RSC medicinal chemistry最新文献

{"title":"Pan-cancer analysis reveals DNAJC9 as an immune-related biomarker and a positive regulator of the PI3K/AKT signaling pathway.","authors":"Zihao Li, Yiwen Wu, Jiayi Li, Meizhu Chen, Honghua Liang, Lingyun He, Liang Han, Jianbin Cao","doi":"10.1039/d6md00532b","DOIUrl":"https://doi.org/10.1039/d6md00532b","url":null,"abstract":"<p><p><i>Background</i>: Heat shock proteins (HSPs) modulate apoptosis, proliferation, and differentiation, positioning them as potential therapeutic targets in cancer. As a member of the J-domain-containing HSP40 family, DnaJ homolog, subfamily C, member 9 (DNAJC9) has not yet been systematically investigated in a pan-cancer context. <i>Method</i>: Multiple public repositories were employed to perform a comprehensive pan-cancer investigation of DNAJC9. We also utilized single-cell datasets to explore how DNAJC9 expression varies across distinct cellular clusters. These efforts covered several key dimensions, including diagnostic and prognostic value, immune landscape, genomic alterations, methylation differences, and pathway enrichment. To determine its biological effects, DNAJC9 was silenced in lung cancer cell lines, and subsequent experiments assessed cellular phenotypes. The downstream PI3K/AKT signaling cascade was examined <i>via</i> western blotting. <i>Results</i>: Across multiple tumor types, DNAJC9 was markedly upregulated, especially in advanced-stage cases, and higher expression levels predicted worse prognosis. DNAJC9 expression also correlated significantly with immune infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). Tumor tissues showed substantially lower DNAJC9 methylation than normal tissues. Single-cell analysis detected DNAJC9 expression in multiple immune cell subsets. Knockdown of DNAJC9 in A549 and H1299 lung cancer cells impaired proliferation, migration, and invasion. Functional enrichment analysis then pointed to the PI3K/AKT signaling pathway. Western blotting further confirmed that silencing DNAJC9 reversed the activated PI3K/AKT cascade in these cells, as shown by decreased p-PI3K/PI3K and p-AKT/AKT ratios. <i>Conclusions</i>: Pan-cancer analyses suggest that DNAJC9 may serve as a diagnostic and prognostic biomarker across cancers. Importantly, its role as an upstream PI3K/AKT activator and its functional validation in lung cancer support DNAJC9 as a potential target for anti-cancer drug discovery in this malignancy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimercaptosuccinic acid (DMSA) mono-esters and amides: synthesis and application in treating metal induced drug resistance in lung cancer.","authors":"Carissa M Lloyd, Hannah L Richards, Katherine E V Deck, Toby Blundell, Natalie Pridmore, Michael Stalhamer, Dan Gelvan, Patricia A J Muller, William D G Brittain","doi":"10.1039/d6md00614k","DOIUrl":"https://doi.org/10.1039/d6md00614k","url":null,"abstract":"<p><p>Dimercaptosuccinic acid (DMSA) mono-esters have been shown to be powerful chelators that are capable of heavy metal removal across a variety of biological applications. Whilst the utility of this class of chelator is widely reported in acute heavy metal poisoning the ability to access a wide variety of derivatives has been a synthetic challenge often relying on the use of statistical mixtures governed by stoichiometry. In this report we detail a robust four-step synthetic route starting from commercially available acetylenedicarboxylic acid that can generate both dimercaptosuccinic acid mono-esters and mono-amides. These compounds were tested for their ability to resensitize transition metal-induced chemotherapy resistance in lung cancer cells. Similarly to previous studies focused on a single dimercaptosuccinic ester (MiADMSA) many of the analogues generated were able to cause resensitisation toward doxorubicin significantly decreasing its IC₅₀ value. This report demonstrates that the enhanced synthetic route for generating DMSA derivatives allows rapid access to novel chelators that are equally or more effective than prior compounds in restoring chemosenstivity. In addition, the modular nature of the route allows for simple substitution of building blocks allowing chemical space to be rapidly assessed.