ACS Chemical Neuroscience最新文献

{"title":"Simulation of Neurotransmitter Release and Its Imaging by Fluorescent Sensors","authors":"Juliana Gretz,&nbsp;Jennifer M. Mohr,&nbsp;Bjoern F. Hill,&nbsp;Valeriia D. Andreeva,&nbsp;Luise Erpenbeck,&nbsp;Sebastian Kruss","doi":"10.1021/acschemneuro.6c00227","DOIUrl":"10.1021/acschemneuro.6c00227","url":null,"abstract":"<p>Cells release signaling molecules such as neurotransmittersthatdiffuse through the extracellular space and bind to receptors. Thesesignaling molecules can be detected by fluorescent sensors and probesto provide images of the signaling process. Such images are not equivalentto a concentration because diffusion and sensor kinetics affect (convolute)them. Therefore, computational approaches are necessary to disentanglethese contributions and allow the interpretation of fluorescent sensor-basedimages. Here, we present a kinetic Monte Carlo framework (fluorescentsensor imaging kinetic simulation, FLIKS) that simulates signalingmolecules undergoing cellular release, stochastic diffusion, and reversiblebinding to sensors in realistic cellular (2D or 3D) geometries. Weapply it to model neurotransmitter (dopamine) release in synapticclefts and for paracrine signaling by immune cells. We also show howsensor location, sensor kinetics, and release location affect fluorescenceimages. For example, we show how sensor sensitivity depends on thedistance from the synaptic cleft and changes when dopamine transporters(DATs) clear dopamine. The approach also allows us to compare theperformance of membrane-bound (genetically encoded) sensors versusartificial sensors such as nanosensors placed outside under or aroundthe cells. As an example, we also demonstrate how the images of catecholaminerelease by immune cells can be modeled and compared with experimentaldata to better understand the release pattern. This framework providesa quantitative basis for analyzing and interpreting the fluorescentsensor imaging data.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 15","pages":"2991–2999"},"PeriodicalIF":4.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Advanced AI Frameworks for Dual PPAR α/γ Agonist Discovery in Alzheimer’s Disease","authors":"Navaneet Chaturvedi,&nbsp;Vaibhav Mishra,&nbsp;Shafiul Haque,&nbsp;Sabiha Khatoon,&nbsp;Kamal Rawal,&nbsp;Vijay Kumar","doi":"10.1021/acschemneuro.6c00148","DOIUrl":"10.1021/acschemneuro.6c00148","url":null,"abstract":"<p>The dual activating potential of peroxisome proliferator-activatedreceptors (PPAR) α and γ offers a promising way to addressmetabolic issues, neuroinflammation, and protein balance in the developmentof Alzheimer’s disease (AD). The current study intends to underscorethe emerging importance of artificial intelligence (AI) in the accelerateddiscovery and optimization of dual PPAR α/γ modulatorsbased on machine learning (ML), deep learning (DL), and generativemodeling. The role of autonomous and agentic-AI systems in hypothesisgeneration, lead optimization, and closed-loop screening processesis highlighted. In addition, AI-enabled digital twin frameworks areemerging as powerful tools to integrate multiomics, neuroimaging,and clinical data for virtual modeling of disease progression andtherapeutic response. Furthermore, the importance of explainable AI(XAI) in improving the interpretability and mechanistic insights ofdrug-receptor interaction models is underscored. Taken together, thisreview integrates recent studies illustrating the utility of AI-optimizeddual PPAR α/γ agonists in enhancing lead selection, dose–responseprediction, and therapeutic outcome prediction, thus bridging pharmacologicalcomputation and neuroimmune targeting for next-generation precisionmedicine approaches in AD therapy.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 15","pages":"2802–2817"},"PeriodicalIF":4.