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 [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 (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.