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Journal of Cancer Research and Clinical Oncology

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01-09-2014 | Original Article – Cancer Research

Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe ¹⁸F-FBEM–Cys³⁹-exendin-4

Authors: Yuping Xu, Donghui Pan, Qing Xu, Chen Zhu, Lizhen Wang, Fei Chen, Runlin Yang, Shineng Luo, Min Yang

Published in: Journal of Cancer Research and Clinical Oncology | Issue 9/2014

Abstract

Purpose

Glucagon-like peptide-1 receptor (GLP-1R) is a specific target for insulinomas imaging since it is overexpressed in the tumor. Exendin-4 exhibits high affinity for the GLP-1R. In this study, a novel ¹⁸F-labeled exendin-4 analog, ¹⁸F-FBEM–Cys³⁹-exendin-4, was synthesized and its potentials for GLP-1R imaging were also evaluated.

Methods

¹⁸F-FBEM was synthesized by coupling ¹⁸F-fluorobenzoic acid (¹⁸F-FBA) with N-(2-aminoethyl) maleimide, and the reaction conditions were optimized. Cys³⁹-exendin-4 was then conjugated with ¹⁸F-FBEM to obtain ¹⁸F-FBEM–Cys³⁹-exendin-4. The GLP-1R targeting potential and pharmacokinetic profile of the tracer were analyzed in INS-1 insulinoma and MDA-MB-435 breast tumor model, respectively.

Results

Under the optimal conditions, the yield of radiolabeled ¹⁸F-FBEM was 49.1 ± 2.0 % (based on ¹⁸F-FBA, non-decay corrected). The yield of ¹⁸F-FBEM–Cys³⁹-exendin-4 was 35.1 ± 2.6 % (based on the starting ¹⁸F-FBEM, non-decay corrected). The radiochemical purity of ¹⁸F-FBEM–Cys³⁹-exendin-4 is >95 %, and the specific activity was at least 35 GBq/μmol. The GLP-1R-positive INS-1 insulinoma xenograft was clearly visible with good contrast to background, whereas GLP-1R-negative MDA-MB435 breast tumor was barely visible. Low levels of radioactivity were also detected at pancreas and lungs due to few GLP-1R expressions. GLP-1R binding specificity was demonstrated by reduced INS-1 tumor uptake of the tracer after coinjection with an excess of unlabeled Cys³⁹-exendin-4 at 1 h postinjection.

Conclusion

The thiol-reactive reagent, ¹⁸F-FBEM, was prepared with high yield and successfully conjugated to Cys³⁹-exendin-4. Favorable preclinical data showing specific and effective tumor targeting by ¹⁸F-FBEM–Cys³⁹-exendin-4 suggest that the tracer may be a potential probe for insulinomas imaging.

Ambrosini V, Fani M, Fanti S et al (2011) Radiopeptide imaging and therapy in Europe. J Nucl Med 52:42S–55SPubMedCrossRef

Cai W, Zhang X, Wu Y et al (2006) A thiol-reactive 18F-labeling agent, N-[2-(4-18F-fluorobenzamido)ethyl]maleimide, and synthesis of RGD peptide-based tracer for PET imaging of alpha v beta 3 integrin expression. J Nucl Med 47:1172–1180PubMedCentralPubMed

Chatziioannou A, Kehagias D, Mourikis D et al (2001) Imaging and localization of pancreatic insulinomas. Clin Imaging 25:275–283PubMedCrossRef

Christ E, Wild D, Forrer F et al (2009) Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J Clin Endocrinol Metab 94:4398–4405PubMedCrossRef

Doyle ME, Theodorakis MJ, Holloway HW et al (2003) The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity. Regul Pept 114:153–158PubMedCrossRef

Gao H, Niu G, Yang M et al (2011) PET of insulinoma using ¹⁸F-FBEM-EM3106B, a new GLP-1 analogue. Mol Pharm 8:1775–1782PubMedCentralPubMedCrossRef

Gotthardt M, Fischer M, Naeher I et al (2002) 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 29:597–606PubMed

Graham MM, Menda Y (2011) Radiopeptide imaging and therapy in the United States. J Nucl Med 52:56S–63SPubMedCrossRef

Grant CS (2005) Insulinoma. Best Pract Res Clin Gastroenterol 19:783–798PubMedCrossRef

