Evaluation of Cu-64 and Ga-68 Radiolabeled Glucagon-Like Peptide-1 Receptor Agonists as PET Tracers for Pancreatic β cell Imaging

Nilantha Bandara; Alex Zheleznyak; Kaavya Cherukuri; David A Griffith; Chris Limberakis; David A Tess; Chen Jianqing; Rikki Waterhouse; Suzanne E Lapi

doi:10.1007/s11307-015-0861-5

Evaluation of Cu-64 and Ga-68 Radiolabeled Glucagon-Like Peptide-1 Receptor Agonists as PET Tracers for Pancreatic β cell Imaging

Mol Imaging Biol. 2016 Feb;18(1):90-8. doi: 10.1007/s11307-015-0861-5.

Authors

Nilantha Bandara¹, Alex Zheleznyak¹, Kaavya Cherukuri¹, David A Griffith², Chris Limberakis³, David A Tess⁴, Chen Jianqing⁵, Rikki Waterhouse⁵, Suzanne E Lapi⁶

Affiliations

¹ Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
² Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
³ Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
⁴ Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
⁵ Clinical and Translational Imaging, Pfizer Worldwide Research and Development, Cambridge, MA, 02139, USA.
⁶ Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. lapis@mir.wustl.edu.

Abstract

Purpose: Copper-64 (Cu-64) and Galium-68 (Ga-68) radiolabeled DO3A and NODA conjugates of exendin-4 were used for preclinical imaging of pancreatic β cells via targeting of glucagon-like peptide-1 receptor (GLP-1R).

Procedures: DO3A-VS- and NODA-VS-tagged Cys(40)exendin-4 (DO3A-VS-Cys(40)-exendin-4 and NODA-VS-Cys(40)-exendin-4, respectively) were labeled with Cu-64 and Ga-68 using standard techniques. Biodistribution and dynamic positron emission tomography (PET) were carried out in normal Sprague-Dawley (SD) rats. Ex vivo autoradiography imaging was conducted with freshly frozen pancreatic thin sections.

Results: DO3A-VS- and NODA-VS-Cys(40)-exendin-4 analogues were labeled with Cu-64 and Ga-68 to a specific activity of 518.7 ± 3.7 Ci/mmol (19.19 ± 0.14 TBq/mmol) and radiochemical yield above 98 %. Biodistribution data demonstrated pancreatic uptake of 0.11 ± 0.02 %ID/g for [(64)Cu]DO3A-VS-, 0.14 ± 0.02 %ID/g for [(64)Cu]NODA-VS-, 0.11 ± 0.03 for [(68)Ga]DO3A-VS-, and 0.26 ± 0.03 for [(68)Ga]NODA-VS-Cys(40)-exendin-4. Excess exendin-4 and exendin-(9-39)-amide displaced all four Cu-64 and Ga-68 labeled exendin-4 derivatives in blocking studies.

Conclusions: [(64)Cu]/[(68)Ga]DO3A-VS-Cys(40)- and [(64)Cu]/[(68)Ga]NODA-VS-Cys(40)-exendin-4 can be used as PET imaging agents specific for GLP-1R expressed on β cells. Here, we report the first evidence of pancreatic uptake visualized with exendin-4 derivative in a rat animal model via in vivo dynamic PET imaging.

Keywords: Cu-64; Exendin-4; GLP-1; GLP-1R; Ga-68; PET; Pancreatic β cells; β cell mass.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Autoradiography
Copper Radioisotopes / metabolism*
Exenatide
Gallium Radioisotopes / metabolism*
Glucagon-Like Peptide-1 Receptor / agonists*
Glucagon-Like Peptide-1 Receptor / metabolism
Heterocyclic Compounds, 1-Ring / chemistry
Insulin-Secreting Cells / diagnostic imaging*
Male
Molecular Imaging / methods*
Peptides / chemistry
Positron-Emission Tomography / methods*
Radiopharmaceuticals / metabolism*
Rats, Sprague-Dawley
Signal Processing, Computer-Assisted
Tissue Distribution
Tomography, X-Ray Computed
Venoms / chemistry
Vinyl Compounds / chemistry

Substances

1,4,7-tris(carboxymethyl)-10-(vinylsulfone)-1,4,7,10-tetraazacyclododecane
Copper Radioisotopes
Gallium Radioisotopes
Glucagon-Like Peptide-1 Receptor
Heterocyclic Compounds, 1-Ring
Peptides
Radiopharmaceuticals
Venoms
Vinyl Compounds
Exenatide

Grants and funding

P30 CA091842/CA/NCI NIH HHS/United States