68Ga-Complex Lipophilicity and the Targeting Property of a Urea-Based PSMA Inhibitor for PET Imaging
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- 13 March 2012
- journal article
- research article
- Published by American Chemical Society (ACS) in Bioconjugate Chemistry
- Vol. 23 (4), 688-697
- https://doi.org/10.1021/bc200279b
Abstract
Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-molecular-weight pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga(III) chelator N,N′-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N′- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA “active binding site”. This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization experiments. Compared to the DOTA-conjugate, the HBED-CC derivative showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The 68Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. 68Ga labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC.Keywords
This publication has 23 references indexed in Scilit:
- 68Ga-Labeled Inhibitors of Prostate-Specific Membrane Antigen (PSMA) for Imaging Prostate CancerJournal of Medicinal Chemistry, 2010
- Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate CancerCancer Research, 2009
- Mortality Results from a Randomized Prostate-Cancer Screening TrialThe New England Journal of Medicine, 2009
- PET Imaging of Prostate Cancer Xenografts with a Highly Specific Antibody against the Prostate-Specific Membrane AntigenJournal of Nuclear Medicine, 2009
- Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate CancerJournal of Medicinal Chemistry, 2008
- 68Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticalsContrast Media & Molecular Imaging, 2008
- A Prostate-Specific Membrane Antigen-Targeted Monoclonal Antibody–Chemotherapeutic Conjugate Designed for the Treatment of Prostate CancerCancer Research, 2004
- Phase I Trial of Yttrium-90—Labeled Anti—Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Androgen-Independent Prostate CancerJournal of Clinical Oncology, 2004
- The homodimer of prostate-specific membrane antigen is a functional target for cancer therapyProceedings of the National Academy of Sciences of the United States of America, 2003
- Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancerJournal of Cellular Biochemistry, 2003