Dongdong Liang, Linhao Li, Yong Ai, Zhihui Li, William D. Hedrich, Srilatha Sakamuru, Caitlin Lynch, Wenbo Yu, Ismael Watts-Ouattara, Scott Heyward, Menghang Xia, Alexander D. MacKerell, Jr., Hongbing Wang, Fengtian Xue
{"title":"Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies","authors":"Dongdong Liang, Linhao Li, Yong Ai, Zhihui Li, William D. Hedrich, Srilatha Sakamuru, Caitlin Lynch, Wenbo Yu, Ismael Watts-Ouattara, Scott Heyward, Menghang Xia, Alexander D. MacKerell, Jr., Hongbing Wang, Fengtian Xue","doi":"10.1021/acs.jmedchem.4c02064","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02064","url":null,"abstract":"Enhancement of the metabolic conversion of cyclophosphamide (CPA) increases its therapeutic effects. Activation of the human constitutive androstane receptor (hCAR) induces CYP2B6, a key enzyme responsible for CPA bioactivation. Based on our previous hCAR activator DL5016, we designed and synthesized a series of new hCAR activators. Compared to DL5016, three new compounds <b>6i</b>, <b>6k</b> (DL5055), and <b>7e</b>, showed significantly improved activating potency for hCAR. Particularly, DL5055 activates hCAR with an EC<sub>50</sub> of 0.35 μM and <i>E</i><sub>MAX</sub> of 4.3, and does not activate hPXR and other related nuclear receptors. It induced the expression of CYP2B6 and caused the translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. DL5055 also induces the expression of Cyp2b10 (the mouse analog of human CYP2B6) in hCAR-transgenic mice. In addition, it significantly enhances the efficacy of CPA-based chemotherapy regimen, CHOP, in a coculture system and a mouse xenograft model <i>in vivo</i>.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"72 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of Highly Potent AKR1C3 Inhibitors Treating Sorafenib-Resistant Hepatocellular Carcinoma","authors":"Shuaishuai Xing, Jiheng Jiang, Xianglin Chu, Xiaolong Wang, Zhiqiang Wang, Xinyu Li, Bingbing Lv, Can Guo, Siyu He, Leyan Wang, Chenyu Zhang, Qinglong Guo, Li Zhao, Pengfei Fang, Feng Feng, Haopeng Sun","doi":"10.1021/acs.jmedchem.4c03035","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03035","url":null,"abstract":"Aldo-keto reductase 1C3 (AKR1C3) plays a key role in tumor progression and chemotherapy resistance, particularly in sorafenib-resistant hepatocellular carcinoma (HCC). Targeting AKR1C3 represents a promising strategy to restore chemosensitivity in resistant HCC. Previous research identified the lead compound <b>S07–2005</b> through a cascade virtual screening approach (AKR1C3 IC<sub>50</sub> = 130 ± 30 nM, SI (selective index) > 77). Using cocrystal-guided drug design, <b>30</b> was optimized to adopt an “L”-shaped conformation targeting AKR1C3′s subpocket 1 (SP1) and oxyanion site (OS), enhancing inhibitory potency and selectivity (AKR1C3 IC<sub>50</sub> = 5 ± 1 nM, SI > 2000). It enhanced sorafenib-induced ROS generation, promoted apoptosis, and restored sorafenib sensitivity in HCC models. In combination with sorafenib, compound <b>30</b> restored sorafenib sensitivity in HCC both <i>in vitro</i> and <i>in vivo</i>. Additionally, compound <b>30</b> demonstrated a favorable safety profile and pharmacokinetic properties, suggesting its potential as an adjunct to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"10 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Advances in Sonodynamic Therapy: Focus on Ferroptosis.","authors":"Wendi Su, Hao Wang, Juhong Pan, Qing Zhou","doi":"10.1021/acs.jmedchem.4c02603","DOIUrl":"10.1021/acs.jmedchem.4c02603","url":null,"abstract":"<p><p>Ferroptosis is a nonapoptotic form of cell death discovered in 2012. Noninvasive treatments regulating ferroptosis are important for a wide range of diseases. Among the noninvasive treatments, sonodynamic therapy (SDT) has become promising due to its strong tissue penetration and few side effects. In recent years, targeted drug delivery platforms constructed on the basis of SDT have provided an efficient delivery mode for the regulation of ferroptosis. Based on the latest research reports, this Perspective introduces the basic mechanism of SDT and the influencing factors of therapeutic effects, elucidates the significance of ferroptosis-targeted SDT, and summarizes the recent studies on ferroptosis-targeted SDT through different pathways. We also present innovative studies of composite ultrasound-responsive drug delivery platforms. Finally, a brief summary and outlook based on current ferroptosis-targeted SDT are presented.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"5976-5992"},"PeriodicalIF":6.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dongliang Guan, Hetti Handi Chaminda Lakmal, Brooke N. Bender, Md Toufiqur Rahman, Elaine A. Gay, Daniel G. Barrus, Alejandro M. Mosera, Andrew T. Kerr, Joyce Besheer, Chunyang Jin
