title: A series of halogenated heterodimeric inhibitors of prostate specific membrane antigen (PSMA) as radiolabeled probes for targeting prostate cancer.
abstract: Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA were designed and synthesized where X = epsilon-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and epsilon-(p-I, p-Br, p-Cl, p-F, H)-phenylureido-Lys. The affinities for PSMA were determined by screening in a competitive binding assay. PSMA binding of the benzyllysine series was significantly affected by the nature of the halogen substituent (IC(50) values, Cl < I = Br << F = H) and the ring position of the halogen atom (IC(50) values, p-I < o-I << m-I). The halogen atom had little affect on the binding affinity in the para substituted phenylureido-Lys series. Two lead iodine compounds were radiolabeled with (123)I and (131)I and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.
authors.affiliation: Molecular Insight Pharmaceuticals, Inc., 160 Second Street, Cambridge, Massachusetts 02142, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Maresca
authors.forename: S M
authors.initials: SM
authors.lastname: Hillier
authors.forename: F J
authors.initials: FJ
authors.lastname: Femia
authors.forename: D
authors.initials: D
authors.lastname: Keith
authors.forename: C
authors.initials: C
authors.lastname: Barone
authors.forename: J L
authors.initials: JL
authors.lastname: Joyal
authors.forename: C N
authors.initials: CN
authors.lastname: Zimmerman
authors.forename: A P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: J A
authors.initials: JA
authors.lastname: Barrett
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: J W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000954:Antigens, Surface; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011869:Radioligand Assay; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000954:Antigens, Surface; D006219:Halogens; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II