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

Herein, we describe the design, synthesis, and biological evaluation of a series of DOTA-conjugated monomeric, dimeric, and tetrameric [Tyr3]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 cycloa...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-05, Vol.53 (10), p.3944-3953
Main Authors: Yim, Cheng-Bin, Dijkgraaf, Ingrid, Merkx, Remco, Versluis, Cees, Eek, Annemarie, Mulder, Gwenn E, Rijkers, Dirk T. S, Boerman, Otto C, Liskamp, Rob M. J
Format: Article
Language:English
Subjects:
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
Octreotide - chemical synthesis
Octreotide - pharmacokinetics
Octreotide - pharmacology
Polymers
Radiopharmaceuticals - chemical synthesis
Radiopharmaceuticals - pharmacokinetics
Radiopharmaceuticals - pharmacology
Rats
Receptors, Somatostatin - metabolism
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Tissue Distribution
Transplantation, Heterologous
Triazoles - chemical synthesis
Triazoles - pharmacokinetics
Triazoles - pharmacology
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Summary:Herein, we describe the design, synthesis, and biological evaluation of a series of DOTA-conjugated monomeric, dimeric, and tetrameric [Tyr3]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 [Tyr3]octreotide conjugate displayed the highest binding affinity (IC50 = 1.32 nM) followed by dimeric [Tyr3]octreotide (2.45 nM), [DOTA0,Tyr3]octreotide (2.45 nM), and tetrameric [Tyr3]octreotide (14.0 nM). Biodistribution studies with BALB/c nude mice with subcutaneous AR42J tumors showed that the 111In-labeled monomeric [Tyr3]octreotide conjugate had the highest tumor uptake (42.3 ± 2.8 %ID/g) at 2 h p.i., which was better than [111In-DOTA0,Tyr3]octreotide (19.5 ± 4.8 %ID/g). The 111In-labeled dimeric [Tyr3]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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100246m