title: Synthesis and Biological Evaluation of Substrate-Based Imaging Agents for the Prostate-Specific Membrane Antigen.
abstract: Prostate-specific membrane antigen (PSMA) is an attractive target for the imaging of prostate cancer (PCa) due to the elevated expression on the surface of prostate tumor cells. Most PSMA-targeted low molecular weight imaging agents are inhibitors of PSMA. We have synthesized a series of substrate-based PSMA-targeted imaging agents by mimicking poly-γ-glutamyl folic acid, an endogenous substrate of PSMA.In vitrotheγ-linked polyglutamate conjugates proved to be better substrates than the correspondingα-linked glutamates. However,in vivoimaging studies ofγ-ray-emitting andγ-linked glutamates did not demonstrate selective uptake in PSMA-pos-itive over PSMA-negative tumors. Subsequent chromatographic studies andin silicomolecular dynamics simulations indicated that hydrolysis of the substrates is slow and access to the enzymatic active site is limited. These results inform the design of future substrate-based imaging agents for PSMA.
authors.affiliation: Department of Radiology, School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA ; College of Pharmacy, Korea University, Chungnam 339-700, Korea.
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.affiliation: Department of Radiology, School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.affiliation: Department of Radiology, School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Haofan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiology, School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.affiliation: Department of Radiology, School of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
keywords: PSMA; SPECT; molecular imaging; prodrug; prostate cancer