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Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.

Publication ,  Journal Article
Vaidyanathan, G; Affleck, DJ; Schottelius, M; Wester, H; Friedman, HS; Zalutsky, MR
Published in: Bioconjug Chem
2006

Carbohydration of N-terminus and substitution of a threonine for the threoninol residue at the C-terminus of Tyr3-octreotide (TOC) has resulted in improved pharmacokinetics and tumor targeting of its radioiodinated derivatives. Yet, these peptides are very susceptible to in vivo deiodination due to the similarity of monoiodotyrosine (MIT) to thyroid hormone. The goal of this work was to develop octreotate analogues containing both a sugar moiety and a nontyrosine prosthetic group on which a radioiodine or 211At can be introduced. Solid-phase synthesis and subsequent modifications delivered an iodo standard of the target peptide N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-iodobenzoyl)-Lys0-octreotate (GIBLO) and the corresponding tin precursor N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-[(3-tri-n-butylstannyl)benzoyl]-Lys0-octreotate (GTBLO). GIBLO displaced [125I]TOC from somatostatin receptor subtype 2 (SSTR2)-positive AR42J rat pancreatic tumor cell membranes with an IC50 of 0.46 +/- 0.05 nM suggesting that GIBLO retained affinity to SSTR2. GTBLO was radiohalogenated to [131I]GIBLO and N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(3-[211At]astatobenzoyl)-Lys0-octreotate ([211At]GABLO) in 21.2 +/- 4.9% and 46.8 +/- 9.5% radiochemical yields, respectively. From a paired-label internalization assay using D341 Med medulloblastoma cells, the maximum specific internalized radioactivity from [131I]GIBLO was 1.78 +/- 0.8% of input dose compared to 9.67 +/- 0.43% for N(alpha)-(1-deoxy-D-fructosyl)-[125I]iodo-Tyr3-octreotate ([125I]I-Gluc-TOCA). Over a 4 h period, the extent of internalization of [131I]GIBLO and [211At]GABLO was similar in this cell line. In D341 Med murine subcutaneous xenografts, the uptake of [125I]I-Gluc-TOCA at 0.5, 1 and 4 h was 21.5 +/- 4.0% ID/g, 18.8 +/- 7.7% ID/g, and 0.9 +/- 0.4% ID/g, respectively. In comparison, these values for [131I]GIBLO were 6.9 +/- 1.2% ID/g, 4.7 +/- 1.4% ID/g, and 0.8 +/- 0.5% ID/g. Both in vitro and in vivo catabolism studies did not suggest the severance of the lys0 along with its appendages from the peptide. Taken together, although GIBLO maintained affinity to SSTR2, its tumor uptake both in vitro and in vivo was substantially lower than that of I-Gluc-TOCA suggesting other factors such as net charge and overall geometry of the peptide may be important.

Duke Scholars

Published In

Bioconjug Chem

DOI

ISSN

1043-1802

Publication Date

2006

Volume

17

Issue

1

Start / End Page

195 / 203

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Tin
  • Receptors, Somatostatin
  • Rats
  • Peptides, Cyclic
  • Peptides
  • Organic Chemistry
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
 

Citation

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Vaidyanathan, G., Affleck, D. J., Schottelius, M., Wester, H., Friedman, H. S., & Zalutsky, M. R. (2006). Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor. Bioconjug Chem, 17(1), 195–203. https://doi.org/10.1021/bc0502560
Vaidyanathan, G., D. J. Affleck, M. Schottelius, H. Wester, H. S. Friedman, and M. R. Zalutsky. “Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.Bioconjug Chem 17, no. 1 (2006): 195–203. https://doi.org/10.1021/bc0502560.
Vaidyanathan G, Affleck DJ, Schottelius M, Wester H, Friedman HS, Zalutsky MR. Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor. Bioconjug Chem. 2006;17(1):195–203.
Vaidyanathan, G., et al. “Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor.Bioconjug Chem, vol. 17, no. 1, 2006, pp. 195–203. Pubmed, doi:10.1021/bc0502560.
Vaidyanathan G, Affleck DJ, Schottelius M, Wester H, Friedman HS, Zalutsky MR. Synthesis and evaluation of glycosylated octreotate analogues labeled with radioiodine and 211At via a tin precursor. Bioconjug Chem. 2006;17(1):195–203.
Journal cover image

Published In

Bioconjug Chem

DOI

ISSN

1043-1802

Publication Date

2006

Volume

17

Issue

1

Start / End Page

195 / 203

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Tin
  • Receptors, Somatostatin
  • Rats
  • Peptides, Cyclic
  • Peptides
  • Organic Chemistry
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice