A high-affinity [ 18 F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

Autor: Clifford E. Berkman, Hendry Cahaya, Stephanie T. Murphy, Joseph E. Blecha, Shorouk Dannoon, Tanushree Ganguly, Salma Jivan, Ella F. Jones, Cyril Barinka, Christopher R. Drake, Henry F. VanBrocklin, Mark R. Hopkins
Rok vydání: 2015
Předmět:
Models
Molecular
Glutamate Carboxypeptidase II
Male
Pathology
Fluorine Radioisotopes
Aging
Cancer Research
Peptidomimetic
Protein Conformation
Phosphoramidate
urologic and male genital diseases
Mice
Drug Stability
Models
Glutamate carboxypeptidase II
Tissue Distribution
Cancer
Tumor
Prostate Cancer
Imaging agent
3. Good health
Surface
Flourine-18
Nuclear Medicine & Medical Imaging
Radiology Nuclear Medicine and imaging
Isotope Labeling
Antigens
Surface
Biomedical Imaging
Molecular Medicine
Urologic Diseases
medicine.medical_specialty
Biodistribution
Clinical Sciences
Article
Cell Line
Inhibitory Concentration 50
In vivo
Cell Line
Tumor
LNCaP
medicine
PSMA
Animals
Humans
Radiology
Nuclear Medicine and imaging
Phosphoric Acids
Protease Inhibitors
Antigens
business.industry
Prostatic Neoplasms
Molecular
Biological Transport
Amides
In vitro
PET
Positron-Emission Tomography
Cancer research
Peptidomimetics
business
Zdroj: Nuclear medicine and biology, vol 42, iss 10
ISSN: 0969-8051
DOI: 10.1016/j.nucmedbio.2015.06.003
Popis: Introduction In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. Methods p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [ 18 F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(−) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. Results The crystallographic data showed interaction of the p -fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [ 18 F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(−) cells (0.08%) at 4h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4h. Conclusions We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [ 18 F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. Advances in Knowledge The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [ 18 F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.
Databáze: OpenAIRE
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