Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Nuclear Medicine
Published in: Annals of Nuclear Medicine 1/2021

01-01-2021 | Insulinoma | Original Article

Indirectly radioiodinated exendin-4 as an analytical tool for in vivo detection of glucagon-like peptide-1 receptor in a disease setting

Authors: Naoya Kondo, Ayaka Oishi, Masahiko Hirata, Takashi Temma

Published in: Annals of Nuclear Medicine | Issue 1/2021

Login to get access

Abstract

Objective

Glucagon-like peptide-1 receptor agonist (GLP-1RA) has been reported to have therapeutic effects on diabetes and various diseases. Precise detection of GLP-1 receptor (GLP-1R) can be useful to diagnose and elucidate the mechanism of such diseases. Here we aimed to develop an imaging probe based on GLP-1RA that has high molar activity and sensitivity for detection of low-level GLP-1R expression in non-pancreatic diseases.

Methods

We selected the agonist exenatide (Ex4) as the parent peptide of a GLP-1R targeting probe and prepared Cys-Ex4 by addition of an N-terminal Cys residue and labeling with the prosthetic agent N-(3-[125I]iodophenyl)maleimide ([125I]IPM) to generate [125I]Ex4ipm. We evaluated the affinity of [125I]Ex4ipm for GLP-1R, as well as cellular binding profiles in insulinoma and prostate cancer cell lines, and in vivo biodistributions in normal and tumor-bearing mice to assess GLP-1R-dependent accumulation of radioactivity in tissues.

Results

[125I]Ex4ipm was easily synthesized with high radiochemical yield (73%), radiochemical purity (> 99%), and molar activity (81 GBq/µmol) via a thiol/maleimide reaction. Following administration to mice, [125I]Ex4ipm accumulated to high levels in the pancreas (23.3% ID/g), with radioactivity co-localizing in areas having insulin-positive β cells. High amounts of radioactivity also accumulated in insulinomas that overexpressed GLP-1R (27.5% ID/g). In contrast, low amounts of [125I]Ex4ipm accumulation, corresponding to low expression levels of GLP-1R, were observed in prostate cancer cells and xenografts used as a model of non-pancreatic applications.

