmedizinische Ansätze in Diagnostik und Therapie neuroendokriner Neoplasien.

Despite, or perhaps because of the rarity of neuroendocrine neoplasms, the diagnosis and treatment of these malignancies is of particular importance. Nuclear medicine can make an important contribution to this challenge. It offers the most sensitive and specific imaging of these tumor entities and can be helpful in treatment due to the radiotherapeutic drugs that have recently been approved. This theragnostic (fusion of therapeutic and diagnostic) concept is based on the frequent overexpression of somatostatin receptors on neuroendocrine tumor cells.Using diagnostic and therapeutic pharmaceuticals based on analogues from somatostatin, most applications from the nuclear medicine are successful, an additional therapeutic method is SIRT, also known as TARE, in which the hypervascularization of NEN-metastases is used as a therapeutic target.

Super Mario sign at somatostatin receptor PET/CT.

68Ga-DOTA NOC PET-CT imaging has been shown to have high accuracy for the evaluation of neuroendocrine tumours. We present the case of a 59-year-old male with well differentiated gastric neuroendocrine tumour (grade II) treated with surgery. 68Ga-DOTA NOC PET/CT was performed to rule out metastasis. 68Ga-DOTA NOC showed physiological uptake in the bilateral adrenal and horseshoe kidney appearing as the famous character Super Mario. There is no evidence of any abnormal somatostatin avid lesion.

Dotatate PET/CT and 225Ac-Dotatate Therapy for Somatostatin Receptor-expressing Metastatic Breast Cancer.

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 (225Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 (P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

Clinical Evaluation of Response to Octreotide and Chemotherapy in High-Grade Malignant Neuroendocrine Tumors and Promising In Vitro Preclinical Results with Pasireotide.

Background and Objectives: High-grade malignant neuroendocrine tumors (G3 NETs) and neuroendocrine carcinomas (NECs) are characterized by rapid proliferation, high metastatic capacity, and strong expression of somatostatin receptors (SSTRs). We aimed to analyze the presence of SSTRs in NET G3 and NEC, and to correlate their expression with the use of octreotide and pasireotide. Materials and Methods: For this purpose, we first performed a retrospective study of G3 NET and NEC patients, which included the determination of SSTR expression and response to octreotide treatment. Second, we selected the H69 small cell lung cancer cell line to determine the effect of octreotide and pasireotide. Results: Our results showed the traditional somatostatin analog (SSA) octreotide was ineffective in patients with NET G3 and NEC. On the other hand, RT-qPCR showed a high expression of SSTR2 and SSTR5 in H69 cells. Interestingly, while octreotide did not modify H69 cell proliferation, a strong inhibition of proliferation was detected with the use of pasireotide. Conclusions: In view of these results, a clinical trial in NET G3 and NEC patients using pasireotide is necessary to determine the usefulness of this drug in improving patient treatment.

Characterization of the somatostatin system in tilapia: implications for growth and reproduction.

Somatostatin (SST) plays diverse physiological roles in vertebrates, particularly in regulating growth hormone secretion from the pituitary. While the function of SST as a neuromodulator has been studied extensively, its role in fish and mammalian reproduction remains poorly understood. To address this gap, we investigated the involvement of the somatostatin system in the regulation of growth and reproductive hormones in tilapia. RNA sequencing of mature tilapia brain tissue revealed the presence of three SST peptides: SST6, SST3, and low levels of SST1. Four different isoforms of the somatostatin receptor (SSTR) subfamily were also identified in the tilapia genome. Phylogenetic and synteny analysis identified tiSSTR2-like as the root of the tree, forming two mega clades, with SSTR1 and SSTR4 in one and SSTR2a, SSTR3a, and SSTR5b in the other. Interestingly, the tiSSTR-5 isoforms 5x1, 5x2, and 5x3 were encoded in the sstr3b gene and were an artifact of misperception in the nomenclature in the database. RNA-seq of separated pituitary cell populations showed that SSTRs were expressed in gonadotrophs, with sstr3a enriched in luteinizing hormone (LH) cells and sstr3b significantly enriched in follicle-stimulating hormone (FSH) cells. Notably, cyclosomatostatin, an SSTR antagonist, induced cAMP activity in all SSTRs, with SSTR3a displaying the highest response, whereas octreotide, an SSTR agonist, showed a binding profile like that observed in human receptors. Binding site analysis of tiSSTRs from tilapia pituitary cells revealed the presence of canonical binding sites characteristic of peptide-binding class A G-protein-coupled receptors. Based on these findings, we explored the effect of somatostatin on gonadotropin release from the pituitary in vivo. Whereas cyclosomatostatin increased LH and FSH plasma levels at 2 h post-injection, octreotide decreased FSH levels after 2 h, but the LH levels remained unaffected. Overall, our findings provide important insights into the somatostatin system and its mechanisms of action, indicating a potential role in regulating growth and reproductive hormones. Further studies of the complex interplay between SST, its receptors, and reproductive hormones may advance reproductive control and management in cultured populations.

Exploring monocyclic core: Discovery of pyrrol-2-one derivatives as a new series of potent MCHR1 antagonists with in vivo efficacy.

