Journal of Medicinal Chemistry p. 5684 - 5694 (2016)
Update date:2022-08-11
Topics:
Dannoon, Shorouk
Ganguly, Tanushree
Cahaya, Hendry
Geruntho, Jonathan J.
Galliher, Matthew S.
Beyer, Sophia K.
Choy, Cindy J.
Hopkins, Mark R.
Regan, Melanie
Blecha, Joseph E.
Skultetyova, Lubica
Drake, Christopher R.
Jivan, Salma
Barinka, Cyril
Jones, Ella F.
Berkman, Clifford E.
Vanbrocklin, Henry F.
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 [18F]4, [18F]5, and [18F]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 [18F]5 and [18F]6 as favorable candidates for future prostate cancer imaging clinical trials.
View MoreContact:+86-25-85281586
Address:13F,Bld2#,South of Longpan Road
Feis International Trade Co,. Ltd
Contact:13961823444-18235944442
Address:Wuxi jiangsu
Hangzhou Yanshan Chemical Co.,Ltd.
Contact:86-571- 87698076
Address:Room 1001, #1 Building, Zhongtian MCC, No.2 Youzhinong, Wenyi West Road, Xihu District, Hangzhou, China
Zhejiang Allied Chemical Co.,Ltd
Contact:18967038207
Address:Area A-30, High-tech Industrial Park, Quzhou, Zhejiang, China.
Shandong Ailitong New Material Co.,Ltd
Contact:+86-536-3226266
Address:zhongjia village, putong town , qingzhou city,Shandong Province,China
Doi:10.1074/jbc.RA118.003329
(2018)Doi:10.1021/jacs.1c02644
(2021)Doi:10.1080/00304940309355848
(2003)Doi:10.1016/j.ica.2013.09.001
(2014)Doi:10.1039/jr9410000496
(1941)Doi:10.1021/ma030343s
(2003)