ACS Chemical Neuroscience最新文献

{"title":"Quantitative Imaging of ATM: PET and Autoradiography Studies Using [¹¹C]AZD1390.","authors":"Ramya Tokala, Chi-Hyeon Yoo, Joseph W Downey, Breanna L Varela, Hsiao-Ying Wey, So Jeong Lee, Jacob M Hooker","doi":"10.1021/acschemneuro.5c00581","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00581","url":null,"abstract":"<p><p>Ataxia-telangiectasia mutated (ATM) kinase plays a crucial role in DNA damage response and has emerged as a promising therapeutic target. AZD1390, an ATM kinase inhibitor developed by AstraZeneca, is currently in phase I clinical trials as a combination therapy with radiation for glioblastoma. Additionally, AZD1390 has been radiolabeled with carbon-11, and its brain penetrability was previously reported. In this study, we investigated <i>in vivo</i> brain uptake and specific binding of [¹¹C]AZD1390 using PET imaging in nonhuman primates (NHP). To assess radiotracer saturability, an <i>in vivo</i> self-competition study was conducted, revealing an unexpected increase in radiotracer uptake after pretreatment with nonradioactive AZD1390, suggesting the involvement of potential efflux mechanisms. Further, <i>in vitro</i> autoradiography studies using competitive and saturation binding using nonhuman primate brain (cortical regions) confirmed the concentration-dependent displaceable and saturable binding of [¹¹C]AZD1390. The binding parameters [<i>K</i>_d (0.23 nM), <i>K_i</i> (0.58 nM), and <i>B</i>_max (267.0 fmol/mg tissue)] demonstrate the high affinity of [¹¹C]AZD1390 and imply that ATM is present at levels (<i>B</i>_max) sufficient for reliable quantification in the brain. While AZD1390 may not be ideal for accurately measuring ATM concentrations due to saturable efflux or other dose nonlinearity mechanisms, these findings support the overall feasibility of quantifying ATM in vivo using PET imaging.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147118","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":"Histidine Focused Covalent Inhibitors Targeting Acetylcholinesterase: A Computational Pipeline for Multisite Therapeutic Discovery in Alzheimer's Disease.","authors":"Sadia Jaman, Salsabil Fatima Tasmi, Imrul Shahriar, Mohammad A Halim","doi":"10.1021/acschemneuro.5c00508","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00508","url":null,"abstract":"<p><p>Alzheimer's disease affects over 10% of individuals above the age of 65, yet current treatments offer only limited and temporary relief. Acetylcholinesterase, a key enzyme in neurotransmitter breakdown, also contributes to disease progression by promoting β-amyloid aggregation. While previous studies have focused on the catalytic serine, a key proton transfer residue, His447 remains unexplored as a potential covalent binding site. In this study, we aim to interrupt the activation of Ser203 by covalently modifying His447, thereby shutting down the entire catalytic process. Here, we reported a computational pipeline to identify epoxide-based small molecules that covalently engage His447 and modulate AChE activity. From a curated library of >7,000 epoxides, three ligands (L5, L6, L7) were selected via covalent docking, molecular dynamics simulations, and drug-likeness profiling. Microsecond-scale simulations revealed stable binding across multiple subsites, with L5 exhibiting the most consistent RMSD and compact <i>R</i>_g values. Covalent engagement of L5 and L6 induced modest shifts in His447 (2.48 and 1.43 Å), whereas L7 maintained apo-like geometry. Furthermore, ADMET predictions indicated favorable profiles, with no cardiotoxicity risk. Our findings highlight His447 as a novel covalent target in AChE and support further in vivo investigation of the specificity and inhibitory mechanisms of these ligands.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135962","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":"Deubiquitinating Enzyme UCH-L1 Regulates Neuronal Ca²⁺ Signaling.","authors":"Marie Perrier, Desirée Loreth, Johannes Brand, Laurence Aubry, Timothy Harrison, Xavier Jacq, Edward W Tate, Gian-Marvin Kipka, Malte Gersch, Catherine Meyer-Schwesinger, Marie-Odile Fauvarque, Alexandre Bouron","doi":"10.1021/acschemneuro.5c00510","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00510","url":null,"abstract":"<p><p>Ubiquitination influences a myriad of biological processes, such as the trafficking or degradation of ubiquitin-tagged target proteins. This posttranslational modification