With an objective to improve the profiles of the 1st generation non-basic MCHR1 antagonists, a lean design approach of replacing the bicyclic thienopyrimidine core with a monocyclic pyrrol-2-one chemotype was examined in the context of reducing aromatic ring count, while also contemplating enhanced flexibility as a means of decreasing flat character. The new compounds exhibited potent antagonism up to the sub-nanomolar range, thereby implying that the monocyclic ring could effectively serve as an effective bioisostere of the bicyclic system. The prototype compound 2m offered benefits like improved potency, reduced half-life, and enhanced solubility, while also demonstrating >5% reduction in weight gain in rats, thereby providing proof-of-concept for this new class of compounds as anti-obesity agents.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

Somatostatin receptors in fibrotic myocardium.

A patient with a neuroendocrine tumor and history of coronary artery disease underwent PET with 68Ga-DOTATATE PET tracer for tumor visualization. Analysis of the scan showed uptake of 68Ga-DOTATATE in the left ventricle corresponding to previous myocardial infarct. 68Ga-DOTATATE binds by somatostatin receptors (SSTR) and it has been proposed that it may be useful for the detection of cardiac inflammatory lesions. We aimed to test whether SSTR could be upregulated in cardiac fibrotic scar. We analyzed SSTR in cardiac samples from patients with end-stage ischemic cardiomyopathy (ICM, n = 8) and control hearts (n = 5). In mature ICM tissue, SSTR1 and SSTR2 expression was unchanged and SSTR5 expression was significantly decreased in ICM samples vs. control. Immunohistochemistry showed increased SSTR1 and SSTR2 in ICM. Areas with SSTR1 or SSTR2 staining were often adjacent to fibrotic areas. The majority of SSTR1 and SSTR2 staining localized in cardiomyocytes in fibrotic scar-rich areas where CD68 macrophage staining was not present. SSTR are occasionally upregulated in cardiac fibrotic areas. When using 68Ga-DOTATATE PET tracer to detect cardiac sarcoidosis or atherosclerotic plaque, the possibility of tracer uptake in fibrotic areas should be considered.

Engineered Exosomes Containing microRNA-29b-2 and Targeting the Somatostatin Receptor Reduce Presenilin 1 Expression and Decrease the ß-Amyloid Accumulation in the Brains of Mice with Alzheimer's Disease.

Purpose: Exosomes are membrane vesicles secreted by various cells and play a crucial role in intercellular communication. They can be excellent delivery vehicles for oligonucleotide drugs, such as microRNAs, due to their high biocompatibility. MicroRNAs have been shown to be more stable when incorporated into exosomes; however, the lack of targeting and immune evasion is still the obstacle to the use of these microRNA-containing nanocarriers in clinical settings. Our goal was to produce functional exosomes loaded with target ligands, immune evasion ligand, and oligonucleotide drug through genetic engineering in order to achieve more precise medical effects. Methods: To address the problem, we designed engineered exosomes with exogenous cholecystokinin (CCK) or somatostatin (SST) as the targeting ligand to direct the exosomes to the brain, as well as transduced CD47 proteins to reduce the elimination or phagocytosis of the targeted exosomes. MicroRNA-29b-2 was the tested oligonucleotide drug for delivery because our previous research showed that this type of microRNA was capable of reducing presenilin 1 (PSEN1) gene expression and decreasing the ß-amyloid accumulation for Alzheimer's disease (AD) in vitro and in vivo. Results: The engineered exosomes, containing miR29b-2 and expressing SST and CD47, were produced by gene-modified dendritic cells and used in the subsequent experiments. In comparison with CD47-CCK exosomes, CD47-SST exosomes showed a more significant increase in delivery efficiency. In addition, CD47-SST exosomes led to a higher delivery level of exosomes to the brains of nude mice when administered intravenously. Moreover, it was found that the miR29b-2-loaded CD47-SST exosomes could effectively reduce PSEN1 in translational levels, which resulted in an inhibition of beta-amyloid oligomers production both in the cell model and in the 3xTg-AD animal model. Conclusion: Our results demonstrated the feasibility of the designed engineered exosomes. The application of this exosomal nanocarrier platform can be extended to the delivery of other oligonucleotide drugs to specific tissues for the treatment of diseases while evading the immune system.

Diagnostic performance and clinical impact of 18F-AlF-NOTA-octreotide in a large cohort of patients with neuroendocrine neoplasms: A prospective single-center study.

