Assessment of an 18F-Labeled Phosphoramidate Peptidomimetic as a New Prostate-Specific Membrane Antigen–Targeted Imaging Agent for Prostate Cancer
| Autor: | Kaveh Vejdani, Henry F. VanBrocklin, Hilla Wahnishe, Suzanne E. Lapi, Lisa Y. Wu, Clifford E. Berkman, Jessie R. Nedrow-Byers, David M. Pham, Ella F. Jones, Tiancheng Liu |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Glutamate Carboxypeptidase II
Male Pathology medicine.medical_specialty Fluorine Radioisotopes Peptidomimetic urologic and male genital diseases Article Prostate cancer Mice In vivo Cell Line Tumor LNCaP medicine Glutamate carboxypeptidase II Animals Humans Radiology Nuclear Medicine and imaging Phosphoric Acids Tissue Distribution IC50 Chemistry Prostatic Neoplasms Phosphoramidate medicine.disease Amides Imaging agent Cell Transformation Neoplastic Isotope Labeling Positron-Emission Tomography Antigens Surface Cancer research Peptides |
| Popis: | 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 (111)In-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.N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-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-(18)F-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.Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC(50)], 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 (6-fold) in kidney activity was seen in mice injected with (2).(18)F-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. |
| Databáze: | OpenAIRE |
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