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Click-engineered codeine derivatives: modulating pharmacological activity <i>via</i> 1,2,3-triazole tethering.","authors":"Saman Gharehnaghadeh, Peyman Salehi, Morteza Bararjanian, Łukasz Pecio, Atefeh Hajiagha Bozorgi, Amir Baghaei, Marziyeh Amiri-Andebili, Mohammad Mohajeri","doi":"10.1039/d6md00525j","DOIUrl":"https://doi.org/10.1039/d6md00525j","url":null,"abstract":"<p><p>The structural modification of morphinan alkaloids remains a vital strategy for developing therapeutics with optimized efficacy and reduced side effects. Herein, we report the rational design and synthesis of a novel library of seventeen 1,4-disubstituted 1,2,3-triazole-tethered codeine derivatives (13a-13q). Utilizing a highly efficient copper-catalyzed alkyne-azide cycloaddition (CuAAC) strategy, these structurally diverse derivatives were synthesized in good to excellent yields (66-86%) under mild, room-temperature conditions within exceptionally short reaction times (12-23 min). The therapeutic potential of the library was evaluated <i>in vivo</i> using formalin-induced paw edema and acute tail-flick models to determine peripheral anti-inflammatory and central antinociceptive profiles, respectively. The resulting pharmacological profiles demonstrate that the electronic and steric properties of the triazole substituents heavily dictate therapeutic outcomes. Central antinociceptive efficacy was favored by electron density, with the 3,4-dimethoxy phenyl derivative 13j (7.03 ± 1.53) significantly outperforming both standard sodium diclofenac and the parent codeine scaffold. Conversely, peripheral anti-inflammatory activity was optimized by specific halogenated and aliphatic architectures, with derivatives 13l, 13e, and 13n exhibiting the most pronounced edema mitigation, while the allyloxy-containing derivative 13q induced a significant pro-inflammatory response. These findings establish triazole tethering at the codeine hydroxyl group as a promising scaffold for the development of dual-action anti-inflammatory and antinociceptive agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First demonstration of benzosultam CRBN ligand-mediated PROTACs for BTK and BRD4 degradation.","authors":"Hoyeong Park, Moonjung Jeun, Ji U Choi, Yeayoung Bang, Chi Hoon Park, Pilho Kim","doi":"10.1039/d6md00815a","DOIUrl":"https://doi.org/10.1039/d6md00815a","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) represent a promising therapeutic approach for degrading disease-relevant proteins through the ubiquitin-proteasome system. Among the various E3 ligases employed, cereblon (CRBN) has been the most widely used in PROTAC preparation. However, currently available CRBN ligands often lack sufficient selectivity, as they can trigger off-target protein degradation, such as Sal-like protein 4 (SALL4), which is implicated in teratogenic toxicities. In this study, benzosultam-based CRBN ligands were utilized to prepare PROTACs targeting BRD4 and BTK. Among the PROTACs synthesized, 10a induced efficient degradation of BRD4, while 14a effectively degraded BTK in TMD-8 cells, showing superior or comparable potency to the known compounds ARV-825 and MT-802, respectively. Furthermore, targeted protein degradation translated into potent anti-proliferative activities in TMD-8 cells, with 10a exhibiting robust cell growth inhibition. In contrast to ARV-825 and MT-802, 10a and 14a showed negligible SALL4 degradation, suggesting a favorable off-target safety profile of benzosultam CRBN ligands. These findings underscore the potential of the benzosultam scaffold as a promising and selective alternative for CRBN-mediated targeted protein degradation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13678588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-targeting theranostic strategies to overcome receptor heterogeneity in neuroendocrine prostate cancer.","authors":"Satyam Dewangan, Boga Vijay Kumar, Niranjan Meher","doi":"10.1039/d6md00655h","DOIUrl":"https://doi.org/10.1039/d6md00655h","url":null,"abstract":"<p><p>Prostate cancer (PC) is a highly heterogeneous malignancy characterized by dynamic alterations in surface biomarker expression during disease progression. Although prostate-specific membrane antigen (PSMA) remains the most clinically established target for PC imaging and therapy, receptor heterogeneity remains a major obstacle in advanced, treatment-resistant, and neuroendocrine prostate cancer (NEPC). These limitations have driven increasing interest in dual-targeting strategies to improve tumor coverage and therapeutic precision. Neurotensin receptor 1 (NTSR1) is predominantly expressed in aggressive androgen-independent and neuroendocrine tumors, whereas gastrin-releasing peptide receptor (GRPR) is highly expressed in early-stage and low-Gleason-score prostate cancer. The complementary expression profiles of PSMA, GRPR, and NTSR1 provide a strong rationale for developing dual-targeted theranostic platforms capable of overcoming tumor heterogeneity and lineage plasticity of advanced PC. This review discusses the biological significance, signaling pathways, expression dynamics, and recent advances in dual-targeting strategies for imaging and therapy of advanced PC.