18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme

PLoS One. 2014 Aug 11;9(8):e104118. doi: 10.1371/journal.pone.0104118. eCollection 2014.

Abstract

Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be resolved to two isomers in a ratio of 9:1 using analytic chiral reversed phase high performance liquid chromatography (RP-HPLC). The two fluorine-18-labeled isomers purified through nonchiral semipreparative RP-HPLC as a mixture were studied by assessing the binding affinity toward L-PGDS through a gel filtration HPLC, by analyzing radiotracer accumulation in C6 glioma cells, and by evaluating the imaging of radiotracer in a C6 glioma rat with positron emission tomography. The inhibition percentage of the production of PGD2 from PGH2 at the presence of 200 µM of FBuEA-GS and 4-Dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)butyl]piperidine (AT-56) were 74.1 ± 4.8% and 97.6 ± 16.0%, respectively. [18F]FBuEA-GS bound L-PGDS (16.3-21.7%) but not the isoform, microsomal prostaglandin E synthase 1. No binding to GST-alpha and GST-pi was observed. The binding strength between [18F]FBuEA-GS and L-PGDS has been evaluated using analytic gel filtration HPLC at the presence of various concentrations of the cold competitor FBuEA-GS. The contrasted images indicated that the radiotracer accumulation in tumor lesions is probably related to the overexpression of L-PGDS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Animals
  • Brain Neoplasms / diagnostic imaging*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Fluorine Radioisotopes*
  • Gene Expression Regulation, Neoplastic*
  • Glutathione / chemistry*
  • Glutathione / pharmacology
  • Intramolecular Oxidoreductases / metabolism*
  • Lipocalins / metabolism*
  • Male
  • Positron-Emission Tomography / methods*
  • Prostaglandin D2 / biosynthesis
  • Prostaglandin H2 / metabolism
  • Radioactive Tracers
  • Radiochemistry
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Amides
  • Fluorine Radioisotopes
  • Lipocalins
  • Radioactive Tracers
  • Prostaglandin H2
  • Intramolecular Oxidoreductases
  • prostaglandin R2 D-isomerase
  • Glutathione
  • Prostaglandin D2

Grant support

Chung-Shan Yu was supported by National Science Council of Taiwan and CGMH_NTHU Joint Research. Ying-Cheng Huang was supported by National Science Council of Taiwan, CGMH_NTHU Joint Research, and Chang-Gung Medical Research Project. The authors are grateful to the National Science Council of Taiwan, CGMH_NTHU Joint Research, and Chang-Gung Medical Research Project for providing financial support via the following grants: NSC-100-2113-M-007-003, NSC-97-2314-B-182A-020-MY3, NSC-97-2314-B-182A-020-MY3, CGTH96N2342E1, CMRPG390931, CMRPG3A0512, CMRPG3B0361, and CMRPG3C0331. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.