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PSMA-targeted SPECT agents: mode of binding effect on in vitro performance
Jessie R Nedrow-Byers1, Adam L Moore, Tanushree Ganguly
1Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USA.
The Prostate
|August 23, 2012
Summary
This study developed a prostate-specific membrane antigen (PSMA)-targeted SPECT agent using click chemistry. An irreversible inhibitor demonstrated superior uptake and internalization in PSMA-positive cells compared to a slowly reversible one.
Area of Science:
- Nuclear medicine
- Radiochemistry
- Prostate cancer diagnostics
Background:
- Prostate-specific membrane antigen (PSMA) is a key biomarker for prostate cancer imaging and therapy.
- PSMA internalization varies based on the binding mode of inhibitors (irreversible, slowly reversible, reversible).
Purpose of the Study:
- To develop and evaluate PSMA-targeted SPECT agents with different inhibitor binding modes.
- To assess the impact of inhibitor binding mode on PSMA-targeted SPECT agent uptake and internalization.
Main Methods:
- Synthesized PSMA-targeted clickable derivatives of irreversible (DBCO-PEG(4)-CTT-54) and slowly reversible (DBCO-PEG(4)-CTT-54.2) inhibitors.
- Assembled PSMA-targeted SPECT agents by clicking inhibitors to (99m)Tc(CO)(3)-DPA-azide.
- Evaluated selectivity, percent uptake, and internalization in PSMA-positive (LNCaP) and PSMA-negative (PC3) cells.
Main Results:
- PSMA-targeted SPECT agents showed selective uptake in PSMA-positive LNCaP cells.
- The agent based on an irreversible inhibitor ((99m)Tc(CO)(3)-DPA-DBCO-PEG(4)-CTT-54) exhibited greater uptake and internalization than the slowly reversible one ((99m)Tc(CO)(3)-DPA-DBCO-PEG(4)-CTT-54.2).
Conclusions:
- Copper-less click chemistry efficiently assembles PSMA-targeted SPECT agents.
- Inhibitor binding mode significantly affects PSMA-targeted SPECT agent internalization and uptake.
- Irreversible PSMA targeting agents show superior performance in PSMA+ cells, supporting modular assembly for imaging and therapeutics.