can be reversed by deubiquitinating enzymes (DUBs) that counterbalance the action of E3 ubiquitin ligases. We investigated the impact of PR-619, a membrane-permeable and broad-spectrum DUB inhibitor, on the entry of Ca²⁺ through native voltage-gated Ca²⁺ channels (VGCCs) of cultured embryonic cortical neurons. Fura-2-based Ca²⁺ imaging experiments showed that PR-619 reduced the cytosolic Ca²⁺ rises induced by depolarization by affecting mainly dihydropyridine-sensitive (L-type) VGCCs. This inhibition was sensitive to dynamin inhibitor Myr-Dip and lysosomal agents chloroquine and bafilomycin-A. PR-619 also reduced the amount of Ca_v1.2 proteins. A pharmacological approach was set out to better delineate the identity of the DUB responsible for this inhibitory action of PR-619. Since UCH-L1 and USP19 are two highly expressed neuronal DUBs, we investigated the effects of selective UCH-L1 (IMP1710, GK13S) and USP19 (ADC141) inhibitors. IMP1710 and GK13S depressed the Ca²⁺ uptake through L-type VGCCs, whereas ADC141 and the UCH-L3 inhibitor TCID had no effects. In addition, UCH-L1 inhibition impaired the neuronal Ca²⁺ storage capacities of neurons and reduced the Ca_v1.2 protein levels. Thus, UCH-L1 influences the neuronal uptake and storage of Ca²⁺, which is likely to have important physiological implications. Altogether, these results posit UCH-L1, the main DUB of the brain, as an important regulator of neuronal Ca²⁺ homeostasis and add to our understanding of its cellular functions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129581","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":"Exogenous Huntingtin-Exon1 Aggregates Exhibit Distinct Levels of Toxicity to <i>Caenorhabditis elegans</i>.","authors":"Ephraim Ezeigbo, Kaitlyn Keith, Zachary L Ellis, Korina Pebley, Tyler Girman, Anjola Adewoye, Alyssa R Stonebraker, Pritom Kumar Biswas, Justin Legleiter","doi":"10.1021/acschemneuro.5c00513","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00513","url":null,"abstract":"<p><p>Many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD), are associated with proteinaceous deposits in the brain comprising amyloid. The aggregation process leading to these deposits proceeds through a variety of intermediates, i.e., oligomers and fibrils. The heterogeneity of aggregates produced complicates the assignment of specific toxic functions to distinct aggregate species. Here, a simple centrifugation strategy was employed to produce well-characterized and relatively homogeneous populations of huntingtin (htt) aggregates <i>in vitro.</i> After characterization of the resulting aggregate populations, <i>C. elegans</i> were exogenously exposed to these different aggregates species to assess their impact on worm viability. Htt oligomers were identified as the most acutely toxic aggregate form. Nonaggregated htt and fibrils did not significantly reduce <i>C. elegans</i> viability. A variety of methods to manipulate htt oligomers were then tested to demonstrate the ability to modify oligomer toxicity in this model system. Chemically cross-linking htt oligomers reduced their toxicity, suggesting that structural flexibility is important in oligomer toxicity. Stabilizing oligomers with truncated peptides based on the first 17 N-terminal amino acids (Nt17) impacted toxicity when specific acetylation-mimicking point mutations were introduced. Nt17-derived peptides without any mutations did not alter toxicity; however, the addition of acetylation-mimicking mutations toward the C-terminus of the peptide reduces toxicity. Finally, two small molecules that modify htt aggregation, EGCG and riluzole, were tested for their impact on oligomer toxicity. In general, this approach provides a simple method to investigate and manipulate the toxicity of aggregate subpopulation in a quasi-controlled manner.