TY - JOUR T1 - Assessment of an <sup>18</sup>F-Labeled Phosphoramidate Peptidomimetic as a New Prostate-Specific Membrane Antigen–Targeted Imaging Agent for Prostate Cancer JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 2042 LP - 2048 DO - 10.2967/jnumed.109.066589 VL - 50 IS - 12 AU - Suzanne E. Lapi AU - Hilla Wahnishe AU - David Pham AU - Lisa Y. Wu AU - Jessie R. Nedrow-Byers AU - Tiancheng Liu AU - Kaveh Vejdani AU - Henry F. VanBrocklin AU - Clifford E. Berkman AU - Ella F. Jones Y1 - 2009/12/01 UR - http://jnm.snmjournals.org/content/50/12/2042.abstract N2 - Prostate-specific membrane antigen (PSMA) is a transmembrane protein commonly found on the surface of late-stage and metastatic prostate cancer and a well-known imaging biomarker for staging and monitoring therapy. Although 111In-labeled capropmab pendetide is the only approved agent available for PSMA imaging, its clinical use is limited because of its slow distribution and clearance that leads to challenging image interpretation. A small-molecule approach using radiolabeled urea-based PSMA inhibitors as imaging agents has shown promise for prostate cancer imaging. The motivation of this work is to explore phosphoramidates as a new class of potent PSMA inhibitors to develop more effective prostate cancer imaging agents with improved specificity and clearance properties. Methods: N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) was conjugated to S-2-((2-(S-4-amino-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (Phosphoramidate (1)), yielding S-2-((2-(S-4-(4-18F-fluorobenzamido)-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (3). In vivo studies were conducted in mice bearing either LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors. PET images were acquired at 1 and 2 h with or without a preinjection of a nonradioactive version of the fluorophosphoramidate. Tissue distribution studies were performed at the end of the 2 h imaging sessions. Results: Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC50], 14 and 0.68 nM, respectively). PSMA-mediated tumor accumulation was noted in the LNCaP versus the PC-3 tumor xenografts. The LNCaP tumor uptake was also blocked by the administration of nonradioactive (2) prior to imaging studies. With the exception of the kidneys, tumor-to-tissue and tumor-to-blood ratios were greater than 5:1 at 2 h. The strong kidney uptake may be due to the known PSMA expression in the mouse kidney, because significant reduction (&gt;6-fold) in kidney activity was seen in mice injected with (2). Conclusion: 18F-labeled phosphoramidate (3) is a representative of a new class of PSMA targeting peptidomimetic molecules that shows great promise as imaging agents for detecting PSMA+ prostate tumors. ER -