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

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

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

Journal Article · Tue May 19 00:00:00 EDT 2015 · Molecular Imaging and Biology

DOI:https://doi.org/10.1007/s11307-015-0861-5· OSTI ID:1467465

Bandara, Nilantha ^[1]; Zheleznyak, Alex ^[2]; Cherukuri, Kaavya ^[2]; Griffith, David A. ^[3]; Limberakis, Chris ^[4]; Tess, David A. ^[5]; Jianqing, Chen ^[6]; Waterhouse, Rikki ^[6]; Lapi, Suzanne E. ^[2]

Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology; Washington Univ., St. Louis, MO (United States)
Washington Univ. School of Medicine, St. Louis, MO (United States). Dept. of Radiology
Pfizer Worldwide Research and Development, Cambridge, MA (United States). Worldwide Medicinal Chemistry
Pfizer Worldwide Research and Development, Groton, CT (United States). Worldwide Medicinal Chemistry
Pfizer Worldwide Research and Development, Cambridge, MA (United States). Pharmacokinetics, Dynamics and Metabolism
Pfizer Worldwide Research and Development, Cambridge, MA (United States). Clinical and Translational Imaging

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 Cys⁴⁰exendin-4 (DO3A-VS-Cys⁴⁰-exendin-4 and NODA-VS-Cys⁴⁰-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 [⁶⁴Cu]DO3A-VS-, 0.14 ± 0.02 %ID/g for [⁶⁴Cu]NODA-VS-, 0.11 ± 0.03 for [⁶⁸Ga]DO3A-VS-, and 0.26 ± 0.03 for [⁶⁸Ga]NODA-VS-Cys⁴⁰-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: [⁶⁴Cu]/[⁶⁸Ga]DO3A-VS-Cys⁴⁰- and [⁶⁴Cu]/[⁶⁸Ga]NODA-VS-Cys⁴⁰-exendin-4 can be used as PET imaging agents specific for GLP-1R expressed on β cells. Here in this paper, we report the first evidence of pancreatic uptake visualized with exendin-4 derivative in a rat animal model via in vivo dynamic PET imaging.

View Accepted Manuscript (DOE)

Research Organization:: The Washington Univ., St. Louis, MO (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: SC0002032

OSTI ID:: 1467465

Journal Information:: Molecular Imaging and Biology, Journal Name: Molecular Imaging and Biology Journal Issue: 1 Vol. 18; ISSN 1536-1632

Country of Publication:: United States

Language:: English

References (36)

Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals: Chelators for copper radionuclides in PET radiopharmaceuticals Cai, Zhengxin; Anderson, Carolyn J. Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 57, Issue 4 https://doi.org/10.1002/jlcr.3165	journal	December 2013
Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Meier, J. J.; Bhushan, A.; Butler, A. E. Diabetologia, Vol. 48, Issue 11 https://doi.org/10.1007/s00125-005-1949-2	journal	October 2005
Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results Gotthardt, Martin; Fischer, Marc; Naeher, Inga European Journal of Nuclear Medicine and Molecular Imaging, Vol. 29, Issue 5 https://doi.org/10.1007/s00259-002-0761-1	journal	March 2002
18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma Kiesewetter, Dale O.; Gao, Haokao; Ma, Ying European Journal of Nuclear Medicine and Molecular Imaging, Vol. 39, Issue 3 https://doi.org/10.1007/s00259-011-1980-0	journal	December 2011
Ex Vivo Imaging of Pancreatic Beta Cells using a Radiolabeled GLP-1 Receptor Agonist Connolly, Brett M.; Vanko, Amy; McQuade, Paul Molecular Imaging and Biology, Vol. 14, Issue 1 https://doi.org/10.1007/s11307-011-0481-7	journal	March 2011
Beta-Cell Imaging: Call for Evidence-Based and Scientific Approach Blomberg, Björn A.; Codreanu, Ion; Cheng, Gang Molecular Imaging and Biology, Vol. 15, Issue 2 https://doi.org/10.1007/s11307-013-0620-4	journal	February 2013
Effects of Chelator Modifications on 68Ga-Labeled [Tyr3]Octreotide Conjugates Lin, Mai; Welch, Michael J.; Lapi, Suzanne E. Molecular Imaging and Biology, Vol. 15, Issue 5 https://doi.org/10.1007/s11307-013-0627-x	journal	March 2013
64Cu- and 68Ga-Labelled [Nle14,Lys40(Ahx-NODAGA)NH2]-Exendin-4 for Pancreatic Beta Cell Imaging in Rats Kirsi, Mikkola; Cheng-Bin, Yim; Veronica, Fagerholm Molecular Imaging and Biology, Vol. 16, Issue 2 https://doi.org/10.1007/s11307-013-0691-2	journal	October 2013
Use of 125I-[Y39]exendin-4 to characterize exendin receptors on dispersed pancreatic acini and gastric chief cells from guinea pig Singh, Gurcharn; Eng, John; Raufman, Jean-Pierre Regulatory Peptides, Vol. 53, Issue 1 https://doi.org/10.1016/0167-0115(94)90158-9	journal	August 1994
Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. Eng, J.; Kleinman, W. A.; Singh, L. Journal of Biological Chemistry, Vol. 267, Issue 11 https://doi.org/10.1016/S0021-9258(18)42531-8	journal	April 1992
Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. Göke, R.; Fehmann, H. C.; Linn, T. Journal of Biological Chemistry, Vol. 268, Issue 26 https://doi.org/10.1016/S0021-9258(19)36565-2	journal	September 1993
Efficient production of high specific activity 64Cu using a biomedical cyclotron McCarthy, Deborah W.; Shefer, Ruth E.; Klinkowstein, Robert E. Nuclear Medicine and Biology, Vol. 24, Issue 1 https://doi.org/10.1016/S0969-8051(96)00157-6	journal	January 1997
A semi-automated system for the routine production of copper-64 Kume, Maiko; Carey, Paul C.; Gaehle, Gregory Applied Radiation and Isotopes, Vol. 70, Issue 8 https://doi.org/10.1016/j.apradiso.2012.03.009	journal	August 2012
Long-term evaluation of TiO2-based 68Ge/68Ga generators and optimized automation of [68Ga]DOTATOC radiosynthesis Lin, Mai; Ranganathan, David; Mori, Tetsuya Applied Radiation and Isotopes, Vol. 70, Issue 10 https://doi.org/10.1016/j.apradiso.2012.05.009	journal	October 2012
GLP-1 receptor antagonist as a potential probe for pancreatic β-cell imaging Mukai, Eri; Toyoda, Kentaro; Kimura, Hiroyuki Biochemical and Biophysical Research Communications, Vol. 389, Issue 3 https://doi.org/10.1016/j.bbrc.2009.09.014	journal	November 2009
Novel hexadentate and pentadentate chelators for 64Cu-based targeted PET imaging Sin, Inseok; Kang, Chi Soo; Bandara, Nilantha Bioorganic & Medicinal Chemistry, Vol. 22, Issue 8 https://doi.org/10.1016/j.bmc.2014.02.041	journal	April 2014
Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development De Silva, Ravindra A.; Jain, Sandeep; Lears, Kimberly A. Nuclear Medicine and Biology, Vol. 39, Issue 8 https://doi.org/10.1016/j.nucmedbio.2012.05.009	journal	November 2012
A new technique for in vivo imaging of specific GLP-1 binding sites: First results in small rodents Gotthardt, Martin; Lalyko, Georg; van Eerd-Vismale, Julliëtte Regulatory Peptides, Vol. 137, Issue 3 https://doi.org/10.1016/j.regpep.2006.07.005	journal	December 2006
In Vivo Imaging of Transplanted Islets with ⁶⁴ Cu-DO3A-VS-Cys ⁴⁰ -Exendin-4 by Targeting GLP-1 Receptor Wu, Zhanhong; Todorov, Ivan; Li, Lin Bioconjugate Chemistry, Vol. 22, Issue 8 https://doi.org/10.1021/bc200132t	journal	August 2011
Glucagon-like Peptide-1 (GLP-1) Analogs: Recent Advances, New Possibilities, and Therapeutic Implications Manandhar, Bikash; Ahn, Jung-Mo Journal of Medicinal Chemistry, Vol. 58, Issue 3 https://doi.org/10.1021/jm500810s	journal	November 2014
PET of Insulinoma Using ¹⁸ F-FBEM-EM3106B, a New GLP-1 Analogue Gao, Haokao; Niu, Gang; Yang, Min Molecular Pharmaceutics, Vol. 8, Issue 5 https://doi.org/10.1021/mp200141x	journal	July 2011
Circulation and Degradation of GIP and GLP-1 Deacon, C. F. Hormone and Metabolic Research, Vol. 36, Issue 11/12 https://doi.org/10.1055/s-2004-826160	journal	November 2004
Glucagon-like Peptide 1–Receptor Scans to Localize Occult Insulinomas Wild, Damian; Mäcke, Helmut; Christ, Emanuel New England Journal of Medicine, Vol. 359, Issue 7 https://doi.org/10.1056/NEJMc0802045	journal	August 2008
Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Thorens, B. Proceedings of the National Academy of Sciences, Vol. 89, Issue 18 https://doi.org/10.1073/pnas.89.18.8641	journal	September 1992
Postmortem Autolysis in the Pancreas: Multivariate Statistical Study. The Influence of Clinicopathological Conditions Shimizu, Michio; Hayashi, Takuji; Saitoh, Yoichi Pancreas, Vol. 5, Issue 1 https://doi.org/10.1097/00006676-199001000-00013	journal	January 1990
Relationship between β-cell mass and diabetes onset Matveyenko, A. V.; Butler, P. C. Diabetes, Obesity and Metabolism, Vol. 10 https://doi.org/10.1111/j.1463-1326.2008.00939.x	journal	November 2008
International Union of Pharmacology. XXXV. The Glucagon Receptor Family Mayo, Kelly E.; Miller, Laurence J.; Bataille, Dominique Pharmacological Reviews, Vol. 55, Issue 1 https://doi.org/10.1124/pr.55.1.6	journal	March 2003
The Physiology of Glucagon-like Peptide 1 Holst, Jens Juul Physiological Reviews, Vol. 87, Issue 4 https://doi.org/10.1152/physrev.00034.2006	journal	October 2007
The Glucagon-Like Peptides Kieffer, Timothy James; Francis Habener, Joel Endocrine Reviews, Vol. 20, Issue 6 https://doi.org/10.1210/edrv.20.6.0385	journal	December 1999
Expression of the GLP-1 Receptor in Mouse, Rat, and Human Pancreas Tornehave, Ditte; Kristensen, Peter; Rømer, John Journal of Histochemistry & Cytochemistry, Vol. 56, Issue 9 https://doi.org/10.1369/jhc.2008.951319	journal	June 2008
Receptors for glucagon-like peptide-1(7–36) amide on rat insulinoma-derived cells Göke, R.; Conlon, J. M. Journal of Endocrinology, Vol. 116, Issue 3 https://doi.org/10.1677/joe.0.1160357	journal	March 1988
-Cell Deficit and Increased -Cell Apoptosis in Humans With Type 2 Diabetes Butler, A. E.; Janson, J.; Bonner-Weir, S. Diabetes, Vol. 52, Issue 1 https://doi.org/10.2337/diabetes.52.1.102	journal	January 2003
GLP-1 Receptor Expression in Human Tumors and Human Normal Tissues: Potential for In Vivo Targeting Korner, M.; Stockli, M.; Waser, B. Journal of Nuclear Medicine, Vol. 48, Issue 5 https://doi.org/10.2967/jnumed.106.038679	journal	May 2007
Exendin-4-Based Radiopharmaceuticals for Glucagonlike Peptide-1 Receptor PET/CT and SPECT/CT Wild, D.; Wicki, A.; Mansi, R. Journal of Nuclear Medicine, Vol. 51, Issue 7 https://doi.org/10.2967/jnumed.110.074914	journal	July 2010
In Vivo Imaging of the Glucagonlike Peptide 1 Receptor in the Pancreas with 68Ga-Labeled DO3A-Exendin-4 Selvaraju, R. K.; Velikyan, I.; Johansson, L. Journal of Nuclear Medicine, Vol. 54, Issue 8 https://doi.org/10.2967/jnumed.112.114066	journal	June 2013
Pancreatic islet plasticity: Interspecies comparison of islet architecture and composition Steiner, Donald J.; Kim, Abraham; Miller, Kevin Islets, Vol. 2, Issue 3 https://doi.org/10.4161/isl.2.3.11815	journal	May 2010

