Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds.
A convenient synthesis of novel bifunctional poly(amino carboxylate) chelating agents allowing chemoselective attachment to highly functionalized biomolecules is described. Based on the well known chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), we synthesized novel bifunctional chelating agents bearing additional functional groups by alkylating 1,4,7,10-tetraazacyclododecane (cyclen) with one equivalent of para-functionalized alkyl 2-bromophenyl-acetate and three equivalents of tert-butyl 2-bromoacetate. The resulting compounds, which contain an additional carbonyl or alkyne functionality, allow site specific labeling of appropriately functionalized unprotected biomolecules in a rapid manner via click reactions. This was demonstrated by the attachment of our new DOTA derivatives to the somatostatin analogue Tyr3-octreotate by chemoselective oxime ligation and CuI-catalyzed azide-alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.
Knör
Sebastian
S
Department Chemie, Lehrstuhl für Organische Chemie II, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
Modlinger
Armin
A
Poethko
Thorsten
T
Schottelius
Margret
M
Wester
Hans-Jürgen
HJ
Kessler
Horst
H
D000480:Alkynes / Q000737:chemistry; D000586:Amination; D000818:Animals; D001386:Azides / Q000737:chemistry; D002255:Carbonic Acid / Q000737:chemistry; D002384:Catalysis; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007659:Ketones / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010091:Oximes / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D051381:Rats; D014443:Tyrosine / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000480:Alkynes; D001386:Azides; D006573:Heterocyclic Compounds, 1-Ring; D007659:Ketones; D010091:Oximes; D010455:Peptides; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D014443:Tyrosine; D002255:Carbonic Acid; D003300:Copper; D010100:Oxygen