Synthesis and characterization of (18)F-labeled active site inhibited factor VII (ASIS)

Activated factor VII blocked in the active site with Phe-Phe-Arg-chloromethyl ketone (active site inhibited factor VII (ASIS)) is a 50-kDa protein that binds with high affinity to its receptor, tissue factor (TF). TF is a transmembrane glycoprotein that plays an important role in, for example, throm...

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Bibliographic Details
Published in:Journal of labelled compounds & radiopharmaceuticals 2015-05, Vol.58 (5), p.196-201
Main Authors: Erlandsson, Maria, Nielsen, Carsten H, Jeppesen, Troels E, Kristensen, Jesper B, Petersen, Lars C, Madsen, Jacob, Kjaer, Andreas
Format: Article
Language:English
Subjects:
Amino Acid Chloromethyl Ketones - chemistry
Amino Acid Chloromethyl Ketones - pharmacology
Animals
Catalytic Domain
Factor VII - antagonists & inhibitors
Factor VII - chemistry
Fluorine Radioisotopes - chemistry
Mice
Radiopharmaceuticals - chemical synthesis
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - pharmacokinetics
Tissue Distribution
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Summary:Activated factor VII blocked in the active site with Phe-Phe-Arg-chloromethyl ketone (active site inhibited factor VII (ASIS)) is a 50-kDa protein that binds with high affinity to its receptor, tissue factor (TF). TF is a transmembrane glycoprotein that plays an important role in, for example, thrombosis, metastasis, tumor growth, and tumor angiogenesis. The aim of this study was to develop an (18)F-labeled ASIS derivative to assess TF expression in tumors. Active site inhibited factor VII was labeled using N-succinimidyl-4-[(18)F]fluorobenzoate, and the [(18)F]ASIS was purified on a PD-10 desalting column. The radiochemical yield was 25 ± 6%, the radiochemical purity was >97%, and the pseudospecific radioactivity was 35 ± 9 GBq/µmol. The binding efficacy was evaluated in pull-down experiments, which monitored the binding of unlabeled ASIS and [(18)F]ASIS to TF and to a specific anti-factor VII antibody (F1A2-mAb). No significant difference in binding efficacy between [(18)F]ASIS and ASIS could be detected. Furthermore, [(18)F]ASIS was relatively stable in vitro and in vivo in mice. In conclusion, [(18)F]ASIS has for the first time been successfully synthesized as a possible positron emission tomography tracer to image TF expression levels. In vivo positron emission tomography studies to evaluate the full potential of [(18)F]ASIS are in progress.
ISSN:1099-1344
DOI:10.1002/jlcr.3282