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G2019S LRRK2 Kinase Inhibition in Heterozygous Mice Avoids Lung Phenotype Observed with Inhibition of WT LRRK2","authors":"Albert W. Garofalo,&nbsp;Marcus D. Schonemann,&nbsp;Matteo Santoro,&nbsp;Jing Zhao,&nbsp;R. Jeremy Nichols,&nbsp;Thomas J. Montine","doi":"10.1021/acschemneuro.6c00147","DOIUrl":"10.1021/acschemneuro.6c00147","url":null,"abstract":"<p>Gain-of-function mutations in the LRRK2 protein elevatekinaseactivity, and heterozygous or homozygous carriers of mutant <em>LRRK2</em> have an increased risk of Parkinson’s disease(PD), together suggesting that inhibition of mutant LRRK2 kinase activitymay be a promising therapeutic target. Conversely, <em>LRRK2</em> knockout mice and people with homozygous loss-of-function <em>LRRK2</em> mutations exhibit prominent pathologic changes in lung and kidney, and nonselective inhibition of wild-type and mutantLRRK2 kinase at therapeutic doses causes on-target toxicity in rodentand nonhuman primate models, most prominently in lung. Numerous LRRK2variants have been described that cause increased phosphorylationof endogenous substrates. The G2019S mutation is the most prevalent,occurring in up to 40% of PD patients in certain populations, withthe vast majority being heterozygous. We previously disclosed a seriesof G2019S LRRK2-selective kinase inhibitors designed to avoid on-targetside effects. In this study, we examined the effect of a LRRK2 inhibitorspecific for the G2019S variant, <strong>STF-3600</strong>, in WT, andheterozygous or homozygous G2019S <em>LRRK2</em> knock-in(KI) mice. This inhibitor did not cause vacuolization in lungs ofWT or heterozygous G2019S <em>LRRK2</em> KI mice but did causelung toxicity in homozygous G2019S <em>LRRK2</em> KI micethat was similar to what was observed with the nonselective inhibitor, <strong>MLi-2</strong>. This study underscores the potential of G2019S LRRK2-selectivekinase inhibitors to be safe and effective for heterozygous G2019S <em>LRRK2</em> PD carriers.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 15","pages":"2982–2990"},"PeriodicalIF":4.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescence Lifetime and Smartphone-Enabled Detection of Amyloid-β for Diagnosis and Staging in Alzheimer’s Disease","authors":"Krithi K. Bhagavath,&nbsp;Madhu Ramesh,&nbsp;Yogendra Kumar,&nbsp;Sabyasachi Mandal,&nbsp;Hiriyakkanavar Ila,&nbsp;Thimmaiah Govindaraju","doi":"10.1021/acschemneuro.6c00230","DOIUrl":"10.1021/acschemneuro.6c00230","url":null,"abstract":"<p>Alzheimer’s disease (AD) is characterized by thepathologicalaggregation of amyloid-β (Aβ) peptides into plaques thatdrive neurodegeneration and cognitive decline. As Aβ remainsthe central and pathological biomarker for early and definitive ADdiagnosis, there is a critical need for sensitive, accessible, andclinically adaptable detection technologies. Here, we report <strong>TZ-48</strong>, a fluorescence lifetime-responsive probe designed forhighly selective and sensitive detection of Aβ in brain tissueand biofluids. <strong>TZ-48</strong> exhibits strong turn-on fluorescence,distinct lifetime signatures, and real-time tracking of Aβ aggregationkinetics. The probe binds Aβ fibrils (Aβf) with high affinity(<em>K</em>_d = 41 nM), exhibits a low detectionlimit (68 nM), and displays exceptional selectivity over off-targetspecies. <strong>TZ-48</strong> crosses the blood–brain barrier(BBB) and enables dual-mode confocal and fluorescence lifetime imaging(FLIM) in AD mouse brains, allowing early visualization and stagingof Aβ burden. It also permits quantitative detection of Aβin serum, distinguishing AD from healthy mice. These findings underscorethe potential of <strong>TZ-48</strong> as a versatile multimodal probefor disease assessment across tissues and biofluids. To translatethis molecular capability into an accessible diagnostic format, wedeveloped <strong>ADxFluor</strong>, a smartphone-enabled platform thatleverages the fluorescence response of the probe for rapid, accurate,and user-friendly assessment of serum Aβ load. Overall, <strong>TZ-48</strong> and <strong>ADxFluor</strong> establish a fluorescence lifetimeand smartphone-enabled diagnostic platform for Aβ detectionand staging, offering a powerful and accessible approach to advanceAD diagnosis, prognosis, and therapeutic development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 15","pages":"3000–3012"},"PeriodicalIF":4.