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benchmarking AI-driven protocols for cyclic peptide conformer prediction and ranking.","authors":"Jovan Damjanovic, Rodrigo Ochoa","doi":"10.1039/d6md00676k","DOIUrl":"https://doi.org/10.1039/d6md00676k","url":null,"abstract":"<p><p>Generative AI is being used in peptide design to optimize binders from early research stages. One notable application is with respect to cyclic peptides, wherein AI assists in modelling conformers in bound or solution states. This work benchmarks state-of-the-art protocols' ability to predict and rank conformers of cyclic peptide binders alone and in complex with their targets, using sequence or all-atom representations. The datasets consist of cyclic peptides with experimental structures available in public repositories. Various tools were included in the benchmark: HighFold, cyclic-aware AlphaFold2 as implemented in EvoBind2, CycPepDock, Boltz-1/1x, Boltz-2, and Chai-1. We found that more recent tools provide a structure prediction advantage over their AlphaFold2-based counterparts, although accurate results with both sets of tools are largely limited to protein-peptide complexes, rather than the free solution structure. In addition, using a cyclic relative positional encoding offset proved key for accurate prediction, and the natural amino acid representation was found to outperform the more general SMILES string input. We mirror prior literature findings on linear peptides by showing that even for accurate predictions, model confidence metrics poorly correlate with experimentally observed binding affinity. Lastly, we compare the performance of AI-based tools to that of physics-based simulations, showing that the latter remain the only way to account for intrinsic conformational flexibility of cyclic peptides, but that the former have a significant price/performance advantage in complex structure prediction. This study provides insights applicable to the design and optimization of cyclic peptides, contributing to advancements in peptide-based therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleanolic acid-derived triterpenoids with dual TGR5 agonistic and RORγ inverse agonistic activity.","authors":"Panagiota Stamou, Alexander F Perhal, Patrik F Schwarz, Jorge Enrique Hernández González, Justin Weal, Ya Chen, Alexios Leandros Skaltsounis, Maria Halabalaki, Johannes Kirchmair, Verena M Dirsch, Ioannis K Kostakis","doi":"10.1039/d6md00471g","DOIUrl":"10.1039/d6md00471g","url":null,"abstract":"<p><p>The Takeda G protein-coupled receptor 5 (TGR5) and the retinoid-related orphan receptor γ (RORγ) are key regulators of metabolic and immune pathways. This makes them attractive targets for developing anti-inflammatory and metabolic therapeutics. In this study, we designed and synthesised a series of oleanolic acid-derived triterpenoid derivatives to explore their potential as dual modulators of these receptors. The focus of the structural modifications was on the double bond, C-3 substitution, and A-ring rearrangements in order to investigate their impact on biological activity and establish structure-activity relationships within the pentacyclic triterpene scaffold. Biological evaluation using CRE-luciferase reporter assays identified oleanolic acid (1), oleanonic acid (5), and compounds 7 and 8 as TGR5 agonists with concentration-dependent activities. Oleanolic acid (1) and the newly identified seco-derivative 8 displayed the most favourable potency and efficacy profiles. Gal4-RORγ reporter assays demonstrated inverse agonistic activity for oleanolic acid (1) and compounds 7 and 8. Although 7 and 8 exhibited lower potency than 1, both retained pronounced inhibitory efficacy, indicating that substantial scaffold rearrangement remains compatible with RORγ modulation. A resazurin conversion assay showed no evidence of cytotoxicity under the conditions tested, supporting that the observed receptor effects were not attributable to general cytotoxicity. Molecular modelling and Nwat-MMGBSA calculations supported the experimental findings and emphasized the role of conserved buried water molecules in stabilising ligand-receptor interactions in both targets. Overall, these findings identify oleanolic acid-derived triterpenoids as promising scaffolds for dual TGR5/RORγ modulation and provide valuable insights for the future development of multitarget-directed ligands targeting inflammatory and metabolic disorders.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149216766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorination of amino-quinones enhances anti-<i>Trypanosoma cruzi</i> activity.","authors":"Zhenhao Zhong, Renata G Almeida, Victor F S Ramos, Andrew J Lacey, Rubem F S Menna-Barreto, Guilherme A M Jardim, Eufrânio N da Silva Júnior, Alastair J J Lennox","doi":"10.1039/d6md00631k","DOIUrl":"https://doi.org/10.1039/d6md00631k","url":null,"abstract":"<p><p>Quinones are well-established antiparasitic agents. Despite the widespread use of fluorine to modulate biological activity and physicochemical properties in drug design, its systematic incorporation into quinoidal frameworks remains underexplored. Here, we report a mild and operationally simple direct electrophilic fluorination of a wide scope of amino-substituted 1,4-naphthoquinones. The fluorinated quinones were evaluated <i>in vitro</i> against <i>Trypanosoma cruzi</i> (<i>T. cruzi</i>), revealing a consistent and pronounced enhancement in trypanocidal activity upon fluorine incorporation compared with their non-fluorinated aminoquinone precursors. Notably, several fluorinated aminoquinone exhibited higher trypanocidal activity than benznidazole, the drug currently used in the clinical treatment of Chagas disease. This work highlights the potential of fluorine to beneficially influence the properties and biological activity of quinoidal systems.