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123801","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":"Molecular Simulation-Based Insights into the Pharmacological Role of Silk Fibroin in Peripheral Nerve Repair.","authors":"Nasser Alotaiq, Samir Chtita, Doni Dermawan","doi":"10.1021/acschemneuro.5c00375","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00375","url":null,"abstract":"<p><p>Peripheral nerve injury (PNI) remains a significant clinical challenge, often leading to impaired nerve regeneration and chronic neuropathic pain. Can Si (Silk Fibroin), a key component of traditional Chinese medicine (TCM), has long been recognized for its regenerative properties, yet its molecular mechanisms in PNI treatment remain unexplored. To elucidate the pharmacological actions of Silk Fibroin, an integrative molecular simulation approach was applied. Network pharmacology was employed to identify the most favorable target receptor for PNI, leading to the selection of the glucocorticoid receptor (GR) due to its critical role in inflammation and nerve repair. Molecular docking simulations evaluated the binding affinities of chemical and protein-based compounds from Silk Fibroin to GR, followed by molecular dynamics (MD) simulations to confirm the stability of these interactions under physiological conditions. Pharmacophore modeling identified key structural features essential for bioactivity, while in silico toxicity assessments evaluated the safety profiles of the compounds. Key bioactive compounds from Silk Fibroin, including Catechin, Hesperetin, and Menaquinone-7, demonstrated strong interactions with GR, with MM/PBSA-based binding free energy values of -35.98 -33.65, and -32.13 kcal/mol, respectively. Protein-based compounds, such as Bombyxin A-5 (-228.06 kcal/mol) and small ribosomal subunit protein uS11 (-204.98 kcal/mol), also displayed promising binding affinities, suggesting potential neuroprotective roles. In silico toxicity assessments revealed favorable safety profiles for most of the compounds. This study highlights Silk Fibroin as a promising source of therapeutic agents for PNI. Future studies should focus on the experimental validation of these computational findings through in vitro and in vivo models.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123822","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":"Multi-Target-Directed Triazole Derivatives: Design, Synthesis, and Evaluation of Synergistic Modulation in Alzheimer’s Disease","authors":"Anjali Sobha,&nbsp;, ,&nbsp;Lekshmy Krishnan,&nbsp;, ,&nbsp;Sreelakshmi Vijayakumar,&nbsp;, ,&nbsp;Shareef Shaik,&nbsp;, ,&nbsp;Aravinda Pai,&nbsp;, ,&nbsp;Jayamurthy Purushothaman,&nbsp;, and ,&nbsp;Sasidhar B. Somappa*,&nbsp;","doi":"10.1021/acschemneuro.5c00602","DOIUrl":"10.1021/acschemneuro.5c00602","url":null,"abstract":"<p >The multifaceted nature of Alzheimer’s disease (AD) paves the way for the development of multitarget-directed ligands (MTDLs) as potential therapeutic agents. Herein, we report a series of triazole-based ligands that function as MTDLs via a fragment splicing strategy (<b>6a-6ah</b> and <b>8a</b>–<b>8m</b>). The synthesized ligands (<b>6a-6ah</b> and <b>8a-8m</b>) were systematically screened for their neuroinflammatory and MAO-B inhibitory efficacy, among which, the pyrrole-appended triazole derivative <b>6a</b> emerged as the most prominent candidate. Additionally, we analyzed the correlation of the <i>in vitro</i> efficacy with <i>in silico</i> studies and found that both align well. Also, <b>6a</b> exhibited appreciable BBB permeability. Further, the multitargeted efficacy of <b>6a</b> was evaluated via ROS scavenging ability, Aβ-induced neuroprotection, and mitigation of various pathogenic mechanisms, including metal dyshomeostasis, mitochondrial dysfunction, and neurodegeneration. Consequently, our findings established <b>6a</b> as a novel multi-target-directed ligand, highlighting its potential as a modifiable agent for attenuating AD symptoms.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3873–3885"},"PeriodicalIF":3.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111527","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":"The Aggregation Continuum of α-Synuclein and Its Relevance to Brain Aging","authors":"Anika Rana,&nbsp;, ,&nbsp;Tejas Nikam,&nbsp;, ,&nbsp;Bhargavi Sreepathi,&nbsp;, ,&nbsp;Shubhini A. Saraf,&nbsp;, and ,&nbsp;Saurabh Awasthi*,&nbsp;","doi":"10.1021/acschemneuro.5c00356","DOIUrl":"10.1021/acschemneuro.5c00356","url":null,"abstract":"<p >α-Synuclein aggregation in synucleinopathies involves abnormal accumulation of α-synuclein protein in neurons. This aggregation process generates oligomers, protofibrils, and fibrils, disrupting cellular function and contributing to the progression of neurodegeneration observed in Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Typically, these aggregates range in size from tens to hundreds of nanometers to a few micrometers. The intermediate-sized aggregation species, so-called oligomers, have been implicated in the neurotoxicity observed in Parkinson’s disease. Small-sized, soluble