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 (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.
Yim
Cheng-Bin
CB
Department of Pharmaceutical Sciences, Faculty of Science, Division of Medicinal Chemistry and Chemical Biology, Utrecht University, Utrecht, The Netherlands.
Dijkgraaf
Ingrid
I
Merkx
Remco
R
Versluis
Cees
C
Eek
Annemarie
A
Mulder
Gwenn E
GE
Rijkers
Dirk T S
DT
Boerman
Otto C
OC
Liskamp
Rob M J
RM
D000480:Alkynes / Q000737:chemistry*; D000818:Animals; D001386:Azides / Q000737:chemistry*; D001667:Binding, Competitive; D002384:Catalysis; D045744:Cell Line, Tumor; D003300:Copper; D003500:Cyclization; D050091:Dendrimers / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D007205:Indium Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011108:Polymers; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D000480:Alkynes; D001386:Azides; D050091:Dendrimers; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D011108:Polymers; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D013449:Sulfonamides; D014230:Triazoles; C045210:3-Tyr-octreotide; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D003300:Copper; D015282:Octreotide