title: Concise site-specific synthesis of DTPA-peptide conjugates: application to imaging probes for the chemokine receptor CXCR4.
abstract: Diethylenetriaminepentaacetic acid (DTPA) is a useful chelating agent for radionuclides such as (68)Ga, (99m)Tc and (111)In, which are applicable to nuclear medicine imaging. In this study, we established a facile synthetic protocol for the production of mono-DTPA-conjugated peptide probes. A novel monoreactive DTPA precursor reagent was synthesized in two steps using the chemistry of the o-nitrobenzenesulfonyl (Ns) protecting group, and under mild conditions this DTPA precursor was incorporated onto an N(ε)-bromoacetylated Lys of a protected peptide resin. The site-specific DTPA conjugation was facilitated by using a highly acid-labile 4-methyltrityl (Mtt) protecting group for the target site of the bioactive peptide during the solid-phase synthesis. A combination of both techniques yielded peptides with disulfide bonds, such as octreotide and polyphemusin II-derived CXCR4 antagonists. DTPA-peptide conjugates were purified in a single step following cleavage from the resin and disulfide bond formation. This site-specific on-resin construction strategy was used for the design and synthesis of a novel In-DTPA-labeled CXCR4 antagonist, which exhibited highly potent inhibitory activity against SDF-1-CXCR4 binding.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Masuda
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kimura
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D004369:Pentetic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D010455:Peptides; D019718:Receptors, CXCR4; D004369:Pentetic Acid