Synthesis and preliminary biological evaluation of radiolabeled O6-benzylguanine derivatives, new potential PET imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in breast cancer

Qi Huang Zheng, Xuan Liu, Xiangshu Fei, Ji Quan Wang, David W. Ohannesian, Leonard C. Erickson, K. Lee Stone, Gary D. Hutchins

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Novel radiolabeled O6-benzylguanine (O6-BG) derivatives, 2-amino-6-O-[11C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([11C]p-O6-AMMP, 1a; [11C]m-O6-AMMP, 1b; [11C]o-O6-AMMP, 1c), 2-amino-6-O-benzyloxy-9-[11C]-[(methoxycarbonyl)methyl]purine ([11C]ABMMP, 2), and 2-amino-6-O-benzyloxy-9-[11C]-[(4′-methoxycarbonyl)benzyl] purine ([11C]ABMBP, 3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in breast cancer. The appropriate precursors for radiolabeling were obtained in two to three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-[11C]methylation of hydroxymethyl or acid precursors using [11C]methyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45-65% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 20-25 min. The activity of unlabeled standard samples of 1-3 was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate the synthesized analogs have similar strong inhibitory effectiveness on AGT in comparison with the parent compound O6-BG. The results warrant further evaluation of these radiotracers as new potential PET imaging agents for the DNA repair protein AGT in breast cancer in vivo.

Original languageEnglish (US)
Pages (from-to)405-415
Number of pages11
JournalNuclear Medicine and Biology
Volume30
Issue number4
DOIs
StatePublished - May 2003

Fingerprint

DNA Repair
Positron-Emission Tomography
Breast Neoplasms
Purines
Solid Phase Extraction
Oligonucleotides
Biological Assay
Methylation
Proteins
Acids
O(6)-benzylguanine
purine
DNA alkyltransferase
methyl triflate
In Vitro Techniques
2-amino-6-chloropurine

Keywords

  • Breast cancer
  • Carbon-11
  • DNA repair protein
  • O-Alkylguanine-DNA alkyltransferase
  • Positron emission tomography
  • Radiolabeled O-benzylguanine derivatives

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Synthesis and preliminary biological evaluation of radiolabeled O6-benzylguanine derivatives, new potential PET imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase in breast cancer. / Zheng, Qi Huang; Liu, Xuan; Fei, Xiangshu; Wang, Ji Quan; Ohannesian, David W.; Erickson, Leonard C.; Stone, K. Lee; Hutchins, Gary D.

In: Nuclear Medicine and Biology, Vol. 30, No. 4, 05.2003, p. 405-415.

Research output: Contribution to journalArticle

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abstract = "Novel radiolabeled O6-benzylguanine (O6-BG) derivatives, 2-amino-6-O-[11C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([11C]p-O6-AMMP, 1a; [11C]m-O6-AMMP, 1b; [11C]o-O6-AMMP, 1c), 2-amino-6-O-benzyloxy-9-[11C]-[(methoxycarbonyl)methyl]purine ([11C]ABMMP, 2), and 2-amino-6-O-benzyloxy-9-[11C]-[(4′-methoxycarbonyl)benzyl] purine ([11C]ABMBP, 3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in breast cancer. The appropriate precursors for radiolabeling were obtained in two to three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-[11C]methylation of hydroxymethyl or acid precursors using [11C]methyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45-65{\%} radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 20-25 min. The activity of unlabeled standard samples of 1-3 was evaluated via an in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate the synthesized analogs have similar strong inhibitory effectiveness on AGT in comparison with the parent compound O6-BG. The results warrant further evaluation of these radiotracers as new potential PET imaging agents for the DNA repair protein AGT in breast cancer in vivo.",
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AU - Fei, Xiangshu

AU - Wang, Ji Quan

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AU - Stone, K. Lee

AU - Hutchins, Gary D.

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