Solid-Phase Synthesis of DOTA-Peptides

• Published in: Chemistry : a European journal Vol. 10; no. 5; pp. 1149 - 1155
• Main Authors: De León-Rodriguez, Luis M., Kovacs, Zoltan, Dieckmann, Gregg R., Sherry, A. Dean
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 05.03.2004; WILEY‐VCH Verlag; Wiley
• Subjects: Amino Acids - chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Fluorenes - chemical synthesis; Gadolinium - chemistry; gadolinium complexes; Heterocyclic Compounds, 1-Ring - chemistry; Ligands; macrocyclic ligands; Macromolecular Substances; Molecular Structure; peptides; Peptides - chemical synthesis; Physical Sciences; Science & Technology; solid-phase synthesis; gadolinium complexes; CELLS; macrocyclic ligands; ANALOG; CHELATORS; peptides; solid-phase synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200305389

A general synthetic route to two DOTA‐linked N‐Fmoc amino acids (DOTA‐F and DOTA‐K) is described that allows insertion of DOTA at any endo‐position within a peptide sequence. Three model pentapeptides were prepared to test the general utility of these derivatives in solid‐phase peptide synthesis. Both DOTA derivatives reacted smoothly by means of standard HBTU activation chemistry to the point of insertion of the DOTA amino acid, but extension of the peptide chain beyond the DOTA‐amino acid insertion required the use of pre‐activated C‐pentafluorophenyl ester N‐α‐Fmoc amino acids. Three Gal‐80 binding peptides (12‐mers) were then prepared by using this methodology with DOTA positioned either at the N terminus or at one of two different internal positions;the binding of the resulting GdDOTA‐12‐mers to Gal‐80 were compared. The methodology described here allows versatile, controlled introduction of DOTA into any location within a peptide sequence. This provides a potential method for the screening of libraries of DOTA‐linked peptides for optimal targeting properties. DOTA‐insertion into peptides: Fmoc protected DOTA–phenylalanine and lysine derivatives were synthesized and incorporated into peptides using solid‐phase peptide synthesis (SPPS) as shown in the reaction below.