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 co-crystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50's ranging from 0.4-1.3nM. In vitro whole cell assays showed binding and rapid internalization (80-95%, 2h) 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, 63.6 and 69.6 for [18F]4, [18F]5 and [18F]6, respectively, at 2h 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 [18F]5 and [18F]6 as favorable candidates for future prostate cancer imaging clinical trials.
FREE DAILY AND WEEKLY NEWSLETTERS OFFERED BY CONTENT OF INTEREST
Did you find this article relevant? Subscribe to UroToday-GUOncToday!
The fields of GU Oncology and Urology are advancing rapidly including new treatments, enrolling clinical trials, screening and surveillance recommendations along with updated guidelines. Join us as one of our subscribers who rely on UroToday as their must-read source for the latest news and data on drugs. Sign up today for blogs, video conversations, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.
Journal of medicinal chemistry. 2016 May 26 [Epub ahead of print]
Shorouk Dannoon, Tanushree Ganguly, Hendry Cahaya, Jonathan J Geruntho, Matthew S Galliher, Sophia K Beyer, Cindy Jan Choy, Mark R Hopkins, Melanie Regan, Joseph E Blecha, Lubica Skultetyova, Christopher R Drake, Salma Jivan, Cyril Barinka, Ella F Jones, Clifford E Berkman, Henry F VanBrocklin