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148274979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of VU6081679, a Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 8 with Efficacy in a Preclinical Model of Parkinson’s Disease","authors":"Alexa E. Richardson,&nbsp;Anthony S. Ferranti,&nbsp;Li Peng,&nbsp;Xia Lei,&nbsp;Allie Han,&nbsp;Aidong Qi,&nbsp;Alice L. Rodriguez,&nbsp;Sichen Chang,&nbsp;Snehal Sant,&nbsp;Irene Zagol-Ikapitte,&nbsp;Srinivasan Krishnan,&nbsp;Analisa Thompson Gray,&nbsp;Joshua C. Wilkinson,&nbsp;Sri H. Kethanapalli,&nbsp;Hyekyung P. Cho,&nbsp;Kayla J. Temple,&nbsp;Dehui Mi,&nbsp;Emily L. Days,&nbsp;Joshua A. Bauer,&nbsp;N. Kithmini Wijesiri,&nbsp;Benjamin P. Brown,&nbsp;Olivier Boutaud,&nbsp;Carrie K. Jones,&nbsp;Darren W. Engers,&nbsp;Craig W. Lindsley,&nbsp;Colleen M. Niswender,&nbsp;Katherine E. Crocker","doi":"10.1021/acschemneuro.6c00364","DOIUrl":"10.1021/acschemneuro.6c00364","url":null,"abstract":"<p>Herein, we report a potent, CNS penetrant, orally bioavailablemetabotropic glutamate receptor subtype 8 (mGlu₈) positiveallosteric modulator (PAM), VU6081679, that shows robust efficacyin a rodent model of Parkinson’s disease. A high-throughputscreening effort and subsequent structure–activity relationshipstudy led to the discovery of VU6081679, an mGlu₈-preferringPAM with good potency at rat, mouse, and human mGlu₈. Moleculardocking into a published cryo-EM structure supports binding in anallosteric pocket at the extracellular TM6/TM7 dimer interface. VU6081679displays a favorable rodent DMPK profile and demonstrates robust efficacyin a haloperidol-induced catalepsy model of Parkinson’s diseasein both rats and mice. Additional studies conducted in mGlu₈ knockout mice confirmed that the observed efficacy is mGlu₈-mediated.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 15","pages":"3023–3034"},"PeriodicalIF":4.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer’s Disease: A Review of Molecular Mechanisms and Interventions Targeting Aβ-Binding Receptors","authors":"Mengke Jia,&nbsp;Jinfei Mei,&nbsp;Yvning Guan,&nbsp;Zhi Wang,&nbsp;Hongqi Ai","doi":"10.1021/acschemneuro.6c00207","DOIUrl":"10.1021/acschemneuro.6c00207","url":null,"abstract":"<p>In the pathogenesis of Alzheimer’sdisease (AD), the aggregationof Aβ peptides into Aβ oligomers (AβOs) plays acritical neurotoxic role. By binding to various cell membrane receptors,AβOs can trigger abnormal intracellular signaling transduction,leading to neuronal damage. This article systematically summarizesthe interaction mechanisms of nearly ten AβO-binding receptorsand focuses on reviewing recent therapeutic strategies aimed at neuroprotectionthrough interventions in AβO–receptor interactions orby blocking/modulating relevant receptor signaling pathways. The discussedcontent provides a molecular theoretical foundation and research perspectivesfor the rational design of anti-AD drugs targeting AβO receptors.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 15","pages":"2823–2842"},"PeriodicalIF":4.5,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide-Based Delivery Systems: Selected Insights into Cell-Penetrating Peptides","authors":"Hussan Adam,&nbsp;Sara Abdollahi and Othman Al Musaimi*,&nbsp;","doi":"10.1021/acschemneuro.6c00266","DOIUrl":"10.1021/acschemneuro.6c00266","url":null,"abstract":"<p >The blood–brain barrier (BBB) is a highly selective biological interface that regulates molecular transport between the bloodstream and the central nervous system (CNS). Its primary function is to protect the brain from harmful substances while maintaining neural homeostasis. This regulatory capacity is attributed to its complex, multilayered structure, comprising