Generic placeholder image

Current Radiopharmaceuticals


ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Research Article

Feasibility of a Scale-down Production of [68Ga]Ga-NODAGA-Exendin-4 in a Hospital Based Radiopharmacy

Author(s): Silvia Migliari*, Antonino Sammartano, Maura Scarlattei, Giorgio Baldari, Barbara Janota, Riccardo C. Bonadonna and Livia Ruffini

Volume 15, Issue 1, 2022

Published on: 09 March, 2021

Page: [63 - 75] Pages: 13

DOI: 10.2174/1874471014666210309151930

Price: $65


Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in β-cells, but it is highly expressed in human insulinomas and gastrinomas. Several GLP-1 receptor– avid radioligands have been developed to image insulin-secreting tumors or to provide a quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4 is a high affinity ligand of the GLP1- R, which is a candidate for being labeled with a PET isotope and used for imaging purposes.

Objective: Here, we report the development and validation results of a semi-manual procedure to label [Lys40,Nle14(Ahx-NODAGA)NH2]exendin-4, with Ga-68.

Methods: A68Ge/68Ga Generator (GalliaPharma®, Eckert and Ziegler) was eluted with 0.1M HCl on an automated synthesis module (Scintomics GRP®).

The peptide contained in the kit vial (Radioisotope Center POLATOM) in different amounts (10-20-30 μg) was reconstituted with 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethansulfonic acid (HEPES) solution and 68GaCl3 (400–900 MBq), followed by 10 min incubation at 95°C. The reaction solution was then purified through an Oasis HLB column.

The radiopharmaceutical product was tested for quality controls (CQs) in accordance with the European Pharmacopoeia standards.

Results: The synthesis of [68Ga]Ga-NODAGA-Exendin-4 provided optimal results with 10 μg of peptide, getting the best radiochemical yield (23.53 ± 2.4%), molar activity (100 GBq/μmol) and radiochemical purity (91.69%).

Conclusion: The study developed an imaging tool [68Ga]Ga-NODAGA-Exendin-4, avoiding pharmacological effects of exendin-4, for the clinical community.

Keywords: [68Ga]Ga-NODAGA-Exendin-4, PET imaging, pancreatic beta cells, insulinoma, type 2 diabetes, GLP-1 receptor.

