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Synthesis of DOTA-conjugated multimeric [Tyr3]octreotide peptides via a combination of Cu(I)-catalyzed "click" cycloaddition and thio acid/sulfonyl azide "sulfo-click" amidation and their in vivo evaluation.

Abstract
Herein, we describe the design, synthesis, and biological evaluation of a series of DOTA-conjugated monomeric, dimeric, and tetrameric [Tyr(3)]octreotide-based analogues as a tool for tumor imaging and/or radionuclide therapy. These compounds were synthesized using a Cu(I)-catalyzed 1,3-dipolar cycloaddition ("click" reaction) between peptidic azides and dendrimer-derived alkynes and a subsequent metal-free introduction of DOTA via the thio acid/sulfonyl azide amidation ("sulfo-click" reaction). In a competitive binding assay using rat pancreatic AR42J tumor cells, the monomeric [Tyr(3)]octreotide conjugate displayed the highest binding affinity (IC(50) = 1.32 nM) followed by dimeric [Tyr(3)]octreotide (2.45 nM), [DOTA(0),Tyr(3)]octreotide (2.45 nM), and tetrameric [Tyr(3)]octreotide (14.0 nM). Biodistribution studies with BALB/c nude mice with subcutaneous AR42J tumors showed that the (111)In-labeled monomeric [Tyr(3)]octreotide conjugate had the highest tumor uptake (42.3 +/- 2.8 %ID/g) at 2 h p.i., which was better than [(111)In-DOTA(0),Tyr(3)]octreotide (19.5 +/- 4.8 %ID/g). The (111)In-labeled dimeric [Tyr(3)]octreotide conjugate showed a long tumor retention (25.3 +/- 5.9 %ID/g at 2 h p.i. and 12.1 +/- 1.3 %ID/g at 24 h p.i.). These promising results can be exploited for therapeutic applications.
AuthorsCheng-Bin Yim, Ingrid Dijkgraaf, Remco Merkx, Cees Versluis, Annemarie Eek, Gwenn E Mulder, Dirk T S Rijkers, Otto C Boerman, Rob M J Liskamp
JournalJournal of medicinal chemistry (J Med Chem) Vol. 53 Issue 10 Pg. 3944-53 (May 27 2010) ISSN: 1520-4804 [Electronic] United States
PMID20411957 (Publication Type: Journal Article)
Chemical References
  • Alkynes
  • Azides
  • Dendrimers
  • Heterocyclic Compounds, 1-Ring
  • Indium Radioisotopes
  • Polymers
  • Radiopharmaceuticals
  • Receptors, Somatostatin
  • Sulfonamides
  • Triazoles
  • 3-Tyr-octreotide
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • Copper
  • Octreotide
Topics
  • Alkynes (chemistry)
  • Animals
  • Azides (chemistry)
  • Binding, Competitive
  • Catalysis
  • Cell Line, Tumor
  • Copper
  • Cyclization
  • Dendrimers (chemistry)
  • Heterocyclic Compounds, 1-Ring (chemistry)
  • Indium Radioisotopes
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Octreotide (analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
  • Polymers
  • Radiopharmaceuticals (chemical synthesis, pharmacokinetics, pharmacology)
  • Rats
  • Receptors, Somatostatin (metabolism)
  • Structure-Activity Relationship
  • Sulfonamides (chemical synthesis, pharmacokinetics, pharmacology)
  • Tissue Distribution
  • Transplantation, Heterologous
  • Triazoles (chemical synthesis, pharmacokinetics, pharmacology)

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