Synthesis and preliminary biological evaluation of O6-[4-(2- [18F]fluoroethoxymethyl)benzyl]guanine as a novel potential PET probe for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in cancer chemotherapy

Ji Quan Wang, Emiko L. Kreklau, Barbara J. Bailey, Leonard C. Erickson, Qi Huang Zheng

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

A novel fluorine-18-labeled O6-benzylguanine (O6-BG) derivative, O6-[4-(2-[18F]fluoroethoxymethyl)benzyl] guanine (O6-[18F]FEMBG, [18F]1), has been synthesized for evaluation as a potential positron emission tomography (PET) probe for the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in cancer chemotherapy. The appropriate radiolabeling precursor N 2,9-bis(p-anisyldiphenylmethyl)-O6-[4-(hydroxymethyl) benzyl]guanine (6) and reference standard O6-[4-(2- fluoroethoxymethyl)benzyl]guanine (O6-FEMBG, 1) were synthesized from 1,4-benzenedimethanol and 2-amino-6-chloropurine in four or six steps, respectively, with moderate to excellent chemical yields. The target tracer O6-[18F]FEMBG was prepared in 20-35% radiochemical yields by reaction of MTr-protected precursor 6 with [18F]fluoroethyl bromide followed by quick deprotection reaction and purification with a simplified Silica Sep-Pak method. Total synthesis time was 60-70 min from the end of bombardment. Radiochemical purity of the formulated product was >95%, with a specific radioactivity of >1.0 Ci/μmol at the end of synthesis. The activity of unlabeled O6-FEMBG was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate that the synthesized analogue has similarly strong inhibiting effect on AGT in comparison with O6-BG and O6-4-fluorobenzylguanine (O 6-FBG). The results warrant further in vivo evaluation of O 6-[18F]FEMBG as a new potential PET probe for AGT.

Original languageEnglish (US)
Pages (from-to)5779-5786
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number20
DOIs
StatePublished - Oct 15 2005

Keywords

  • Cancer
  • O-[4-(2-[F]fluoroethoxymethyl)benzyl]guanine
  • O-alkylguanine-DNA alkyltransferase
  • Positron emission tomography
  • Probe

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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