Purpose: Somatostatin receptor imaging with 18F-AlF-NOTA-octreotide (18F-AlF-OC) has shown promising performance in neuroendocrine neoplasms (NENs). In this study, we aim to investigate the diagnostic performance and clinical impact of 18F-AlF-OC in a large prospective cohort of patients with NEN. Methods: Between January 2023 and November 2023, a total of 219 patients with confirmed or suspected NEN were enrolled prospectively and underwent 18F-AlF-OC PET/CT at 2 h post-injection. The primary endpoint was the diagnostic performance, including sensitivity, specificity, and accuracy. An additional primary endpoint was the impact of 18F-AlF-OC on clinical management. The reference standard was based on the results of histopathology or radiological follow-up. Results: 205 patients were included in the final analysis. The patient-level sensitivity, specificity, and accuracy of 18F-AlF-OC PET/CT compared with contrast-enhanced CT/MRI were 90.5% vs. 81.8%, 93.1% vs. 71.1%, and 91.2% vs. 79.4%, respectively. 26 patients had tiny gastrointestinal NENs (smaller than 1 cm in diameter). The patient-based sensitivity of 18F-AlF-OC PET/CT and contrast-enhanced CT/MRI were 61.5% (16/26) and 37.5% (9/24), respectively. The smallest diameter of gastrointestinal NEN detected by 18F-AlF-OC PET/CT was 0.6 cm in the rectum, 0.3 cm in the stomach, and 0.5 cm in the duodenum. 18F-AlF-OC PET/CT results led to changes in clinical management in 19.5% of patients (40/205), owing mainly to new or unexpected findings compared to contrast-enhanced CT/MRI. Conclusion: 18F-AlF-OC PET/CT demonstrated great diagnostic performance in patients with NEN, particularly for detecting tiny gastrointestinal NEN. Furthermore, 18F-AlF-OC PET/CT impacted the therapeutic management in 19.5% of patients. Our results further validate the role of 18F-AlF-OC as a somatostatin receptor imaging tracer in clinical practice.

Enhanced Detection of Early Pulmonary Fibrosis Disease Using 68Ga-FAPI-LM3 PET.

Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a 68Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3 alongside the heterobivalent probe 68Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the 68Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including 68Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and 68Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe 68Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of 68Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of 68Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.

Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists.

Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high-resolution cryogenicelectron microscope structures of the SSTR5-Gi complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 Å and 2.9 Å, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling Gαi protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure-based drug development targeting this therapeutically relevant receptor.

Inhibitory actions of melanin-concentrating hormone in the lateral septum.

Melanin-concentrating hormone (MCH) neurons can co-express several neuropeptides or neurotransmitters and send widespread projections throughout the brain. Notably, there is a dense cluster of nerve terminals from MCH neurons in the lateral septum (LS) that innervate LS cells by glutamate release. The LS is also a key region integrating stress- and anxiety-like behaviours, which are also emerging roles of MCH neurons. However, it is not known if or where the MCH peptide acts within the LS. We analysed the projections from MCH neurons in male and female mice anteroposteriorly throughout the LS and found spatial overlap between the distribution pattern of MCH-immunoreactive (MCH-ir) fibres with MCH receptor Mchr1 mRNA hybridization or MCHR1-ir cells. This overlap was most prominent along the ventral and lateral border of the rostral part of the LS (LSr). Most MCHR1-labelled LS neurons lay adjacent to passing MCH-ir fibres, but some MCH-ir varicosities directly contacted the soma or cilium of MCHR1-labelled LS neurons. We thus performed whole-cell patch-clamp recordings from MCHR1-rich LSr regions to determine if and how LS cells respond to MCH. Bath application of MCH to acute brain slices activated a bicuculline-sensitive chloride current that directly hyperpolarized LS cells. This MCH-mediated hyperpolarization was blocked by calphostin C, which suggested that the inhibitory actions of MCH were mediated by protein kinase C-dependent activation of GABAA receptors. Taken together, these findings define potential hotspots within the LS that may elucidate the contributions of MCH to stress- or anxiety-related feeding behaviours. KEY POINTS: Melanin-concentrating hormone (MCH) neurons have dense nerve terminals within the lateral septum (LS), a key region underlying stress- and anxiety-like behaviours that are emerging roles of the MCH system, but the function of MCH in the LS is not known. We found spatial overlap between MCH-immunoreactive fibres, Mchr1 mRNA, and MCHR1 protein expression along the lateral border of the LS. Within MCHR1-rich regions, MCH directly inhibited LS cells by increasing chloride conductance via GABAA receptor activation in a protein kinase C-dependent manner. Electrophysiological MCH effects in brain slices have been elusive, and few studies have described the mechanisms of MCH action. Our findings demonstrated, to our knowledge, the first description of MCHR1 Gq-coupling in brain slices, which was previously predicted in cell or primary culture models only. Together, these findings defined hotspots and mechanistic underpinnings for MCH effects such as in feeding and anxiety-related behaviours.

Treatment of acromegaly with the nonpeptide, highly selective somatostatin receptor type 2 agonist paltusotine.

Injectable first-generation somatostatin receptor ligands (fg-SRLs) are the standard of care of medical treatment for acromegaly. While fg-SRLs control acromegaly in up to 50 % of patients, they may lead to bothersome injection pain and site reactions. Paltusotine is an investigational, highly selective somatostatin receptor subtype 2 agonist, which is administered orally once a day. To date, phase 2 and 3 clinical trials suggest paltusotine treatment can achieve biochemical and symptom control in acromegaly, with a safety profile comparable to those of the fg-SRLs. Since paltusotine is a once-daily oral drug, it may represent a future treatment option for addressing patient preference or improving quality of life.

Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog.

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.