{"title":"Development of Diphenyl-1,2,4-Oxadiazole Analogues as Allosteric Modulators of the RXFP3 Receptor: Evaluation of Importance of the N-Substituted-2-Pyrrolidone Moiety in RLX-33","authors":"Dongliang Guan, Hetti Handi Chaminda Lakmal, Brooke N. Bender, Md Toufiqur Rahman, Elaine A. Gay, Daniel G. Barrus, Alejandro M. Mosera, Andrew T. Kerr, Joyce Besheer, Chunyang Jin","doi":"10.1021/acs.jmedchem.5c00361","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00361","url":null,"abstract":"Relaxin-3/RXFP3 antagonism is a novel strategy for drug development to treat alcohol use disorder (AUD). We recently discovered the first-in-class RXFP3 negative allosteric modulators (NAMs), represented by RLX-33, which significantly reduced alcohol consumption in rats. In this study, we report the design and synthesis of a series of diphenyl-1,2,4-oxadiazole analogues derived from RLX-33. Structure–activity relationship studies of sites A and B of RLX-33 revealed that the aromatic ring at site A is not required for RXFP3 allosteric modulation and the pyrrolidone linker at site B could be replaced with a cyclic or linear alkylamine. Compound (<i>R</i>,<i>R</i>)-<b>3</b> has improved potency and ADME properties (e.g., solubility and metabolic stability) compared to RLX-33, while maintaining high receptor subtype selectivity over RXFP1 and RXFP4. Importantly, (<i>R</i>,<i>R</i>)-<b>3</b> significantly attenuated alcohol self-administration without affecting sucrose self-administration and general locomotor activity in rats, demonstrating the potential of RXFP3 NAMs as promising drug candidates for AUD.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"18 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhangping Xiao, Angelina Osipyan, Shanshan Song, Deng Chen, Reinder A Schut, Ronald van Merkerk, Petra E van der Wouden, Robbert H Cool, Wim J Quax, Barbro N Melgert, Gerrit J Poelarends, Frank J Dekker
{"title":"Correction to \"Thieno[2,3-<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)-dione Derivative Inhibits d-Dopachrome Tautomerase Activity and Suppresses the Proliferation of Non-Small Cell Lung Cancer Cells\".","authors":"Zhangping Xiao, Angelina Osipyan, Shanshan Song, Deng Chen, Reinder A Schut, Ronald van Merkerk, Petra E van der Wouden, Robbert H Cool, Wim J Quax, Barbro N Melgert, Gerrit J Poelarends, Frank J Dekker","doi":"10.1021/acs.jmedchem.5c00406","DOIUrl":"10.1021/acs.jmedchem.5c00406","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"6844-6845"},"PeriodicalIF":6.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liping H. Pettus, Matthew Bourbeau, Nuria A. Tamayo, Albert Amegadzie, Diane Beylkin, Shon K. Booker, John Butler, Michael J. Frohn, Matthew R. Kaller, Todd Kohn, Brian A. Lanman, Kexue Li, Qingyian Liu, Vu Ma, Jose Medina, Ana E. Minatti, Patricia Lopez, Francesco Manoni, Alex Pickrell, Nicholas Weires, Jan Andersson, Sanne Cowland, Sanne Glad, Ian Sarvary, Mikkel Vestergaard, Weikun Li, Sudipa Ghimire-Rijal, Narbe Mardirossian, Susmith Mukund, Qing Chen, Mei-Chu Lo, Rachel Ngo, Jawahar Khetan, Franck Madoux, Christiana Sanders, Pooja Sharma, Paul Wang, Bernd Bruenner, Stuart McCloud, Manuel Ponce, Marcus Soto, Jan Wahlstrom, Fang Xie, Yajing Yang, Siyuan Liu, Hong Tan, Antonia Policheni, Sean Caenepeel, Katherine K. Slemmons, Brian Belmontes, Paul Hughes, Jennifer R. Allen