oligomers exhibit pore formation in lipid bilayers, impair synaptic transmission, and induce oxidative stress, ultimately leading to neuronal dysfunction. This review explores the size-dependent toxicity of α-synuclein aggregates, focusing on how variations in aggregate size influence their pathological effects in neurodegenerative diseases. It discusses the diverse structural forms of α-synuclein, including monomers, oligomers, protofibrils, and large-sized fibrils, and their differential impact on cellular function and viability. By elucidating the size-dependent mechanisms underlying α-synuclein toxicity, this review aims to inform therapeutic strategies targeting specific aggregate sizes to mitigate neuronal damage and halt Parkinson’s disease progression.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3634–3652"},"PeriodicalIF":3.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090754","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":"Green-Synthesized Silver Nanoparticles with Nigella sativa: A Multifaceted Approach against Parkinson’s Disease in Rats via MicroRNA Modulation","authors":"Salma H. Hassan*,&nbsp;, ,&nbsp;Iman A. Sharaf,&nbsp;, ,&nbsp;Amal Suliman Mohamed,&nbsp;, ,&nbsp;Mohammed Salama,&nbsp;, ,&nbsp;Maher A. Kamel,&nbsp;, and ,&nbsp;Hala A. Hafez,&nbsp;","doi":"10.1021/acschemneuro.5c00496","DOIUrl":"10.1021/acschemneuro.5c00496","url":null,"abstract":"<p >Parkinson’s disease (PD) is a prevalent neurodegenerative disease. As the disease advances, patients become less receptive to levodopa and disease progression continues. So, there is a need for alternative treatment. Green synthesis of silver nanoparticles using <i>Nigella sativa</i> (NS-AgNPs) gives AgNPs additional pharmacological properties. We aimed to explore the possible therapeutic and/or protective effects of NS-AgNPs on PD-like model rats at different levels: histological, behavioral, α-synuclein (α-syn) aggregation, redox, neurotransmitters, apoptosis, and microRNAs (miR-34c and miR-124). The PD-like model was induced in rats by subcutaneous injection of rotenone (2 mg/kg) daily for 30 days. Then, PD-like rats were divided into the Nanotreated group, receiving NS-AgNPs (orally, 10 mg/kg daily for 30 days); Sinemet-treated group, receiving Sinemet 25 mg/250 mg (orally 10 mg/kg daily for 30 days); and Nanoprotected group, receiving rotenone and NS-AgNPs (10 mg/kg daily for 30 days) simultaneously. The PD-like rats disturbed the striatal histoarchitecture, increased α-syn content, oxidative stress, inflammation, and apoptosis, and decreased neurotransmission and microRNAs (miRs) levels. The Sinemet-treated group showed moderate histoarchitectural improvement and partially enhanced behavioral performance, neurotransmission, inflammation, and oxidative stress. In contrast, the NS-AgNPs ameliorated these effects and targeted multiple key pathways in the development and progression of PD, mainly through the modulation of miR-34a and miR-124 expression and significant elevation in dopamine content. It also decreased α-syn aggregation, inhibited microglial activation and apoptosis, decreased oxidative stress levels, and upregulated vesicular monoamine transporter 2 (VMAT2). This goes accordingly with the histopathological examination of the striatum and improvement in the behavioral performance of the PD-like rats. All of these effects, together with no adverse effects of NS-AgNPs, make it a promising therapeutic and neuroprotective agent for PD management.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3801–3815"},"PeriodicalIF":3.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084507","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":"Intraventricular Creatine Treatment Attenuates Alzheimer’s Disease-Related Neuropathological Changes and Memory Impairment via Inhibiting STAT1 Phosphorylation","authors":"Xiangqi Shao,&nbsp;, ,&nbsp;Jianru Sun,&nbsp;, ,&nbsp;Xue Wang,&nbsp;, ,&nbsp;Xiang-Sha Yin,&nbsp;, ,&nbsp;Zhen Chen,&nbsp;, ,&nbsp;Yuanyuan Xu,&nbsp;, ,&nbsp;Tao Wang,&nbsp;, ,&nbsp;Bo Yuan,&nbsp;, ,&nbsp;Wenying Qiu,&nbsp;, ,&nbsp;Fan Liu*,&nbsp;, ,&nbsp;Yongmei Chen*,&nbsp;, and ,&nbsp;Chao Ma*,&nbsp;","doi":"10.1021/acschemneuro.5c00475","DOIUrl":"10.1021/acschemneuro.5c00475","url":null,"abstract":"<p >The importance of neuroinflammation in Alzheimer’s disease (AD) has attracted increasing attention, and the functions of the STAT1 signaling pathway have also generated widespread interest. However, the role of STAT1 in