{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:23:51Z","timestamp":1790508231287,"version":"4.1.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T00:00:00Z","timestamp":1739318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008658","name":"Deutsches Krebsforschungszentrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008658","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004240","name":"Akademie Ved Cesk? Republiky","doi-asserted-by":"publisher","award":["86652036"],"award-info":[{"award-number":["86652036"]}],"id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031478","name":"NextGenerationEU","doi-asserted-by":"publisher","award":["LX22NPO5102"],"award-info":[{"award-number":["LX22NPO5102"]}],"id":[{"id":"10.13039\/100031478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>PSMA-617 is recognized as a benchmark ligand for prostate-specific membrane antigen (PSMA) owing to its broad utilization in prostate cancer (PCa) targeted radionuclide therapy. In this study, the structure\u2013activity relationships (SAR) of PSMA-617 and two novel analogs featuring modified linkers were investigated. In compounds P17 and P18, the 2-naphthyl-l-Ala moiety was replaced with a less lipophilic 3-styryl-l-Ala moiety while the cyclohexyl ring in P18 was replaced with a phenyl group. The first ever crystal structure of the PSMA\/PSMA-617 complex reported here revealed a folded conformation of the PSMA-617 linker while for the PSMA\/P17 and PSMA\/P18 complexes, the extended orientations of the linkers revealed linker flexibility within the PSMA cavity, a change in binding that can be exploited for the structure-guided design of PSMA-targeting agents. Despite structural differences from PSMA-617, the analogs maintained high PSMA inhibition potency, cellular binding, and internalization. In vivo biodistribution studies revealed comparable tumor uptake across all three compounds with P18 displaying higher spleen accumulation, likely due to phenyl ring lipophilicity. These SAR findings provide a strategic framework for the rational design of PSMA ligands, paving the way for the development of next-generation theranostic agents for PCa.<\/jats:p>","DOI":"10.1021\/acsomega.4c10142","type":"journal-article","created":{"date-parts":[[2025,2,12]],"date-time":"2025-02-12T10:16:06Z","timestamp":1739355366000},"page":"7077-7090","source":"Crossref","is-referenced-by-count":17,"title":["Structure\u2013Activity Relationships and Biological\nInsights into PSMA-617 and Its Derivatives with Modified Lipophilic\nLinker Regions"],"prefix":"10.1021","volume":"10","author":[{"given":"Martin","family":"Scha\u0308fer","sequence":"first","affiliation":[{"name":"German Cancer Research Center (DKFZ) , , Im Neuenheimer Feld 280 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Bauder-Wu\u0308st","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ) , , Im Neuenheimer Feld 280 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Roscher","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ) , , Im Neuenheimer Feld 280 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-8737","authenticated-orcid":true,"given":"Lucia","family":"Motlova\u0301","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology of the Czech Academy of Sciences , , Pru\u030amyslova\u0301 595 , ,","place":["Vestec, Czech Republic, 25250"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-9518","authenticated-orcid":true,"given":"Zso\u0301fia","family":"Kutilova\u0301","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology of the Czech Academy of Sciences , , Pru\u030amyslova\u0301 595 , ,","place":["Vestec, Czech Republic, 25250"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Remde","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ) , , Im Neuenheimer Feld 280 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7009-1487","authenticated-orcid":true,"given":"Karel D.","family":"Klika","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ) , , Im Neuenheimer Feld 280 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9107-4843","authenticated-orcid":true,"given":"Ju\u0308rgen","family":"Graf","sequence":"additional","affiliation":[{"name":"Heidelberg University , , Im Neuenheimer Feld 270 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2751-3060","authenticated-orcid":true,"given":"Cyril","family":"Bar\u030cinka","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology of the Czech Academy of Sciences , , Pru\u030amyslova\u0301 595 , ,","place":["Vestec, Czech