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antibacterial profiling of novel pyrimidine-sulfonyl chlorides: a new class of antimicrobials targeting multidrug-resistant bacterial strains.","authors":"Sithabile Mokoena, Babita Kushwaha, Narva Deshwar Kushwaha, Elliasu Yakubu Salifu, Blessing Ike, John Alake, Darko Kwabena Adu, Afsana Kajee, Vishal Kumar, Subhankar P Mandal, Rajshekhar Karpoormath","doi":"10.1039/d5md00860c","DOIUrl":"https://doi.org/10.1039/d5md00860c","url":null,"abstract":"<p><p>Bacteria's ability to resist current antibiotics has grave implications for future treatment options. Herein, we report novel pyrimidine-sulfonyl chloride derivatives as potential antimicrobial agents against multi-drug resistance, synthesised through a molecular hybridisation technique. FTIR, ¹H-NMR and ¹³C-NMR analysis data corroborated the structural confirmation of all synthesised compounds. The compounds were screened against a panel of Gram-positive and Gram-negative bacterial strains, including <i>Mycobacterium tuberculosis</i> strains. Cell permeability assays were also performed for MRSA and <i>S. aureus</i>. Among the tested compounds, 6l and 6m exhibited the most potent antibacterial activity against MRSA with a MIC value of 0.2 μg mL^-1, more potent than both ciprofloxacin (MIC = 3.91 μg mL^-1) and vancomycin (MIC = 0.49 μg mL^-1). Further 6j and 6m also displayed good antibacterial activity against clinically isolated MRSA with MIC values of 0.97 and 7.8 μg mL^-1, respectively. In contrast, compounds 6g and 6q showed the best activity against Gram-negative bacteria <i>E. hormaechei</i> (MIC = 0.97 μg mL^-1), comparable to ciprofloxacin (MIC = 0.2 μg mL^-1). In the antimycobacterial studies, compounds 6a, 6c, 6i, 6k and 6l were more potent (MIC = 3.91 μg mL^-1) against the extensively drug-resistant <i>Mycobacterium tuberculosis</i> (XDR) strain than the standard drugs used and against H37Rv, compounds 6i and 6k exhibited the best potency with a MIC value of 3.91 μg mL^-1. The cell penetration experiment demonstrated that compounds 6h-6m achieved greater than 90% propidium iodide penetration in <i>S. aureus</i> (translating to cell death) at the stated MIC well, whereas less than 80% cell penetration was achieved for methicillin-resistant <i>S. aureus</i>. Computational simulation studies were conducted to validate the biological findings, showing potential binding affinity at the binding site of MurB and FemA enzymes. Thus, pyrimidine-based sulfonyl chloride derivatives exhibited promising anti-microbial and anti-mycobacterial activities.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of dual SST₂/SST₅ targeting radioligands through rational structural design.","authors":"Fabienne Spinnler, Luigi Del Pozzo, Lennart Bohrmann, Sandra Zanger, Nina Kathleen Blum, Monique Brendel, Stefan Schulz, Rosalba Mansi, Melpomeni Fani","doi":"10.1039/d6md00646a","DOIUrl":"https://doi.org/10.1039/d6md00646a","url":null,"abstract":"<p><p>Radioligand therapy targeting somatostatin receptors has emerged as a highly effective treatment strategy for neuroendocrine tumors, with growing evidence indicating that SST₂ antagonists and dual SST₂/SST₅ targeting approaches may further enhance tumor coverage and therapeutic efficacy. In this study, DOTA-NOC, a somatostatin analog with high affinity for SST₂ and SST₅, served as the scaffold for the design of novel ligands incorporating structural features associated with receptor antagonism. The resulting ligands were conjugated to DOTA for ¹⁷⁷Lu radiolabeling and evaluated for receptor affinity, antagonistic potency, and <i>in vivo</i> properties. Among the series, ¹⁷⁷Lu-10 displayed high affinity for both receptor subtypes while acting selectively as an SST₅ antagonist. Compared to [¹⁷⁷Lu]Lu-DOTA-NOC, it showed similar SST₂ tumor uptake but nearly 5-fold higher accumulation in SST₅-expressing tumors. This work provides new insights into the structural determinants underlying SST₂ and SST₅ affinity, selectivity, and antagonistic behavior, demonstrating that receptor recognition and functional activity arise from the combined contribution of multiple structural elements and supporting the development of dual SST₂/SST₅-targeted radioligands.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}