Graphical Abstract
Reubi, J.C.; 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(5), 781-793.
[] [PMID: 12707737]
Thorens, B.; Porret, A.; Bühler, L.; Deng, S.P.; Morel, P.; Widmann, C. 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(11), 1678-1682.
[] [PMID: 8405712]
Gros, L.; Thorens, B.; Bataille, D.; Kervran, A. Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line. Endocrinology, 1993, 133(2), 631-638.
[] [PMID: 8102095]
Zhang, Y.; Sun, B.; Feng, D.; Hu, H.; Chu, M.; Qu, Q.; Tarrasch, J. T.; Li, S.; Kobilka, T.S.; Kobilka, B.K.; Skiniotis, G. Cryo-EM structure of the activated GLP-1 receptor in complex with G protein. Nature., 2017, 546(7657), 248-253..
Baggio, L.L.; Drucker, D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology, 2007, 132(6), 2131-2157.
[] [PMID: 17498508]
Aroda, V.R. A review of GLP-1 receptor agonists: Evolution and advancement, through the lens of randomised controlled trials. Diabetes Obes. Metab., 2018, 20(Suppl. 1), 22-33.
[] [PMID: 29364586]
Körner, M.; Christ, E.; Wild, D.; Reubi, J.C. Glucagon-like peptide-1 receptor overexpression in cancer and its impact on clinical applications. Front. Endocrinol. (Lausanne), 2012, 3, 158.
[] [PMID: 23230431]
Reubi, J.C.; Christ, E.; Wild, D.; Reubi, J.C. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr. Rev., 2003, 24(4), 389-427.
[] [PMID: 12920149]
Nauck, M.A. Unraveling the science of incretin biology. Eur. J. Intern. Med., 2009, 20(Suppl. 2), S303-S308.
[] [PMID: 19580949]
Reubi, J.C.; Maecke, H.R. Peptide-based probes for cancer imaging. J. Nucl. Med., 2008, 49(11), 1735-1738.
[] [PMID: 18927341]
Gotthardt, M.; Fischer, M.; Naeher, I.; Holz, J.B.; Jungclas, H.; Fritsch, H.W.; Béhé, M.; Göke, B.; Joseph, K.; Behr, T.M. 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(5), 597-606.
[] [PMID: 11976797]
Wild, D.; Béhé, M.; Wicki, A.; Storch, D.; Waser, B.; Gotthardt, M.; Keil, B.; Christofori, G.; Reubi, J.C.; Mäcke, H.R. [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(12), 2025-2033.
[PMID: 17138746]
Brom, M.; Oyen, W.J.G.; Joosten, L.; Gotthardt, M.; Boerman, O.C. 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET. Eur. J. Nucl. Med. Mol. Imaging, 2010, 37(7), 1345-1355.
[] [PMID: 20111963]
Wild, D.; Wicki, A.; Mansi, R.; Béhé, M.; Keil, B.; Bernhardt, P.; Christofori, G.; Ell, P.J.; Mäcke, H.R. Exendin-4-based radiopharmaceuticals for glucagonlike peptide-1 receptor PET/CT and SPECT/CT. J. Nucl. Med., 2010, 51(7), 1059-1067.
[] [PMID: 20595511]
Wu, Z.; Todorov, I.; Li, L.; Bading, J.R.; Li, Z.; Nair, I.; Ishiyama, K.; Colcher, D.; Conti, P.E.; Fraser, S.E.; Shively, J.E.; Kandeel, F.; Kandeel, F. In vivo imaging of transplanted islets with 64Cu-DO3A-VS-Cys40-Exendin-4 by targeting GLP-1 receptor. Bioconjug. Chem., 2011, 22(8), 1587-1594.
[] [PMID: 21692471]
Kiesewetter, D.O.; Gao, H.; Ma, Y.; Niu, G.; Quan, Q.; Guo, N.; Chen, X. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma. Eur. J. Nucl. Med. Mol. Imaging, 2012, 39(3), 463-473.
[] [PMID: 22170321]
Nedrow, J.R.; White, A.G.; Modi, J.; Nguyen, K.; Chang, A.J.; Anderson, C.J. Positron emission tomographic imaging of copper 64- and gallium 68-labeled chelator conjugates of the somatostatin agonist tyr3-octreotate. Mol. Imaging, 2014, 13, 13.
[] [PMID: 25060207]
Mikkola, K.; Yim, C.B.; Lehtiniemi, P.; Kauhanen, S.; Tarkia, M.; Tolvanen, T.; Nuutila, P.; Solin, O. Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, 18F-labeled [Nle14,Lys40]exendin-4 analog, shows promise for clinical imaging. EJNMMI Res., 2016, 6(1), 91.
