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 Citations (Scopus)

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

Fingerprint

Positron emission tomography
Chemotherapy
DNA Probes
Guanine
DNA Repair
Positron-Emission Tomography
Assays
Repair
Drug Therapy
Fluorine
Radioactivity
Bromides
Oligonucleotides
Silicon Dioxide
Biological Assay
Purification
Neoplasms
Proteins
Derivatives
DNA alkyltransferase

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

Cite this

@article{746e0f7630b74594acbe1cc13c936a59,
title = "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",
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.",
keywords = "Cancer, O-[4-(2-[F]fluoroethoxymethyl)benzyl]guanine, O-alkylguanine-DNA alkyltransferase, Positron emission tomography, Probe",
author = "Wang, {Ji Quan} and Kreklau, {Emiko L.} and Bailey, {Barbara J.} and Erickson, {Leonard C.} and Qi-Huang Zheng",
year = "2005",
month = "10",
day = "15",
doi = "10.1016/j.bmc.2005.05.061",
language = "English",
volume = "13",
pages = "5779--5786",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "20",

}

TY - JOUR

T1 - 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

AU - Wang, Ji Quan

AU - Kreklau, Emiko L.

AU - Bailey, Barbara J.

AU - Erickson, Leonard C.

AU - Zheng, Qi-Huang

PY - 2005/10/15

Y1 - 2005/10/15

N2 - 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.

AB - 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.

KW - Cancer

KW - O-[4-(2-[F]fluoroethoxymethyl)benzyl]guanine

KW - O-alkylguanine-DNA alkyltransferase

KW - Positron emission tomography

KW - Probe

UR - http://www.scopus.com/inward/record.url?scp=24344483502&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24344483502&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2005.05.061

DO - 10.1016/j.bmc.2005.05.061

M3 - Article

C2 - 15993610

AN - SCOPUS:24344483502

VL - 13

SP - 5779

EP - 5786

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 20

ER -