A phosphoramidate-based prostate-specific membrane antigen-targeted SPECT agent

BACKGROUND Prostate‐specific membrane antigen (PSMA) remains an active target for imaging and therapeutic applications for prostate cancer. METHODS In the present study, an irreversible phosphoramidate inhibitor, CTT‐54 (IC50 = 14 nM), has been modified to deliver 99mTc‐(CO)3‐DTPA as a SPECT imaging payload to PSMA+ cells in vivo and in vitro. Percent uptake, competitive binding, and internalization will evaluate the imaging agent in vitro. Preliminary biodistribution and imaging will be utilized for in vivo evaluation. RESULTS In vitro studies demonstrate that the radiotracer 99mTc‐(CO)3‐DTPA‐CTT‐54 exhibits increasing cellular uptake in the PSMA+ LNCaP cells over time. More importantly, it was found that 99mTc‐(CO)3‐DTPA‐CTT‐54 is rapidly internalized into LNCaP cells, presumably through the PSMA enzyme‐inhibitor complex. In a pilot biodistribution study, increasing accumulation of the radiotracer in LNCaP xenografts was observed from 2 to 4 hr and significant clearance from non‐target tissues. CONCLUSIONS While DTPA may not represent the ideal chelate structure for 99mTc(CO)3, the data provides proof‐of‐concept support for the development of a next‐generation phosphoramidate‐based PSMA inhibitor‐conjugates for use as SPECT imaging agents. Prostate 72:904–912, 2012. © 2011 Wiley Periodicals, Inc.