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
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.
(2010) Journal of Medicinal Chemistry, volume 53, issue 10, pp. 3944 - 3953
(Article)
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
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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 (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 [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. © 2010 American Chemical Society.
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Keywords: tetraxetan, acid, alkyne derivative, azide, copper, dimer, indium 111, monomer, octreotide, octreotide[3 tyrosine], octreotide[3 tyrosine] 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid, radioisotope, sulfonyl azide, tetramer, thio acid, unclassified drug, amidation, animal cell, animal experiment, animal model, animal tissue, article, binding assay, catalysis, controlled study, cycloaddition, drug blood level, drug design, drug distribution, drug screening, drug synthesis, drug tissue level, drug uptake, imaging, in vivo study, isotope labeling, lipophilicity, male, mouse, nonhuman, rat, receptor binding, subcutaneous tissue
ISSN: 0022-2623
Publisher: American Chemical Society : Division of Carbohydrate Chemistry
(Peer reviewed)