Republic, 25250"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-5376","authenticated-orcid":true,"given":"Martina","family":"Benes\u030cova\u0301-Scha\u0308fer","sequence":"additional","affiliation":[{"name":"German Cancer Research Center (DKFZ) , , Im Neuenheimer Feld 280 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,2,12]]},"reference":[{"issue":"16","key":"2026081811165604000_cit1","doi-asserted-by":"publisher","first-page":"3029","DOI":"10.1002\/cncr.33587","article-title":"The ever-increasing\nimportance of cancer as a leading cause of premature death worldwide","volume":"127","author":"Bray","year":"2021","journal-title":"Cancer"},{"issue":"3","key":"2026081811165604000_cit1a","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics\n2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for\n36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"Ca-Cancer J. Clin."},{"issue":"13","key":"2026081811165604000_cit2","doi-asserted-by":"publisher","first-page":"3402","DOI":"10.3390\/cancers15133402","article-title":"The Impact of PSMA PET\/CT on Modern Prostate Cancer\nManagement and Decision Making-The Urological Perspective","volume":"15","author":"Hoffman","year":"2023","journal-title":"Cancers"},{"issue":"Supplement 2","key":"2026081811165604000_cit2a","doi-asserted-by":"publisher","first-page":"17S","DOI":"10.2967\/jnumed.116.186775","article-title":"Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane\nAntigen: Lessons Learned During the Development of a Novel Class of\nLow-Molecular-Weight Theranostic Radiotracers","volume":"58","author":"Kopka","year":"2017","journal-title":"J. Nucl. Med."},{"issue":"7","key":"2026081811165604000_cit3","first-page":"1807","article-title":"Expression\nof the prostate-specific membrane antigen","volume":"54","author":"Israeli","year":"1994","journal-title":"Cancer\nRes."},{"issue":"2","key":"2026081811165604000_cit3a","first-page":"227","article-title":"Molecular cloning of a complementary\nDNA encoding a prostate-specific membrane antigen","volume":"53","author":"Israeli","year":"1993","journal-title":"Cancer Res."},{"issue":"9","key":"2026081811165604000_cit4","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1158\/1078-0432.CCR-22-2875","article-title":"FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan\nfor Patients with Metastatic Castration-Resistant Prostate Cancer","volume":"29","author":"Fallah","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"2026081811165604000_cit4a","unstructured":"Balfour, H.\n          \n          MHRA approves Pluvicto\u00ae\nand Locametz\u00ae for prostate cancer. European\nPharmaceutical Review, 2022."},{"key":"2026081811165604000_cit4b","unstructured":"Eckford, C.\n          \n          European Commission approves\nPluvicto\u00ae for prostate cancer; European\nPharmaceutical Review, 2022."},{"issue":"5","key":"2026081811165604000_cit5","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1021\/acs.jmedchem.5b01210","article-title":"Linker Modification\nStrategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting\nand Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors","volume":"59","author":"Benesova","year":"2016","journal-title":"J. Med. 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Soc."},{"issue":"10","key":"2026081811165604000_cit15","first-page":"2645","article-title":"Prostate-specific membrane antigen\nassociation with filamin A modulates its internalization and NAALADase\nactivity","volume":"63","author":"Anilkumar","year":"2003","journal-title":"Cancer Res."},{"issue":"3","key":"2026081811165604000_cit16","doi-asserted-by":"publisher","first-page":"400","DOI":"10.2967\/jnumed.118.214403","article-title":"Evaluation of (111)\u00adIn-DOTA-5D3, a Surrogate SPECT Imaging\nAgent for Radioimmunotherapy of Prostate-Specific Membrane Antigen","volume":"60","author":"Banerjee","year":"2019","journal-title":"J. Nucl. Med."},{"issue":"2","key":"2026081811165604000_cit17","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1021\/acsptsci.1c00035","article-title":"Lipophilicity Determines Routes of Uptake and\nClearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor\nRadiotherapy","volume":"4","author":"Tafreshi","year":"2021","journal-title":"ACS Pharmacol. Transl. Sci."