AD-related neuroinflammation and memory impairment is unclear. Therefore, this study was undertaken to elucidate the roles of the STAT1 signaling pathway in the brain tissue of AD patients and mouse of an AD model. Our results revealed that STAT1 phosphorylation was largely colocalized with the neuronal marker NeuN. Compared with that in control (non-AD) brain tissues, STAT1 phosphorylation was significantly upregulated in the brain cortex and hippocampus of both AD patients and FAD mice. Intraventricular injection of creatine (STAT1 signaling inhibitor) significantly reduced the level of neuronal STAT1 phosphorylation in the brain cortex and markedly alleviated cognitive impairment in FAD mice. Furthermore, intraventricular creatine treatment also reduced the number of Aβ plaques and the level of IBA1 expression in IBA1-positive microglia in FAD mice. These findings indicate that STAT1 phosphorylation may play an important role in AD-related neuroinflammation and memory impairment. The alleviation effects of intraventricular creatine in FAD mice may suggest that STAT1 is a potential therapeutic target for the treatment of AD in humans.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3790–3800"},"PeriodicalIF":3.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084526","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":"Tritium-Labeled Compounds in PET Tracer Discovery? A Case Study from Roche’s Internal Monoacylglycerol Lipase Program","authors":"Martin R. Edelmann*,&nbsp;, ,&nbsp;Luca C. Gobbi*,&nbsp;, ,&nbsp;Svenja Schmalzbauer,&nbsp;, ,&nbsp;Jennifer Beck,&nbsp;, ,&nbsp;Mathias C. Müller,&nbsp;, ,&nbsp;Jean-Christophe Hau,&nbsp;, ,&nbsp;Sylwia Huber,&nbsp;, ,&nbsp;Achi Haider,&nbsp;, ,&nbsp;Matthias B. Wittwer,&nbsp;, ,&nbsp;Anto Pavlovic,&nbsp;, ,&nbsp;Ludovic Collin,&nbsp;, ,&nbsp;Dominik Heer,&nbsp;, ,&nbsp;Andreas Topp,&nbsp;, ,&nbsp;Lea Leibrock-Thielen,&nbsp;, ,&nbsp;Jörg Benz,&nbsp;, ,&nbsp;Manuel Hilbert,&nbsp;, ,&nbsp;Michael Honer,&nbsp;, and ,&nbsp;Uwe Grether,&nbsp;","doi":"10.1021/acschemneuro.5c00531","DOIUrl":"10.1021/acschemneuro.5c00531","url":null,"abstract":"<p >The discovery and development of PET tracers is a complex and costly process requiring direct access to ¹¹C or ¹⁸F, radiochemistry infrastructure, as well as an imaging facility equipped with PET tomographs. In the absence of access to a fully equipped PET center facility, a valid alternative for the selection of promising PET tracer candidates is the use of tritium as a surrogate radioisotope in the early stages of development. Tritium-labeled compounds enable detailed binding or displacement assays on tissues and <i>ex vivo</i> radioligand performance assessments, such as rodent experiments, while offering unique advantages including a long half-life and superior spatial resolution. Furthermore, the radiation safety requirements for handling tritium-labeled compounds are less stringent compared with those needed for working with short-lived PET nuclides, such as ¹¹C or ¹⁸F, due to the lower energy emissions of tritium. Candidates are selected based on critical attributes, including low half-maximal inhibitory concentration (IC₅₀), brain penetration, and binding to target proteins, ensuring optimal properties for PET imaging. This approach minimizes reliance on a specialized infrastructure while accelerating the identification and optimization of radioligand candidates. As an example, to illustrate this workflow using tritiated compounds, an internal program targeting monoacylglycerol lipase (MAGL) in the CNS is presented. From a pool of 617 in-house MAGL inhibitors, five compounds were selected for tritium labeling and evaluated alongside literature-reported PET tracers. Among the newly synthesized ligands, compound <b>9</b> demonstrated a favorable pharmacological profile, while autoradiography experiments highlighted superior properties in the chemotype of T-401, originating from the literature. This study reports on the synthesis and characterization of tritium-labeled MAGL ligands as critical steps in PET tracer development. Promising candidates identified in this workflow will subsequently be handed over to PET centers for further evaluation in imaging applications, bridging preclinical research with clinical translation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 19","pages":"3834–3850"},"PeriodicalIF":3.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084490","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}