[] [PMID: 27957723]
Mikkola, K.; Yim, C.B.; Fagerholm, V.; Ishizu, T.; Elomaa, V.V.; Rajander, J.; Jurttila, J.; Saanijoki, T.; Tolvanen, T.; Tirri, M.; Gourni, E.; Béhé, M.; Gotthardt, M.; Reubi, J.C.; Mäcke, H.; Roivainen, A.; Solin, O.; Nuutila, P. 64Cu- and 68Ga-labelled [Nle(14),Lys(40)(Ahx-NODAGA)NH2]-exendin-4 for pancreatic beta cell imaging in rats. Mol. Imaging Biol., 2014, 16(2), 255-263.
[] [PMID: 24101374]
Selvaraju, R.K.; Velikyan, I.; Johansson, L.; Wu, Z.; Todorov, I.; Shively, J.; Kandeel, F.; Korsgren, O.; Eriksson, O. In vivo imaging of the glucagonlike peptide 1 receptor in the pancreas with 68Ga-labeled DO3A-exendin-4. J. Nucl. Med., 2013, 54(8), 1458-1463.
[] [PMID: 23761918]
Eriksson, O.; Rosenström, U.; Selvaraju, R.K.; Eriksson, B.; Velikyan, I. Species differences in pancreatic binding of DO3A-VS- Cys40-Exendin4. Acta Diabetol., 2017, 54(11), 1039-1045.
[] [PMID: 28891030]
Velikyan, I.; Eriksson, O. Advances in GLP-1 receptor targeting radiolabeled agent development and prospective of theranostics. Theranostics, 2020, 10(1), 437-461.
[] [PMID: 31903131]
Jansen, T.J.P.; van Lith, S.A.M.; Boss, M.; Brom, M.; Joosten, L.; Béhé, M.; Buitinga, M.; Gotthardt, M. Exendin-4 analogs in insulinoma theranostics. J. Labelled Comp. Radiopharm., 2019, 62(10), 656-672.
[] [PMID: 31070270]
Velikyan, I.; Rosenstrom, U.; Eriksson, O. Fully automated GMP production of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 for clinical use. Am. J. Nucl. Med. Mol. Imaging, 2017, 7(3), 111-125.
[PMID: 28721305]
Fineman, M.S.Z.; Shen, L.Z.; Taylor, K.; Kim, D.D.; Baron, A.D. Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes. Diabetes Metab. Res. Rev., 2004, 20(5), 411-417.
[] [PMID: 15343588]
Eriksson, O.; Velikyan, I.; Selvaraju, R.K.; Kandeel, F.; Johansson, L.; Antoni, G.; Eriksson, B.; Sörensen, J.; Korsgren, O. Detection of metastatic insulinoma by positron emission tomography with [(68)ga]exendin-4-a case report. J. Clin. Endocrinol. Metab., 2014, 99(5), 1519-1524.
[] [PMID: 24512490]
Luo, Y.; Yu, M.; Pan, Q.; Wu, W.; Zhang, T.; Kiesewetter, D.O.; Zhu, Z.; Li, F.; Chen, X.; Zhao, Y. 68Ga-NOTA-exendin-4 PET/CT in detection of occult insulinoma and evaluation of physiological uptake. Eur. J. Nucl. Med. Mol. Imaging, 2015, 42(3), 531-532.
[] [PMID: 25398421]
Luo, Y.; Pan, Q.; Yao, S.; Yu, M.; Wu, W.; Xue, H.; Kiesewetter, D.O.; Zhu, Z.; Li, F.; Zhao, Y.; Chen, X. 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(5), 715-720.
[] [PMID: 26795291]
Parihar, A.S.; Vadi, S.K.; Kumar, R.; Mittal, B.R.; Singh, H.; Bal, A.; Walia, R.; Shukla, J.; Sinha, S.K. 68Ga DOTA‐exendin PET/CT for detection of insulinoma in a patient with persistent hyperinsulinemic hypoglycemia. Clin. Nucl. Med., 2018, 43(8), e285-e286.
[] [PMID: 29877881]
Antwi, K.; Fani, M.; Nicolas, G.; Rottenburger, C.; Heye, T.; Reubi, J.C.; Gloor, B.; Christ, E.; Wild, D. Localization of hidden insulinomas with (6)(8)Ga-DOTA-exendin-4 PET/CT: a pilot study. J. Nucl. Med., 2015, 56(7), 1075-1078.
[] [PMID: 25999434]
Antwi, K.; Fani, M.; Heye, T.; Nicolas, G.; Rottenburger, C.; Kaul, F.; Merkle, E.; Zech, C.J.; Boll, D.; Vogt, D.R.; Gloor, B.; Christ, E.; Wild, D. Comparison of glucagon-like peptide-1 receptor (GLP-1R) PET/CT, SPECT/CT and 3T MRI for the localisation of occult insulinomas: evaluation of diagnostic accuracy in a prospective crossover imaging study. Eur. J. Nucl. Med. Mol. Imaging, 2018, 45(13), 2318-2327.
[] [PMID: 30054698]