},{"issue":"6","key":"2026081811165604000_cit18","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1002\/pros.23770","article-title":"PSMA\nexpression in the Hi-Myc model; extended utility of a representative\nmodel of prostate adenocarcinoma for biological insight and as a drug\ndiscovery tool","volume":"79","author":"Simons","year":"2019","journal-title":"Prostate"},{"issue":"46","key":"2026081811165604000_cit19","doi-asserted-by":"publisher","first-page":"14712","DOI":"10.1002\/anie.201709532","article-title":"An Eighteen-Membered Macrocyclic Ligand for Actinium-225\nTargeted Alpha Therapy","volume":"56","author":"Thiele","year":"2017","journal-title":"Angew. Chem., Int. Ed.\nEngl."},{"issue":"5","key":"2026081811165604000_cit20","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.3390\/pharmaceutics14051098","article-title":"Design, Synthesis, and Evaluation\nof Linker-Optimised PSMA-Targeting Radioligands","volume":"14","author":"Lundmark","year":"2022","journal-title":"Pharmaceutics"},{"key":"2026081811165604000_cit21","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1021\/acs.molpharmaceut.4c00974","article-title":"Novel Radiotheranostic Ligands Targeting\nProstate-Specific Membrane Antigen Based on Dual Linker Approach","volume":"22","author":"Kazuta","year":"2025","journal-title":"Mol. Pharm."},{"issue":"6","key":"2026081811165604000_cit22","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.mencom.2020.11.022","article-title":"Influence of the\ndipeptide linker configuration on the activity of PSMA ligands","volume":"30","author":"Uspenskaya","year":"2020","journal-title":"Mendeleev Commun."},{"issue":"1","key":"2026081811165604000_cit23","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s41181-024-00237-3","article-title":"A novel PSMA-targeting\ntracer with highly negatively charged linker demonstrates decreased\nsalivary gland uptake in mice compared to [(68)\u00adGa]\u00adGa-PSMA-11","volume":"9","author":"Huang","year":"2024","journal-title":"EJNMMI Radiopharm. Chem."},{"issue":"15","key":"2026081811165604000_cit24","doi-asserted-by":"publisher","first-page":"4959","DOI":"10.3390\/molecules27154959","article-title":"Application of Cleavable\nLinkers to Improve Therapeutic Index of Radioligand Therapies","volume":"27","author":"Lau","year":"2022","journal-title":"Molecules"},{"key":"2026081811165604000_cit25","doi-asserted-by":"publisher","first-page":"289638","DOI":"10.1155\/2014\/289638","article-title":"The Application\nof Simple and Easy to Implement Decoupling Pulse Scheme Combinations\nto Effect Decoupling of Large J Values with Reduced Artifacts","volume":"2014","author":"Klika","year":"2014","journal-title":"Int. J. Spectr."},{"issue":"16","key":"2026081811165604000_cit26","doi-asserted-by":"publisher","first-page":"2924","DOI":"10.1039\/b505508c","article-title":"Synthesis, characterisation\nand theoretical calculations of 2,6-diaminopurine etheno derivatives","volume":"3","author":"Virta","year":"2005","journal-title":"Org. Biomol. Chem."},{"issue":"12","key":"2026081811165604000_cit26a","doi-asserted-by":"publisher","first-page":"4416","DOI":"10.1021\/jo001695p","article-title":"Unexpected formation of a spiro acridine and fused\nring system from the reaction between an N-acridinylmethyl-substituted\nthiourea and bromoacetonitrile under basic conditions","volume":"66","author":"Klika","year":"2001","journal-title":"J. Org. Chem."},{"issue":"3","key":"2026081811165604000_cit26b","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1002\/jhet.5570430318","article-title":"Stereochemistry, Tautomerism, and\nReactions of Acridinyl Thiosemicarbazides in the Synthesis of 1,3-Thiazolidines","volume":"43","author":"Balentova\u0301","year":"2006","journal-title":"J. Heterocycl. Chem."},{"key":"2026081811165604000_cit26c","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1002\/poc.840","article-title":"Restricted\nrotation\/tautomeric equilibrium anddetermination of the site and extent\nof protonation inbi-imidazole nucleosides by multinuclear NMR andGIAO-DFT\ncalculations","volume":"18","author":"Ma\u0308ki","year":"2005","journal-title":"J. Phys. Org. Chem."},{"issue":"3","key":"2026081811165604000_cit27","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1093\/protein\/gzv065","article-title":"Selection and characterization of Anticalins targeting\nhuman prostate-specific membrane antigen (PSMA)","volume":"29","author":"Barinka","year":"2016","journal-title":"Protein Eng. Des. Sel."},{"key":"2026081811165604000_cit28","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1107\/S1600576716004416","article-title":"Xdsapp2.0","volume":"49","author":"Sparta","year":"2016","journal-title":"J. Appl. 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