title: Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors.
abstract: Since prostate-specific membrane antigen (PSMA) is up-regulated in nearly all stages of prostate cancer (PCa), PSMA can be considered as a viable diagnostic biomarker and treatment target in PCa. This project is focused on the development and evaluation of a series of compounds directed against PSMA. The modifications to the linker are designed to improve the binding potential and pharmacokinetics for theranostic application. In addition, the results help to further elucidate the structure-activity relationships (SAR) of the resulting PSMA inhibitors. Both in vitro and in vivo experiments of 18 synthesized PSMA inhibitor variants showed that systematic chemical modification of the linker has a significant impact on the tumor-targeting and pharmacokinetic properties. This approach can lead to an improved management of patients suffering from recurrent prostate cancer by the use of one radiolabeling precursor, which can be radiolabeled either with (68)Ga for diagnosis or with (177)Lu or (225)Ac for therapy.
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Benešová
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bauder-Wüst
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Molecular Structure Analysis, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Karel D
authors.initials: KD
authors.lastname: Klika
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg , 69120 Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg , 69120 Heidelberg, Germany.|Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center , 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D049268:Positron-Emission Tomography; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D017430:Prostate-Specific Antigen