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Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer

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    Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer
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    Russell H. Morgan Department of Radiology and Radiological Sciences, Department of Pharmacology & Molecular Sciences, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts 02142
    * To whom correspondence should be addressed. Phone: 410-955-2789. Fax: 443-956-5055. E-mail: [email protected]. Address: Johns Hopkins Medical Institutions, 1550 Orleans Street, 492 CRB II, Baltimore, MD 21231.
    †Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions.
    ‡Department of Pharmacology & Molecular Sciences, Johns Hopkins Medical Institutions.
    §Department of Urology, Johns Hopkins Medical Institutions.
    ∥Molecular Insight Pharmaceuticals, Inc.
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2008, 51, 24, 7933–7943
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    https://doi.org/10.1021/jm801055h
    Published December 3, 2008
    Copyright © 2008 American Chemical Society
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    Abstract

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    To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-[3-(5-amino-1-carboxy-pentyl)-ureido]-pentanedioic acid (Lys-C(O)-Glu), which allows ready incorporation of radiohalogens for single photon emission computed tomography (SPECT) and positron emission tomography (PET). We prepared 2-[3-[1-carboxy-5-(4-[125I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([125I]3), 2-[3-[1-carboxy-5-(4-[18F]fluoro-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([18F]6), and 2-(3-[1-carboxy-5-[(5-[125I]iodo-pyridine-3-carbonyl)-amino]-pentyl]-ureido)-pentanedioic acid ([125I]8) in 65−80% (nondecay-corrected), 30−35% (decay corrected), and 59−75% (nondecay-corrected) radiochemical yields. Compound [125I]3 demonstrated 8.8 ± 4.7% injected dose per gram (%ID/g) within PSMA+ PC-3 PIP tumor at 30 min postinjection, which persisted, with clear delineation of the tumor by SPECT. Similar tumor uptake values at early time points were demonstrated for [18F]6 (using PET) and [125I]8. Because of the many radiohalogenated moieties that can be attached via the ε amino group, the intermediate Lys-C(O)-Glu is an attractive template upon which to develop new imaging agents for prostate cancer.

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    Methods of molecular modeling, protein preparation, ligand preparation, and docking studies with CDOCKER are described in detail. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2008, 51, 24, 7933–7943
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    https://doi.org/10.1021/jm801055h
    Published December 3, 2008
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