title: Radiofluorinated derivatives of 2-(phosphonomethyl)pentanedioic acid as inhibitors of prostate specific membrane antigen (PSMA) for the imaging of prostate cancer.
abstract: For prostate cancer, prostate specific membrane antigen (PSMA) has been identified as a diagnostic and therapeutic target. Fluorinated derivatives of 2-(phosphonomethyl)pentanedioic acid were designed and synthesized to explore whether this fluorine-substituent is tolerated in the pentanedioic acid moiety that is common to almost all PSMA targeting small molecule inhibitors. The binding affinities of the racemic and individual stereoisomers of 2-fluoro-4-(phosphonomethyl)pentanedioic acid were determined and showed that the introduction of fluorine was well tolerated. The radiosynthesis of the analogous 2-[(18)F]fluoro-4-(phosphonomethyl)pentanedioic acid was developed and evaluated in vivo with the PSMA positive LNCaP human prostate cancer cell. The biological results demonstrated specific binding of the tracer to PSMA positive tumors in mice. These results warrant the further evaluation of this class of compounds as radiolabeled tracers for the detection and staging of prostate cancer.
authors.affiliation: Global Drug Discovery, Bayer HealthCare, Müllerstrasse 178, 13353, Berlin, Germany. keith.graham@bayer.com
authors.forename: Keith
authors.initials: K
authors.lastname: Graham
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Gromov
authors.forename: Niels
authors.initials: N
authors.lastname: Böhnke
authors.forename: Martina
authors.initials: M
authors.lastname: Schäfer
authors.forename: Jorma
authors.initials: J
authors.lastname: Hassfeld
authors.forename: Ludger
authors.initials: L
authors.lastname: Dinkelborg
authors.forename: Georg
authors.initials: G
authors.lastname: Kettschau
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D064847:Multimodal Imaging; D009943:Organophosphorus Compounds / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011854:Radiochemistry; D019275:Radiopharmaceuticals; D013237:Stereoisomerism; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D009943:Organophosphorus Compounds; D019275:Radiopharmaceuticals; D043425:Glutamate Carboxypeptidase II