nonfenestrated endothelial cells, astrocytic end-feet, pericytes, specialized transporters, and efflux pumps, along with dynamic mechanisms that adapt to physiological changes. Despite its essential protective role, the BBB presents a significant obstacle to the delivery of therapeutics targeting CNS disorders, limiting the ability of many drugs to reach their intended sites of action. Numerous invasive and noninvasive strategies have been explored to enhance CNS drug delivery; however, many are hindered by limitations such as low efficacy, poor specificity, and immunogenicity. Peptides, as endogenous short chains of amino acids, offer a promising alternative due to their high biocompatibility, ease of synthesis, and structural versatility. Their cationic charge facilitates interactions with negatively charged proteoglycans on cell surfaces, while their amphiphilic nature enhances membrane permeability, enabling efficient cellular uptake and translocation. These properties make peptide-based vectors particularly suitable for transporting diverse therapeutic cargoes across biological barriers. This review discusses the structural characteristics, origins, and classifications of peptide vectors, as well as the mechanisms underlying their cellular internalization. It further evaluates their advantages and current limitations in clinical applications, and highlights emerging strategies aimed at optimizing peptide-mediated delivery across the BBB.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 14","pages":"2560–2576"},"PeriodicalIF":4.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00266","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of Raphe Nuclei in Depressive-like Behaviors and Short-Term Memory in an Animal Model of Parkinson’s Disease","authors":"Daniele C. Ramos,&nbsp;Jeane C. F. Vieira,&nbsp;Leonardo C. Souza,&nbsp;Mariza Bortolanza,&nbsp;Elaine Del Bel,&nbsp;Roberto Andreatini and Maria A. B. F. Vital*,&nbsp;","doi":"10.1021/acschemneuro.5c00987","DOIUrl":"10.1021/acschemneuro.5c00987","url":null,"abstract":"<p >Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms and nonmotor disturbances such as fatigue, cognitive impairment, constipation, anxiety, and depression. The dopaminergic neurodegeneration is a hallmark of PD; however, the serotonergic system also presents alterations. Dorsal raphe nucleus (DRN) and median raphe nucleus (MNR) neurons are responsible for the central biosynthesis of serotonin (5-HT). We aimed to investigate whether the rotenone model would affect serotonergic neurons of the DRN and MRN and reduce 5-HT levels in target structures related to depressive-like behavior and short-term memory. Adult male Wistar rats were treated for 10 days with rotenone or sunflower oil. One day after the last rotenone injection, animals exhibited hypolocomotion in the open field. Furthermore, rotenone impaired the short-term memory assessed in the social recognition test performed 22 days after the last injection. In the forced swim test, performed on day 28, we observed depressive-like behavior, indicated by an increase in immobility time in the rotenone group. Immunohistochemical analysis revealed a reduction of serotonergic neurons in the MRN on the 28th day after the last administration of rotenone. Moreover, the ventrolateral part of DRN presented a decrease of serotonergic neurons. Neurochemical quantification revealed a reduction of serotonin levels in the prefrontal cortex and striatum, and a reduction of dopamine and noradrenaline levels in the prefrontal cortex, striatum, and amygdala. Overall, the results revealed that the development of behavioral impairments induced by systemic rotenone is involved with MRN, and likewise 5-HT, other neurotransmitters such as dopamine and noradrenaline may play a role in nonmotor disorders in the animal model of PD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 14","pages":"2628–2640"},"PeriodicalIF":4.