BACKGROUND: The enzyme-biomarker prostate-specific membrane antigen (PSMA) is an active target for imaging and therapeutic applications for prostate cancer. The internalization of PSMA has been shown to vary with inhibitors' mode of binding: irreversible, slowly reversible, and reversible. METHODS: In the present study, PSMA-targeted clickable derivatives of an irreversible phosphoramidate inhibitor DBCO-PEG(4) -CTT-54 (IC(50) = 1.0 nM) and a slowly reversible phosphate inhibitor, DBCO-PEG(4) -CTT-54.2 (IC(50) = 6.6 nM) were clicked to (99m) Tc(CO)(3) -DPA-azide to assemble a PSMA-targeted SPECT agent. The selectivity, percent uptake, and internalization of these PSMA-targeted SPECT agents were evaluated in PSMA-positive and PSMA-negative cells. RESULTS: In vitro studies demonstrated that PSMA-targeted SPECT agents exhibited selective cellular uptake in the PSMA-positive LNCaP cells compared to PSMA-negative PC3 cells. More importantly, it was found that (99m) Tc(CO)(3) -DPA-DBCO-PEG(4) -CTT-54 based on an irreversible PSMA inhibitor core, exhibited greater uptake and internalization than (99m) Tc(CO)(3) -DPA-DBCO-PEG(4) -CTT-54.2 constructed from a slowly reversible PSMA inhibitor core. CONCLUSIONS: We have demonstrated that a PSMA-targeted SPECT agent can be assembled efficiently using copper-less click chemistry. In addition, we demonstrated that mode of binding has an effect on internalization and percent uptake of PSMA-targeted SPECT agents; with the irreversible targeting agent demonstrating superior uptake and internalization in PSMA+ cells. The approach demonstrated in this work now supports a modular approach for the assembly of PSMA-targeted imaging and therapeutic agents.
BACKGROUND: The enzyme-biomarker prostate-specific membrane antigen (PSMA) is an active target for imaging and therapeutic applications for prostate cancer. The internalization of PSMA has been shown to vary with inhibitors' mode of binding: irreversible, slowly reversible, and reversible. METHODS: In the present study, PSMA-targeted clickable derivatives of an irreversible phosphoramidate inhibitor DBCO-PEG(4) -CTT-54 (IC(50) = 1.0 nM) and a slowly reversible phosphate inhibitor, DBCO-PEG(4) -CTT-54.2 (IC(50) = 6.6 nM) were clicked to (99m) Tc(CO)(3) -DPA-azide to assemble a PSMA-targeted SPECT agent. The selectivity, percent uptake, and internalization of these PSMA-targeted SPECT agents were evaluated in PSMA-positive and PSMA-negative cells. RESULTS: In vitro studies demonstrated that PSMA-targeted SPECT agents exhibited selective cellular uptake in the PSMA-positive LNCaP cells compared to PSMA-negative PC3 cells. More importantly, it was found that (99m) Tc(CO)(3) -DPA-DBCO-PEG(4) -CTT-54 based on an irreversible PSMA inhibitor core, exhibited greater uptake and internalization than (99m) Tc(CO)(3) -DPA-DBCO-PEG(4) -CTT-54.2 constructed from a slowly reversible PSMA inhibitor core. CONCLUSIONS: We have demonstrated that a PSMA-targeted SPECT agent can be assembled efficiently using copper-less click chemistry. In addition, we demonstrated that mode of binding has an effect on internalization and percent uptake of PSMA-targeted SPECT agents; with the irreversible targeting agent demonstrating superior uptake and internalization in PSMA+ cells. The approach demonstrated in this work now supports a modular approach for the assembly of PSMA-targeted imaging and therapeutic agents.
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: Jack Maung; Jeremy P Mallari; Teri A Girtsman; Lisa Y Wu; Jennifer A Rowley; Nicholas M Santiago; Alan N Brunelle; Clifford E Berkman Journal: Bioorg Med Chem Date: 2004-09-15 Impact factor: 3.641
Authors: Martin G Pomper; John L Musachio; Jiazhong Zhang; Ursula Scheffel; Yun Zhou; John Hilton; Atul Maini; Robert F Dannals; Dean F Wong; Alan P Kozikowski Journal: Mol Imaging Date: 2002 Apr-Jun Impact factor: 4.488
Authors: Giulio Fracasso; Giuseppe Bellisola; Sara Cingarlini; Deborah Castelletti; Tommaso Prayer-Galetti; Francesco Pagano; Giuseppe Tridente; Marco Colombatti Journal: Prostate Date: 2002-09-15 Impact factor: 4.104
Authors: Sangeeta Ray Banerjee; Zhengping Chen; Mrudula Pullambhatla; Ala Lisok; Jian Chen; Ronnie C Mease; Martin G Pomper Journal: Bioconjug Chem Date: 2016-05-09 Impact factor: 4.774
Authors: Benjamin B Kasten; Tiancheng Liu; Jessie R Nedrow-Byers; Paul D Benny; Clifford E Berkman Journal: Bioorg Med Chem Lett Date: 2012-11-16 Impact factor: 2.823
Authors: Sangeeta Ray Banerjee; Mrudula Pullambhatla; Catherine A Foss; Alexander Falk; Youngjoo Byun; Sridhar Nimmagadda; Ronnie C Mease; Martin G Pomper Journal: J Med Chem Date: 2013-07-22 Impact factor: 7.446
Authors: Tanushree Ganguly; Shorouk Dannoon; Mark R Hopkins; Stephanie Murphy; Hendry Cahaya; Joseph E Blecha; Salma Jivan; Christopher R Drake; Cyril Barinka; Ella F Jones; Henry F VanBrocklin; Clifford E Berkman Journal: Nucl Med Biol Date: 2015-06-09 Impact factor: 2.408
Authors: A P Kiess; S R Banerjee; R C Mease; S P Rowe; A Rao; C A Foss; Y Chen; X Yang; S Y Cho; S Nimmagadda; M G Pomper Journal: Q J Nucl Med Mol Imaging Date: 2015-07-24 Impact factor: 2.346
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