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Radioiodinated O(6)-Benzylguanine derivatives containing an azido function.

Publication ,  Journal Article
Vaidyanathan, G; White, B; Affleck, DJ; McDougald, D; Zalutsky, MR
Published in: Nucl Med Biol
January 2011

INTRODUCTION: Drug resistance to alkylator chemotherapy has been primarily attributed to the DNA repair protein alkylguanine-DNA alkyltransferase (AGT); thus, personalizing chemotherapy could be facilitated if tumor AGT content could be quantified prior to administering chemotherapy. We have been investigating the use of radiolabeled O(6)-benzylguanine (BG) analogues to label and quantify AGT in vivo. BG derivatives containing an azido function were sought to potentially enhance the targeting of these analogues to AGT, which is primarily present in the cell nucleus, either by conjugating them to nuclear localization sequence (NLS) peptides or by pretargeting via bio-orthogonal approaches. METHODS: Two O(6)-(3-iodobenzyl)guanine (IBG) derivatives containing an azido moiety-O(6)-(4-azidohexyloxymethyl-3-iodobenzyl)guanine (AHOMIBG) and O(6)-(4-azido-3-iodobenzyl)guanine (AIBG)--and their tin precursors were synthesized in multiple steps and the tin precursors were converted to radioiodinated AHOMIBG and AIBG, respectively. Both unlabeled and radioiodinated AHOMIBG analogues were conjugated to alkyne-derivatized NLS peptide heptynoyl-PK(3)RKV. The ability of these radioiodinated compounds to bind to AGT was determined by a trichloroacetic acid precipitation assay and gel electrophoresis/phosphor imaging. Labeling of an AGT-AIBG conjugate via Staudinger ligation using the (131)I-labeled phosphine ligand, 2-(diphenylphosphino)phenyl 4-[(131)I]iodobenzoate, also was investigated. RESULTS: [(131)I]AHOMIBG was synthesized in two steps from its tin precursor in 52.2 ± 7.5% (n = 5) radiochemical yield and conjugated to the NLS peptide via click reaction in 50.7 ± 4.9% (n = 6) yield. The protected tin precursor of AIBG was radioiodinated in an average radiochemical yield of 69.6 ± 4.5% (n = 7); deprotection of the intermediate gave [(131)I]AIBG in 17.8 ± 4.2% (n = 9) yield. While both [(131)I]AHOMIBG and its NLS conjugate bound to AGT pure protein, their potency as a substrate for AGT was substantially lower than that of [(125)I]IBG. Uptake of [(131)I]AHOMIBG-NLS conjugate in DAOY medulloblastoma cells was up to eightfold higher than that of [(125)I]IBG; however, the uptake was not changed when the cellular AGT content was first depleted with BG treatment. [(131)I]AIBG was almost equipotent as [(125)I]IBG with respect to binding to pure AGT; however, attempts to radiolabel AGT by treatment with unlabeled AIBG followed by Staudinger ligation using the radiolabeled phosphine ligand, 2-(diphenylphosphino)phenyl 4-[(131)I]iodobenzoate were not successful. CONCLUSION: Although AHOMIBG, and AIBG were synthesized successfully in both unlabeled and radioiodinated forms, the radioiodinated compounds failed to label AGT either after NLS peptide conjugation or via Staundiger ligation. Currently, other bio-orthogonal approaches are being evaluated for labeling AGT by pretargeting.

Duke Scholars

Published In

Nucl Med Biol

DOI

EISSN

1872-9614

Publication Date

January 2011

Volume

38

Issue

1

Start / End Page

77 / 92

Location

United States

Related Subject Headings

  • Radiochemistry
  • O(6)-Methylguanine-DNA Methyltransferase
  • Nuclear Medicine & Medical Imaging
  • Nuclear Localization Signals
  • Iodine Radioisotopes
  • Humans
  • Guanine
  • Cell Line, Tumor
  • Azides
  • 3202 Clinical sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Vaidyanathan, G., White, B., Affleck, D. J., McDougald, D., & Zalutsky, M. R. (2011). Radioiodinated O(6)-Benzylguanine derivatives containing an azido function. Nucl Med Biol, 38(1), 77–92. https://doi.org/10.1016/j.nucmedbio.2010.07.006
Vaidyanathan, Ganesan, Benjamin White, Donna J. Affleck, Darryl McDougald, and Michael R. Zalutsky. “Radioiodinated O(6)-Benzylguanine derivatives containing an azido function.Nucl Med Biol 38, no. 1 (January 2011): 77–92. https://doi.org/10.1016/j.nucmedbio.2010.07.006.
Vaidyanathan G, White B, Affleck DJ, McDougald D, Zalutsky MR. Radioiodinated O(6)-Benzylguanine derivatives containing an azido function. Nucl Med Biol. 2011 Jan;38(1):77–92.
Vaidyanathan, Ganesan, et al. “Radioiodinated O(6)-Benzylguanine derivatives containing an azido function.Nucl Med Biol, vol. 38, no. 1, Jan. 2011, pp. 77–92. Pubmed, doi:10.1016/j.nucmedbio.2010.07.006.
Vaidyanathan G, White B, Affleck DJ, McDougald D, Zalutsky MR. Radioiodinated O(6)-Benzylguanine derivatives containing an azido function. Nucl Med Biol. 2011 Jan;38(1):77–92.
Journal cover image

Published In

Nucl Med Biol

DOI

EISSN

1872-9614

Publication Date

January 2011

Volume

38

Issue

1

Start / End Page

77 / 92

Location

United States

Related Subject Headings

  • Radiochemistry
  • O(6)-Methylguanine-DNA Methyltransferase
  • Nuclear Medicine & Medical Imaging
  • Nuclear Localization Signals
  • Iodine Radioisotopes
  • Humans
  • Guanine
  • Cell Line, Tumor
  • Azides
  • 3202 Clinical sciences