Kiesewetter DO, Jacobson O, Lang L et al (2011) Automated radiochemical synthesis of [18F]FBEM: a thiol reactive synthon for radiofluorination of peptides and proteins. Appl Radiat Isot 69:410–414PubMedCentralPubMedCrossRef

Kiesewetter DO, Gao H, Ma Y et al (2012) 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur J Nucl Med Mol Imaging 39:463–473PubMedCentralPubMed

Körner M, Stöckli M, Waser B et al (2007) GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 48:736–743PubMedCrossRef

Körner M, Christ E, Wild D et al (2012) Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications. Front Endocrinol (Lausanne) 3:158

Lütje S, Boerman OC, van Rij CM et al (2012) Prospects in radionuclide imaging of prostate cancer. Prostate 72:1262–1272PubMedCrossRef

Norton JA (2006) Surgery for primary pancreatic neuroendocrine tumors. J Gastrointest Surg 10:327–331PubMedCrossRef

Pan DH, Yan RH, Xu YP, Pan D, Yan Y, Yang R, Xu Y, Chen F, Wang L, Luo S, Yang M et al (2014) PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN. Contrast Media Mol I. doi:10.1002/cmmi.1583

Parry JJ, Kelly TS, Andrews R et al (2007) In vitro and in vivo evaluation of 64Cu-labeled DOTA-linker-bombesin(7–14) analogues containing different amino acid linker moieties. Bioconjug Chem 18:1110–1117PubMedCrossRef

Pery C, Meurette G, Ansquer C et al (2010) Role and limitations of 18F-FDG positron emission tomography (PET) in the management of patients with pancreatic lesions. Gastroenterol Clin Biol 34:465–474PubMedCrossRef

Ramage JK, Davies AH, Ardill J et al (2005) Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 54:iv1–iv16PubMedCentralPubMedCrossRef

Reubi JC, Waser B (2003) Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging 30:781–793PubMed

Sowa-Staszczak A, Pach D, Mikołajczak R et al (2013) Glucagon-like peptide-1 receptor imaging with [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 for the detection of insulinoma. Eur J Nucl Med Mol Imaging 40:524–531PubMedCentralPubMed

Wang Y, Lim K, Normandin M et al (2012a) Synthesis and evaluation of [¹⁸F]exendin (9–39) as a potential biomarker to measure pancreatic β-cell mass. Nucl Med Biol 39:167–176PubMedCrossRef

Wang H, Gao H, Guo N et al (2012b) Site-specific labeling of scVEGF with fluorine-18 for positron emission tomography imaging. Theranostics 2:607–617PubMedCentralPubMedCrossRef

Wicki A, Wild D, Storch D et al (2007) [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 13:3696–3705PubMedCrossRef

Wiesli P, Brandle M, Schmid C et al (2004) Selective arterial calcium stimulation and hepatic venous sampling in the evaluation of hyperinsulinemic hypoglycemia: potential and limitations. J Vasc Interv Radiol 15:1251–1256PubMedCrossRef

Wild D, Béhé M, Wicki A et al (2006) Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting. J Nucl Med 47:2025–2033PubMed

Wild D, Wicki A, Mansi R et al (2010) Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT. J Nucl Med 51:1059–1067PubMedCrossRef

Wild D, Christ E, Caplin ME et al (2011) Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J Nucl Med 51:1073–1078CrossRef

Wu Z, Liu S, Hassink M et al (2013) Development and evaluation of 18F-TTCO-Cys40-exendin-4: a PET probe for imaging transplanted islets. J Nucl Med 54:244–251PubMedCrossRef

Yue X, Kiesewetter DO, Guo J et al (2013) Development of a new thiol site-specific prosthetic group and Its conjugation with [Cys(40)]-exendin-4 for in vivo targeting of insulinomas. Bioconjug Chem 24:1191–1200PubMedCentralPubMedCrossRef

Title: Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe 18F-FBEM–Cys39-exendin-4
Authors: Yuping Xu
Donghui Pan
Qing Xu
Chen Zhu
Lizhen Wang
Fei Chen
Runlin Yang
Shineng Luo
Min Yang
Publication date: 01-09-2014
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 9/2014
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-014-1701-8

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Insulinoma imaging with glucagon-like peptide-1 receptor targeting probe ¹⁸F-FBEM–Cys³⁹-exendin-4

Abstract

Purpose

Methods

Results

Conclusion

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