INTRODUCTION: In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. METHODS: p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [(18)F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(-) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. RESULTS: The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [(18)F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(-) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h. CONCLUSIONS: We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [(18)F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. ADVANCES IN KNOWLEDGE: The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [(18)F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.
INTRODUCTION: In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. METHODS:p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [(18)F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(-) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1tumor, with or without blocking agent. RESULTS: The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [(18)F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(-) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h. CONCLUSIONS: We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [(18)F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. ADVANCES IN KNOWLEDGE: The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [(18)F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.
Authors: Neil H Bander; Matthew I Milowsky; David M Nanus; Lale Kostakoglu; Shankar Vallabhajosula; Stanley J Goldsmith Journal: J Clin Oncol Date: 2005-04-18 Impact factor: 44.544
Authors: Catherine A Foss; Ronnie C Mease; Hong Fan; Yuchuan Wang; Hayden T Ravert; Robert F Dannals; Rafal T Olszewski; Warren D Heston; Alan P Kozikowski; Martin G Pomper Journal: Clin Cancer Res Date: 2005-06-01 Impact factor: 12.531
Authors: Marc O Anderson; Lisa Y Wu; Nicholas M Santiago; Jamie M Moser; Jennifer A Rowley; Erin S D Bolstad; Clifford E Berkman Journal: Bioorg Med Chem Date: 2007-08-11 Impact factor: 3.641
Authors: Cyril Barinka; Miroslava Rovenská; Petra Mlcochová; Klára Hlouchová; Anna Plechanovová; Pavel Majer; Takashi Tsukamoto; Barbara S Slusher; Jan Konvalinka; Jacek Lubkowski Journal: J Med Chem Date: 2007-06-14 Impact factor: 7.446
Authors: David M Nanus; Matthew I Milowsky; Lale Kostakoglu; Peter M Smith-Jones; Shankar Vallabahajosula; Stanley J Goldsmith; Neil H Bander Journal: J Urol Date: 2003-12 Impact factor: 7.450
Authors: Lisa Y Wu; Marc O Anderson; Yoko Toriyabe; Jack Maung; Tammy Y Campbell; Cheryl Tajon; Marat Kazak; Jamie Moser; Clifford E Berkman Journal: Bioorg Med Chem Date: 2007-08-21 Impact factor: 3.641
Authors: Thomas A Hope; Ali Afshar-Oromieh; Matthias Eiber; Louise Emmett; Wolfgang P Fendler; Courtney Lawhn-Heath; Steven P Rowe Journal: AJR Am J Roentgenol Date: 2018-06-27 Impact factor: 3.959
Authors: Spencer C Behr; Rahul Aggarwal; Henry F VanBrocklin; Robert R Flavell; Kenneth Gao; Eric J Small; Joseph Blecha; Salma Jivan; Thomas A Hope; Jeffry P Simko; John Kurhanewicz; Susan M Noworolski; Natalie J Korn; Romelyn De Los Santos; Matthew R Cooperberg; Peter R Carroll; Hao G Nguyen; Kirsten L Greene; Beatrice Langton-Webster; Clifford E Berkman; Youngho Seo Journal: J Nucl Med Date: 2018-11-21 Impact factor: 10.057
Authors: Leslie Ann Caromile; Kristina Dortche; M Mamunur Rahman; Christina L Grant; Christopher Stoddard; Fernando A Ferrer; Linda H Shapiro Journal: Sci Signal Date: 2017-03-14 Impact factor: 8.192
Authors: Shorouk Dannoon; Tanushree Ganguly; Hendry Cahaya; Jonathan J Geruntho; Matthew S Galliher; Sophia K Beyer; Cindy J 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 Journal: J Med Chem Date: 2016-06-13 Impact factor: 7.446
Authors: Jessie R Nedrow; Joseph D Latoche; Kathryn E Day; Jalpa Modi; Tanushree Ganguly; Dexing Zeng; Brenda F Kurland; Clifford E Berkman; Carolyn J Anderson Journal: Mol Imaging Biol Date: 2016-06 Impact factor: 3.488