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.5c00987","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Cu2+ and Zn2+ Ions’ Nonbonded Interactions on the Aggregation of β-Amyloid 1–16 and 25–35 Fragments─A Molecular Dynamics Simulation Study","authors":"Rayla Kelly Magalhães Costa,&nbsp;Felipe Rodrigues Souza,&nbsp;Rudielson dos Santos Silva,&nbsp;Nicolás A. Rey and Andre Silva Pimentel*,&nbsp;","doi":"10.1021/acschemneuro.6c00057","DOIUrl":"10.1021/acschemneuro.6c00057","url":null,"abstract":"<p >Alzheimer’s disease is linked to the formation and accumulation of extracellular β-amyloid aggregates, with toxicity primarily attributed to soluble oligomeric species, as proposed by the oligomeric hypothesis. Concurrently, the metal ion hypothesis suggests that transition metal ions, such as Cu²⁺ and Zn²⁺, directly modulate the aggregation process and the structural stability of β-amyloid (Aβ) fragments. In this study, molecular dynamics simulations were employed to produce collective variables to investigate the effects of these ions and their concentrations on the aggregation of the β-amyloid 1–16 and 25–35 fragments in aqueous solution for the first time. The free energy profile of aggregation indicates that the presence of Cu²⁺ ions slightly decreases the energy associated with the aggregation of the β-amyloid 1–16 fragment, suggesting it acts as a modulator that partially stabilizes the oligomers. In contrast, we report for the first time that Zn²⁺ ions do not reduce the energy barrier for the aggregation of the β-amyloid 1–16 fragment in aqueous solution. Zn²⁺ displays a higher affinity for the acidic residues of Aβ_1–16, establishing more frequent, yet less selective, contacts compared to those observed for Cu²⁺ ions. The main finding is that Cu²⁺ and Zn²⁺ ions modulate the early aggregation pathway of β-amyloid. In particular, at high concentrations, Cu²⁺ favors the formation of small, structurally ordered proto-oligomers enriched in antiparallel β-sheets, rather than simply increasing aggregate size, whereas Zn²⁺ does not exhibit an analogous effect under the conditions studied. This metal-induced stabilization of β-sheet-rich low-order oligomers, particularly pronounced for Cu²⁺, identifies early secondary structure transitions as the primary determinant of amyloid toxicity and a critical molecular event in Alzheimer’s disease. The evidence presented in this study enhances our understanding of the oligomeric and metal ion hypotheses of Alzheimer’s disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 14","pages":"2603–2619"},"PeriodicalIF":4.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of VU6066098: A Selective and CNS-Penetrant mGlu2 NAM with Robust Antidepressant-, Antipsychotic-, and Procognitive-like Activity in Rodents","authors":"Jeremy S. Coleman*,&nbsp;Rory A. Capstick,&nbsp;Sichen Chang,&nbsp;Derek J. Rios,&nbsp;Michael Bubser,&nbsp;Analisa D. Thompson Gray,&nbsp;Irene Zagol-Ikapitte,&nbsp;Srinivasan Krishnan,&nbsp;Hyekyung P. Cho,&nbsp;Alice L. Rodriguez,&nbsp;Colleen M. Niswender,&nbsp;Olivier Boutaud,&nbsp;Georgina Perez Garcia,&nbsp;Gregory A. Elder,&nbsp;Darren W. Engers,&nbsp;Carrie K. Jones* and Craig W. Lindsley*,&nbsp;","doi":"10.1021/acschemneuro.6c00324","DOIUrl":"10.1021/acschemneuro.6c00324","url":null,"abstract":"<p >Herein, we report the discovery and development of an optimized mGlu₂ Negative Allosteric Modulator (NAM) <i>in vivo</i> tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu₂ NAM with excellent rat PK (CL_p = 23.9 mL/min/kg, <i>t</i>_1/2 = 2.2 h, %F = 100, K_p = 1.28, K_p,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu₂ inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu₂ NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer’s disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu₂ NAMs for future clinical development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 14","pages":"2730–2738"},"PeriodicalIF":4.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.6c00324","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}