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A Series of Halogenated Heterodimeric Inhibitors of Prostate Specific Membrane Antigen (PSMA) as Radiolabeled Probes for Targeting Prostate Cancer

2008; American Chemical Society; Volume: 52; Issue: 2 Linguagem: Inglês

10.1021/jm800994j

1520-4804

Kevin P. Maresca, Shawn Hillier, F.J. Femia, Donna Keith, Catherine M. Barone, John L. Joyal, Craig Zimmerman, Alan P. Kozikowski, John Barrett, W.C. Eckelman, John W. Babich,

Prostate Cancer Treatment and Research

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 = ε-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and ε-(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 (IC50 values, Cl < I = Br ≪ F = H) and the ring position of the halogen atom (IC50 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 123I and 131I and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.