Cited By (4)

Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas Abbas, Ahmed; Beamish, Christine; McGirr, Rebecca F1000Research, Vol. 5 https://doi.org/10.12688/f1000research.9129.1	journal	January 2016
Radiomanganese PET Detects Changes in Functional β-Cell Mass in Mouse Models of Diabetes Hernandez, Reinier; Graves, Stephen A.; Gregg, Trillian Diabetes, Vol. 66, Issue 8 https://doi.org/10.2337/db16-1285	journal	May 2017
Radiolabeled Cationic Peptides for Targeted Imaging of Infection Aweda, Tolulope A.; Muftuler, Zumrut F. B.; Massicano, Adriana V. F. Contrast Media & Molecular Imaging, Vol. 2019 https://doi.org/10.1155/2019/3149249	journal	October 2019
Characterization of 5-(2-18F-fluoroethoxy)-L-tryptophan for PET imaging of the pancreas Abbas, Ahmed; Beamish, Christine; McGirr, Rebecca F1000Research, Vol. 5 https://doi.org/10.12688/f1000research.9129.2	journal	January 2016

Similar Records

Non-invasive glucagon-like peptide-1 receptor imaging in pancreas with {sup 18}F-Al labeled Cys{sup 39}-exendin-4

Journal Article · Thu Feb 25 23:00:00 EST 2016 · Biochemical and Biophysical Research Communications · OSTI ID:22594258

GLP-1 receptor antagonist as a potential probe for pancreatic {beta}-cell imaging

Journal Article · Thu Nov 19 23:00:00 EST 2009 · Biochemical and Biophysical Research Communications · OSTI ID:22199885

Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic {beta}-cell mass

Journal Article · Fri Sep 02 00:00:00 EDT 2011 · Biochemical and Biophysical Research Communications · OSTI ID:22207477

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
Cu-64
Exendin-4
GLP-1
GLP-1R
Ga-68
PET
Pancreatic β cells
β cell mass

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

Citation Formats

References (36)

Cited By (4)

Similar Records

Related Subjects