Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-03-2012 | Original Article

¹⁸F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

Authors: Dale O. Kiesewetter, Haokao Gao, Ying Ma, Gang Niu, Qimeng Quan, Ning Guo, Xiaoyuan Chen

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2012

Abstract

Purpose

Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging.

Methods

We prepared ¹⁸F radioligands for GLP-1R by the reaction of [¹⁸F]FBEM, a maleimide prosthetic group, with [Cys⁰] and [Cys⁴⁰] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice.

Results

The [¹⁸F]FBEM-[Cys^x]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [¹⁸F]FBEM), and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [¹⁸F]FBEM-[Cys⁴⁰]-exendin-4, had higher affinity for INS-1 tumor cells (IC₅₀ 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [¹⁸F]FBEM-[Cys⁰]-exendin-4 (IC₅₀ 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys^x]-exendin-4 (p < 0.05).

Conclusion

[¹⁸F]FBEM-[Cys⁴⁰]-exendin-4 and [¹⁸F]FBEM-[Cys⁰]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [¹⁸F]FBEM-[Cys⁴⁰]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.

Holst JJ, Deacon CF, Vilsboll T, Krarup T, Madsbad S. Glucagon-like peptide-1, glucose homeostasis and diabetes. Trends Mol Med. 2008;14:161–8.PubMedCrossRef

Aaboe K, Krarup T, Madsbad S, Holst JJ. GLP-1: physiological effects and potential therapeutic applications. Diabetes Obes Metab. 2008;10:994–1003.PubMedCrossRef

Tornehave D, Kristensen P, Romer J, Knudsen LB, Heller RS. Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem. 2008;56:841–51.PubMedCrossRef

Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in-vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in-vivo. J Clin Endocrinol Metab. 1995;80:952–7.PubMedCrossRef

Mukai E, Toyoda K, Kimura H, Kawashima H, Fujimoto H, Ueda M, et al. GLP-1 receptor antagonist as a potential probe for pancreatic beta-cell imaging. Biochem Biophys Res Commun. 2009;389:523–6.PubMedCrossRef

Wu Z, Kandeel F. Radionuclide probes for molecular imaging of pancreatic beta-cells. Adv Drug Deliv Rev. 2010;62:1125–38.PubMedCrossRef

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.PubMedCrossRef

Hohmeier HE, Mulder H, Chen G, Henkel-Rieger R, Prentki M, Newgard CB. Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes. 2000;49:424–30.PubMedCrossRef

Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004;117:77–88.PubMedCrossRef

10.

Wild D, Behe M, Wicki A, Storch D, Waser B, Gotthardt M, et al. [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.

Wild D, Wicki A, Mansi R, Behe M, Keil B, Bernhardt P, et al. Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT. J Nucl Med. 2010;51:1059–67.PubMedCrossRef

12.

Brom M, Oyen WJ, Joosten L, Gotthardt M, Boerman OC. 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET. Eur J Nucl Med Mol Imaging. 2010;37:1345–55.PubMedCrossRef

13.

Gotthardt M, Fischer M, Naeher I, Holz JB, Jungclas H, Fritsch HW, et al. Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results. Eur J Nucl Med Mol Imaging. 2002;29:597–606.PubMedCrossRef

14.

Wicki A, Wild D, Storch D, Seemayer C, Gotthardt M, Behe M, et al. [Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma. Clin Cancer Res. 2007;13:3696–705.PubMedCrossRef

15.

Wild D, Macke H, Christ E, Gloor B, Reubi JC. Glucagon-like peptide 1-receptor scans to localize occult insulinomas. N Engl J Med. 2008;359:766–8.PubMedCrossRef

16.

Christ E, Wild D, Forrer F, Brandle M, Sahli R, Clerici T, et al. Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J Clin Endocrinol Metab. 2009;94:4398–405.PubMedCrossRef

17.

Pattou F, Kerr-Conte J, Wild D. GLP-1-receptor scanning for imaging of human beta cells transplanted in muscle. N Engl J Med. 2010;363:1289–90.PubMedCrossRef

18.

Gao H, Niu G, Yang M, Quan Q, Ma Y, Murage E, et al. PET of insulinoma using 18F-FBEM-EM3106B, a new GLP-1 analog. Mol Pharm. 2011;8:1775–82.PubMedCrossRef

19.

Murage EN, Gao G, Bisello A, Ahn JM. Development of potent glucagon-like peptide-1 agonists with high enzyme stability via introduction of multiple lactam bridges. J Med Chem. 2010;53:6412–20.PubMedCrossRef

20.

Cai W, Zhang X, Wu Y, Chen X. A thiol-reactive F-18-labeling agent, N-[2-(4-F-18-fluorobenzamido)ethyl]maleimide, and synthesis of RGD peptide-based tracer for PET imaging of αvβ3 integrin expression. J Nucl Med. 2006;47:1172–80.PubMed

21.

Kiesewetter DO, Jacobson O, Lang L, Chen X. Automated radiochemical synthesis of [18F]FBEM: a thiol reactive synthon for radiofluorination of peptides and proteins. Appl Radiat Isot. 2011;69:410–4.PubMedCrossRef

22.

Chambers AF. MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res. 2009;69:5292–3.PubMedCrossRef

23.

Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;227:680–5.PubMedCrossRef

24.

Grieve DJ, Cassidy RS, Green BD. Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control? Br J Pharmacol. 2009;157:1340–51.PubMedCrossRef

25.

Kiesewetter DO, Kramer-Marek G, Ma Y, Capala J. Radiolabeling of HER2 specific Affibody® molecule with F-18. J Fluor Chem. 2008;129:799–805.PubMedCrossRef

26.

Froelich JM, Reid GE. The origin and control of ex vivo oxidative peptide modifications prior to mass spectrometry analysis. Proteomics. 2008;8:1334–45.PubMedCrossRef

27.

Hargrove DM, Kendall ES, Reynolds JM, Lwin AN, Herich JP, Smith PA, et al. Biological activity of AC3174, a peptide analog of exendin-4. Regul Pept. 2007;141:113–9.PubMedCrossRef

28.

Chen J, Yu L, Wang L, Fang X, Li L, Li W. Stability of synthetic exendin-4 in human plasma in vitro. Protein Pept Lett. 2007;14:19–25.PubMedCrossRef

29.

Goke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, et al. 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. J Biol Chem. 1993;268:19650–5.PubMed

Title: 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma
Authors: Dale O. Kiesewetter
Haokao Gao
Ying Ma
Gang Niu
Qimeng Quan
Ning Guo
Xiaoyuan Chen
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2012
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-011-1980-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

¹⁸F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2012

18F-Labelled exendin to image GLP-1 receptor-expressing tissues: from niche to blockbuster?

Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin’s lymphoma using 89Zr-ibritumomab tiuxetan and PET

Assessment of response to endocrine therapy using FDG PET/CT in metastatic breast cancer: a pilot study

Comparison of sequential planar 177Lu-DOTA-TATE dosimetry scans with 68Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy

Monitoring anti-inflammatory therapies in patients with atherosclerosis: FDG PET emerges as the method of choice

18F-FDG PET/CT for detection and localization of residual or recurrent disease in patients with multiple myeloma after stem cell transplantation