Development of PSMA-targeted imaging agents for prostate cancer

Tanushree Ganguly

The cell-surface enzyme prostate-specific membrane antigen (PSMA) is up-regulated and strongly expressed on prostate cancer cells associated with high grade primary, androgen independent and metastatic tumors. The ability to target and detect PSMA overexpression in human prostate cancer offers the promise of new avenues of diagnosis and treatment by allowing earlier identification of patients that are at risk for aggressive metastatic disease and provides an opportunity for development of a more personalized course of treatment for patients that would otherwise face poor clinical outcome. ProstaScint (Cytogen) is the only clinically approved PSMA targeted imaging agent for prostate cancer. ProstaScint utilizes an 111In labeled murine antibody for targeted imaging of PSMA. This antibody targets an intracellular epitope of PSMA in primarly non-viable cells and is limited by its slow distribution and clearance. Our lab has developed irreversible phosphoramidate that also target PSMA with high specificity and affinity. These small molecule PSMA inhibitors were outfitted chemically with imaging payloads without impacting their binding affinity to PSMA. A new-generation phosphoramidate-based inhibitor was synthesized having enhanced acid-stability than the previous analogs which was appended with SPECT and PET based imaging payloads and their performance was tested in vitro and in vivo, in PSMA(+) cells and tumors respectively. Our SPECT-based radioagent exhibited increasing uptake in the PSMA(+) LNCaP cells over time both in vitro and in vivo. More importantly, it was found that it was rapidly internalized into LNCaP cells, presumably through the PSMA enzyme-inhibitor complex. In addition, a convergent approach for generating the radio-agent was explored. Our new-generation PET-based radioagents displayed superior in vitro and in vivo properties as compared to our previous PET agent. This series of compounds was built to explore the structure activity relationship of these inhibitors with PSMA. Crystallization of the cold compounds with PSMA provided interesting insights into the binding of these inhibitors. Results indicated higher affinity can be induced by designing inhibitors that could utilize bidentate interactions with PSMA. The effect of increased lipophilicity on overall uptake and clearance was also assessed and radioagent with optimal lipophilicity was identified. This work demonstrates the successful development of PSMA-targeted imaging agents using our new-generation phosphoramidate inhibitor modified to deliver 99mTc, a SPECT radionuclide and 18F, a PET radionuclide. The PET-based agents in particular, showed phenomenal in vivo properties and a couple of these radioagents present themselves as candidates for clinical trials in humans.

Development of PSMA-targeted imaging agents for prostate cancer

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