Conclusion

Our results suggested that [123I]Ex4ipm could be valuable for GLP-1R imaging in diabetes, insulinomas, and various diseases related to GLP-1R.
Literature
1.
Thorens B, Porret A, Buhler L, et al. Cloning and functional expression of the human islet GLP-1 receptor: demonstration that exendin-4 is an agonist and exendin-(9–39) an antagonist of the receptor. Diabetes. 1993;42:1678–82.CrossRef
2.
Andersen A, Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide 1 in health and disease. Nat Rev Endocrinol. 2018;14:390–403.CrossRef
3.
Buteau J. GLP-1 receptor signaling: effects on pancreatic beta-cell proliferation and survival. Diabetes Metab. 2008;34(Suppl 2):S73-77.CrossRef
4.
Aroda VR. A review of GLP-1 receptor agonists: Evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes Metab. 2018;20:22–33.CrossRef
5.
Deacon CF. A review of dipeptidyl peptidase-4 inhibitors. Hot topics from randomized controlled trials. Diabetes Obes Metab. 2018;20:34–46.CrossRef
6.
Chen B-D, Zhao W-C, Dong J-D, Sima H. Expression of GLP-1R protein and its clinical role in intrahepatic cholangiocarcinoma tissues. Mol Biol Rep. 2014;41:4313–20.CrossRef
7.
Wu Z, Todorov I, Li L, et al. In vivo imaging of transplanted islets with 64Cu-DO3A-VS-Cys40-exendin-4 by targeting GLP-1 receptor. Bioconjug Chem. 2011;22:1587–94.CrossRef
8.
9.
Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. 2003;30:781–93.CrossRef
10.
Wild DBM, Wicki A, Storch D, Waser B, Gotthardt M, Keil B, Christofori G, Reubi JC, Mäcke HR. [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med. 2006;47:2025–33.PubMed
11.
Antwi K, Fani M, Nicolas G, et al. Localization of hidden insulinomas with 68Ga-DOTA-exendin-4 PET/CT: a pilot study. J Nucl Med. 2015;56:1075–8.CrossRef
12.
Bauman A, Valverde IE, Fischer CA, et al. Development of 68Ga- and 89Zr-labeled exendin-4 as potential radiotracers for the imaging of insulinomas by PET. J Nucl Med. 2015;56:1569–74.CrossRef
13.
Wiciński M, Socha M, Malinowski B, et al. Liraglutide and its neuroprotective properties—focus on possible biochemical mechanisms in Alzheimer’s disease and cerebral ischemic events. Int J Mol Sci. 2019;20:1050.CrossRef
14.
15.
Athauda D, Foltynie T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: mechanisms of action. Drug Discov Today. 2016;21:802–18.CrossRef
16.
Rakipovski G, Rolin B, Nøhr J, et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE−/− and LDLr−/− mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3:844–57.CrossRef
17.
Nomiyama T, Kawanami T, Irie S, et al. Exendin-4, a GLP-1 receptor agonist, attenuates prostate cancer growth. Diabetes. 2014;63:3891–905.CrossRef
18.
Selvaraju RK, Velikyan I, Asplund V, et al. Pre-clinical evaluation of [68Ga]Ga-DO3A-VS-Cys40-exendin-4 for imaging of insulinoma. Nucl Med Biol. 2014;41:471–6.CrossRef
19.
Khawli LA, van den Abbeele AD, Kassis AI. N-(m-[125I]iodophenyl)maleimide: an agent for high yield radiolabeling of antibodies. Int J Rad Appl Instrum B. 1992;19:289–95.CrossRef
20.
Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155:1280–90.CrossRef
21.
Tornehave D, Kristensen P, Rømer J, et al. Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem. 2008;56:841–51.CrossRef
22.
Läppchen T, Tönnesmann R, Eersels J, et al. Radioiodinated exendin-4 is superior to the radiometal-labelled glucagon-like peptide-1 receptor probes overcoming their high kidney uptake. PLoS ONE. 2017;12:e0170435.CrossRef
23.
Eriksson O, Velikyan I, Selvaraju RK, et al. Detection of metastatic insulinoma by positron emission tomography with [68Ga]exendin-4—a case report. J Clin Endocrinol Metab. 2014;99:1519–24.CrossRef
24.
Rylova SN, Waser B, Del Pozzo L, et al. Approaches to improve the pharmacokinetics of radiolabeled glucagon-like peptide-1 receptor ligands using antagonistic tracers. J Nucl Med. 2016;57:1282–8.CrossRef
25.
Khera E, Zhang L, Roberts S, et al. Blocking glucagon like peptide-1 receptors in the exocrine pancreas improves specificity for beta cells in a mouse model of type 1 diabetes. J Nucl Med. 2019;60:1635–41.CrossRef
26.
Xu Y, Pan D, Xu Q, et al. Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe 18F-FBEM–Cys39-exendin-4. J Cancer Res Clin Oncol. 2014;140:1479–88.CrossRef
27.
Wu Z, Liu S, Nair I, et al. (64)Cu labeled sarcophagine exendin-4 for microPET imaging of glucagon like peptide-1 receptor expression. Theranostics. 2014;4:770–7.CrossRef
28.
Luo Y, Pan Q, Shao Y, et al. Glucagon-like peptide-1 receptor PET/CT with 68Ga-NOTA-exendin-4 for detecting localized insulinoma: a prospective cohort study. J Nucl Med. 2016;57:715–20.CrossRef
29.
Sowa-Staszczak A, Trofimiuk-Müldner M, Stefańska A, et al. 99mTc labeled glucagon-like peptide-1-Analogue (99mTc-GLP1) scintigraphy in the management of patients with occult insulinoma. PLoS ONE. 2016;11:e0160714.CrossRef
30.
Viby NE, Isidor MS, Buggeskov KB, et al. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice. Endocrinology. 2013;154:4503–11.CrossRef
Metadata
Title
Indirectly radioiodinated exendin-4 as an analytical tool for in vivo detection of glucagon-like peptide-1 receptor in a disease setting
Authors
Naoya Kondo
Ayaka Oishi
Masahiko Hirata
Takashi Temma
Publication date
01-01-2021
Publisher
Springer Singapore
Published in
Annals of Nuclear Medicine / Issue 1/2021
Print ISSN: 0914-7187
Electronic ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-020-01540-0

Other articles of this Issue 1/2021

Annals of Nuclear Medicine 1/2021 Go to the issue

Original Article

Absorbed dose simulation of meta-211At-astato-benzylguanidine using pharmacokinetics of 131I-MIBG and a novel dose conversion method, RAP

Original Article

Development of a new Python-based cardiac phantom for myocardial SPECT imaging

Original Article

Performance assessment of the ALBIRA II pre-clinical SPECT S102 system for 99mTc imaging

Original Article

Quantitative Monte Carlo-based brain dopamine transporter SPECT imaging

Short Communication

18F-FDG PET/CT of off-target lymphoid organs in CD19-targeting chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma

Original Article

131I-MIBG negative progressive symptomatic metastatic paraganglioma: response and outcome with 177Lu-DOTATATE peptide receptor radionuclide therapy