| Literature DB >> 27228467 |
Shorouk Dannoon1, Tanushree Ganguly2, Hendry Cahaya1, Jonathan J Geruntho2, Matthew S Galliher2, Sophia K Beyer2, Cindy J Choy2, Mark R Hopkins2, Melanie Regan1, Joseph E Blecha1, Lubica Skultetyova3, Christopher R Drake1, Salma Jivan1, Cyril Barinka3, Ella F Jones1, Clifford E Berkman2,4, Henry F VanBrocklin1.
Abstract
A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.Entities:
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Year: 2016 PMID： 27228467 PMCID： PMC6016545 DOI： 10.1021/acs.jmedchem.5b01850
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446