{"title":"Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers","authors":"Liping H. Pettus, Matthew Bourbeau, Nuria A. Tamayo, Albert Amegadzie, Diane Beylkin, Shon K. Booker, John Butler, Michael J. Frohn, Matthew R. Kaller, Todd Kohn, Brian A. Lanman, Kexue Li, Qingyian Liu, Vu Ma, Jose Medina, Ana E. Minatti, Patricia Lopez, Francesco Manoni, Alex Pickrell, Nicholas Weires, Jan Andersson, Sanne Cowland, Sanne Glad, Ian Sarvary, Mikkel Vestergaard, Weikun Li, Sudipa Ghimire-Rijal, Narbe Mardirossian, Susmith Mukund, Qing Chen, Mei-Chu Lo, Rachel Ngo, Jawahar Khetan, Franck Madoux, Christiana Sanders, Pooja Sharma, Paul Wang, Bernd Bruenner, Stuart McCloud, Manuel Ponce, Marcus Soto, Jan Wahlstrom, Fang Xie, Yajing Yang, Siyuan Liu, Hong Tan, Antonia Policheni, Sean Caenepeel, Katherine K. Slemmons, Brian Belmontes, Paul Hughes, Jennifer R. Allen","doi":"10.1021/acs.jmedchem.4c03121","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03121","url":null,"abstract":"<i>MTAP</i> deletion occurs in 10–15% of all human cancers due to its proximity to the tumor suppressor gene <i>CDKN2A</i>. The loss of MTAP leads to accumulation of methylthioadenosine (MTA), which shares structural similarity to <i>S</i>-adenosyl methionine (SAM), the methyl donor for the cell-essential protein arginine methyltransferase 5 (PRMT5). By competing with SAM, MTA partially inhibits PRMT5, making <i>MTAP</i>-deleted tumors susceptible to further PRMT5 inhibition. Herein, we report the discovery of MTA-cooperative PRMT5 inhibitor <b>AMG 193</b>, a molecule that inhibited the proliferation of HCT116 <i>MTAP</i>-deleted cells with ∼40x selectivity over HCT116 <i>MTAP</i>-WT cells. <b>AMG 193</b> was orally efficacious in mouse xenografts of endogenous <i>MTAP</i>-null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD) and U87MG (88% TGI @ 100 mg/kg QD). Preclinical data indicate that <b>AMG 193</b> is brain-penetrant. <b>AMG 193</b> is currently in Phase I/II clinical trials for the treatment of advanced <i>MTAP</i>-deleted solid tumors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"15 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chantal Fürstner, Jens Ackerstaff, Heinrich Meier, Alexander Straub, Joachim Mittendorf, Jens Schamberger, Martina Schäfer, Kirsten Börngen, Hannah Jörißen, Dmitry Zubov, Katja Zimmermann, Adrian Tersteegen, Volker Geiss, Elke Hartmann, Barbara Albrecht-Küpper, Pedro D'Orléans-Juste, Catherine Lapointe, Laurence Vincent, Stefan Heitmeier, Hanna Tinel
{"title":"Discovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution.","authors":"Chantal Fürstner, Jens Ackerstaff, Heinrich Meier, Alexander Straub, Joachim Mittendorf, Jens Schamberger, Martina Schäfer, Kirsten Börngen, Hannah Jörißen, Dmitry Zubov, Katja Zimmermann, Adrian Tersteegen, Volker Geiss, Elke Hartmann, Barbara Albrecht-Küpper, Pedro D'Orléans-Juste, Catherine Lapointe, Laurence Vincent, Stefan Heitmeier, Hanna Tinel","doi":"10.1021/acs.jmedchem.4c01819","DOIUrl":"10.1021/acs.jmedchem.4c01819","url":null,"abstract":"<p><p>Chymase is a serine-protease produced by mast cells. In the past few decades, its role in fibrotic diseases triggered the search for orally available chymase inhibitors. Aiming at reducing adverse cardiac remodeling after myocardial infarction, our research efforts resulted in the discovery of fulacimstat (BAY 1142524). While clinical trials did not demonstrate efficacy in this indication, the recent discovery of a new unexpected biological role of chymase spurred a revival of interest in chymase inhibition: chymase was shown to inactivate plasmin within fibrin-rich clots. Chymase inhibitors are now considered as potential profibrinolytic drugs with low bleeding risk and therefore exceptional safety for the treatment of acute thrombosis settings such as stroke, pulmonary embolism, or venous thrombosis. This article describes the chemical optimization journey from a screening hit to the discovery of fulacimstat (BAY 1142524), a selective chymase inhibitor with a good safety profile, as well as its preclinical <i>in vitro</i> and <i>in vivo</i> characterization.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":"6108-6126"},"PeriodicalIF":6.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Towards P2X4 Positron Emission Tomography Tracing","authors":"Stephanie Federico","doi":"10.1021/acs.jmedchem.5c00772","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00772","url":null,"abstract":"The P2X4 receptor is involved in immunological and inflammatory processes and potent antagonists are potentially useful for therapeutic, investigational, and diagnostic purposes. This Viewpoint summarizes the discovery of potent and selective P2X4 antagonists that bring researchers closer to obtaining valuable PET tracers for studying the P2X4 receptor.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"49 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143713748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pulkit Dhiman, Satyajeet Das, Vikas Pathania, Suraj Rawat, Hemraj S. Nandanwar, Krishan G. Thakur, Vinod D. Chaudhari
