DEVELOPMENT OF PSMA-TARGETED SPECT IMAGING AGENTS FOR PROSTATE CANCER

Jessie Rae Byers

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 and slowly reversible phosphate inhibitors 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. Our 1st generation PSMA-targeted SPECT agent based on an irreversible PSMA inhibitor core 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. The 2nd generation SPECT imaging agents focused on two objectives: 1) Modular technology for assembly and 2) Evaluating the effects of mode of binding on uptake and internalization. It was found that our 2nd generation SPECT imaging agents based on an irreversible PSMA inhibitor core, exhibited greater uptake and internalization than 2nd generation SPECT imaging agent constructed from a slowly-reversible PSMA inhibitor core. This work demonstrates the successful development of PSMA-targeted SPECT imaging agents using phosphoramidate and phosphate inhibitors modified to deliver 99mTc, a SPECT radionuclide. In addition, our 2nd generation PSMA-targeted SPECT agent demonstrated that it can be assembled efficiently using copper-less click chemistry, supporting a modular approach for the assembly of PSMA-targeted imaging and therapeutic agents.

DEVELOPMENT OF PSMA-TARGETED SPECT IMAGING AGENTS FOR PROSTATE CANCER

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