Design, synthesis and in vitro characterization of Glucagon-Like Peptide-1 derivatives for pancreatic beta cell imaging by SPECT

Babak Behnam Azad, Vanessa A. Rota, Daniel Breadner, Savita Dhanvantari, Leonard G. Luyt

Research output: Contribution to journalArticle

Abstract

Novel Glucagon-Like Peptide-1 (GLP-1) derivatives containing the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and naturally occurring Indium (113/115In) were prepared using solid-phase Fmoc methods. All synthesized peptides contained d-Ala-8, a modification known to improve resistance towards degradation by dipeptidyl peptidase-IV. The effect of increased distance between DOTA and the peptide chain was investigated using an (aminoethyl) ethoxy acetyl linker, in order to reduce steric effects imposed by DOTA. Placement of linker and DOTA moieties were also varied within the GLP-1 sequence to test for optimal metal-complex location. The binding affinity of the peptide derivatives was determined in vitro with Chinese hamster ovary cells stably transfected with a human GLP-1 receptor (CHO/GLP-1R) cell line and was shown to be in the nM range. Gamma camera imaging of an insulinoma cell line was carried out using 111In-labeled peptides. Our results suggest that the prepared GLP-1 derivatives are suitable imaging probes for studying pancreatic islet function in vivo.

Original languageEnglish (US)
Pages (from-to)1265-1272
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2010
Externally publishedYes

Fingerprint

Glucagon-Like Peptide 1
Insulin-Secreting Cells
Single-Photon Emission-Computed Tomography
Derivatives
Imaging techniques
Peptides
Cells
Dipeptidyl Peptidase 4
Cell Line
Insulinoma
Indium
Coordination Complexes
Chelating Agents
Cricetulus
Islets of Langerhans
Radionuclide Imaging
Ovary
Metals
Cameras
Degradation

Keywords

  • Beta cells
  • Glucagon-Like Peptide-1
  • Indium-111
  • Metal conjugates
  • Molecular imaging
  • Pancreatic islets
  • SPECT

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Design, synthesis and in vitro characterization of Glucagon-Like Peptide-1 derivatives for pancreatic beta cell imaging by SPECT. / Behnam Azad, Babak; Rota, Vanessa A.; Breadner, Daniel; Dhanvantari, Savita; Luyt, Leonard G.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 3, 01.02.2010, p. 1265-1272.

Research output: Contribution to journalArticle

Behnam Azad, Babak ; Rota, Vanessa A. ; Breadner, Daniel ; Dhanvantari, Savita ; Luyt, Leonard G. / Design, synthesis and in vitro characterization of Glucagon-Like Peptide-1 derivatives for pancreatic beta cell imaging by SPECT. In: Bioorganic and Medicinal Chemistry. 2010 ; Vol. 18, No. 3. pp. 1265-1272.
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