{"title":"Discovery of Conformationally Constrained Dihydro Benzo-Indole Derivatives as Metallo-β-Lactamase Inhibitors to Tackle Multidrug-Resistant Bacterial Infections","authors":"Pulkit Dhiman, Satyajeet Das, Vikas Pathania, Suraj Rawat, Hemraj S. Nandanwar, Krishan G. Thakur, Vinod D. Chaudhari","doi":"10.1021/acs.jmedchem.4c02207","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02207","url":null,"abstract":"The discovery of metallo-β-lactamase (MBL) inhibitors is crucial in the fight against bacterial infections following the emergence and rapid spread of New Delhi metallo-β-lactamase-1 (NDM-1), as well as clinically relevant Verona integrin-encoded metallo-β-lactamase (VIM), and Imipenemase (IMP). The situation is alarming as there are insufficient antibiotics in the pipeline to combat critical multidrug-resistant infections. Here, we report the discovery of novel dihydrobenzo-indole (dBI) derivatives as a new class of potent metallo-β-lactamase inhibitors (MBLIs) by applying scaffold hopping, conformation constrained, and substituent-decorating strategies. Among them, compound <b>17u</b> exhibited the best inhibitory activity against MBL with acceptable physicochemical and ADME properties. <b>17u</b> exhibited remarkable enhancement of carbapenems’ effectiveness against a range of MBL-producing clinical strains. This efficacy extended to <i>in vivo</i> settings when combined with the imipenem antibiotic, significantly reducing the bacterial load in a thigh infection model. Consequently, it qualifies as a prime candidate for further development as an MBLI.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Lis, Friedrich-Alexander Ludwig, Steffen Fischer, Martin Ullrich, Hans-Joachim Lankau, Wiebke Sihver, Daniel Gündel, Desna Joseph, Christoph Meyer, Klaus Kopka, Jens Pietzsch, Peter Brust, Alexander Hoepping
{"title":"Development of [99mTc]TcO-ABX474: Design, Synthesis, and Biological Evaluation of PSMA-Binding Technetium-99m Radioligands for SPECT Imaging of Prostate Cancer","authors":"Christian Lis, Friedrich-Alexander Ludwig, Steffen Fischer, Martin Ullrich, Hans-Joachim Lankau, Wiebke Sihver, Daniel Gündel, Desna Joseph, Christoph Meyer, Klaus Kopka, Jens Pietzsch, Peter Brust, Alexander Hoepping","doi":"10.1021/acs.jmedchem.4c02767","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02767","url":null,"abstract":"A current global limitation to the timely and equitable patient access to PSMA-based therapies for prostate cancer (PCa) is the insufficient PET capacity for pretreatment imaging. However, the extensive global availability of SPECT cameras renders this imaging technology as an attractive alternative. The lack of regulatory approved PSMA radioligands for SPECT imaging of PCa prompted us to design new <sup>99m</sup>Tc-labeled radioligands with a fast pharmacokinetic profile by harnessing proven complexation of the [<sup>99m</sup>Tc][TcO]<sup>3+</sup> core by a bis(aminoethanethiol) chelator. Six <sup>99m</sup>Tc-labeled PSMA radioligands were synthesized and biologically characterized in cell-based assays and by SPECT imaging in LNCaP tumor-bearing mice. From this series, [<sup>99m</sup>Tc]TcO-<b>5</b> ([<sup>99m</sup>Tc]TcO-ABX474, <i>K</i><sub>d</sub>(PSMA) = 6.1 ± 1.7 nM) displayed the most advantageous properties for SPECT imaging of PCa: high and fast tumor uptake accompanied by rapid clearance from nontarget tissues, leading to faster pharmacokinetics than observed for the reference [<sup>99m</sup>Tc]Tc-PSMA-I&S. Furthermore, [<sup>99m</sup>Tc]TcO-<b>5</b> performed similar to the established PSMA–PET radioligand [<sup>68</sup>Ga]Ga-PSMA-11.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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