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Synthesis of Novel 1,4,7,10‐Tetraazacyclodecane‐1,4,7,10‐Tetraacetic Acid (DOTA) Derivatives for Chemoselective Attachment to Unprotected Polyfunctionalized Compounds
Author(s) -
Knör Sebastian,
Modlinger Armin,
Poethko Thorsten,
Schottelius Margret,
Wester HansJürgen,
Kessler Horst
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700231
Subject(s) - dota , bifunctional , chemistry , biodistribution , alkyne , chelation , click chemistry , combinatorial chemistry , chemoselectivity , oxime , cyclen , moiety , carboxylate , alkyl , organic chemistry , biochemistry , in vitro , catalysis
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 Tyr 3 ‐octreotate by chemoselective oxime ligation and Cu I ‐catalyzed azide–alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.