Bongetti, E.; Lee, M.H.; Pattison, D.A.; Hicks, R.J.; Norris, R.; Sachithanandan, N.; MacIsaac, R.J. Diagnostic challenges in a patient with an occult insulinoma:68 Ga-DOTA-exendin-4 PET/CT and 68Ga-DOTATATE PET/CT. Clin. Case Rep., 2018, 6(4), 719-722.
[] [PMID: 29636947]
Luo, Y.; Li, J.; Yang, A.; Yang, H.; Li, F. 68Ga-exendin-4 PET/CT in evaluation of endoscopic ultrasound-guided ethanol ablation of an insulinoma. Clin. Nucl. Med., 2017, 42(4), 310-311.
[] [PMID: 28134698]
Luo, Y.; Li, N.; Kiesewetter, D.O.; Chen, X.; Li, F. 68Ga-NOTA-exendin-4 PET/CT in localization of an occult insulinoma and appearance of coexisting esophageal carcinoma. Clin. Nucl. Med., 2016, 41(4), 341-343.
[] [PMID: 26647001]
Wild, D.; Mäcke, H.; Christ, E.; Gloor, B.; Reubi, J.C. Glucagon- like peptide 1-receptor scans to localize occult insulinomas. N. Engl. J. Med., 2008, 359(7), 766-768.
[] [PMID: 18703486]
Christ, E.; Wild, D.; Forrer, F.; Brändle, M.; Sahli, R.; Clerici, T.; Gloor, B.; Martius, F.; Maecke, H.; Reubi, J.C. Glucagon-like peptide-1 receptor imaging for localization of insulinomas. J. Clin. Endocrinol. Metab., 2009, 94(11), 4398-4405.
[] [PMID: 19820010]
Sowa-Staszczak, A.; Pach, D.; Mikołajczak, R.; Mäcke, H.; Jabrocka-Hybel, A.; Stefańska, A.; Tomaszuk, M.; Janota, B.; Gilis-Januszewska, A.; Małecki, M.; Kamiński, G.; Kowalska, A.; Kulig, J.; Matyja, A.; Osuch, C.; Hubalewska-Dydejczyk, A. 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, 2013, 40(4), 524-531.
[] [PMID: 23224740]
Wild, D.; Christ, E.; Caplin, M.E.; Kurzawinski, T.R.; Forrer, F.; Brändle, M.; Seufert, J.; Weber, W.A. Jamshed Bomanji, Perren A., Ell P. J., Reubi J. C. Glucagonlike peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. J. Nucl. Med., 2011, 52, 1073-1078.
[] [PMID: 21680696]
Christ, E.; Wild, D.; Ederer, S.; Béhé, M.; Nicolas, G.; Caplin, M.E.; Brändle, M.; Clerici, T.; Fischli, S.; Stettler, C.; Ell, P.J.; Seufert, J.; Gloor, B.; Perren, A.; Reubi, J.C.; Forrer, F. Glucagon- like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study. Lancet Diabetes Endocrinol., 2013, 1(2), 115-122.
[] [PMID: 24622317]
Christ, E.; Wild, D.; Antwi, K.; Waser, B.; Fani, M.; Schwanda, S.; Heye, T.; Schmid, C.; Baer, H.U.; Perren, A.; Reubi, J.C. Preoperative localization of adult nesidioblastosis using Ga-DOTA-exendin-4-PET/CT. Endocrine, 2015, 50(3), 821-823.
[] [PMID: 26001537]
Velikyan, I.; Sundin, A.; Eriksson, B.; Lundqvist, H.; Sörensen, J.; Bergström, M.; Långström, B. In vivo binding of [68Ga]-DOTATOC to somatostatin receptors in neuroendocrine tumours- impact of peptide mass. Nucl. Med. Biol., 2010, 37(3), 265-275.
[] [PMID: 20346866]
Sörensen, J.; Velikyan, I.; Sandberg, D.; Wennborg, A.; Feldwisch, J.; Tolmachev, V.; Orlova, A.; Sandström, M.; Lubberink, M.; Olofsson, H.; Carlsson, J.; Lindman, H. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT. Theranostics, 2016, 6(2), 262-271.
[] [PMID: 26877784]
Velikyan, I.; Wennborg, A.; Feldwisch, J.; Lindman, H.; Carlsson, J.; Sörensen, J. Good manufacturing practice production of [(68)Ga]Ga-ABY-025 for HER2 specific breast cancer imaging. Am. J. Nucl. Med. Mol. Imaging, 2016, 6(2), 135-153.
[PMID: 27186441]
Brom, M.; Franssen, G.M.; Joosten, L.; Gotthardt, M.; Boerman, O.C. The effect of purification of Ga-68-labeled exendin on in vivo distribution. EJNMMI Res., 2016, 6(1), 65.
[] [PMID: 27518873]
Coenen, H.H.; Gee, A.D.; Adam, M.; Antoni, G.; Cutler, C.S.; Fujibayashi, Y.; Jeong, J.M.; Mach, R.H.; Mindt, T.L.; Pike, V.W.; Windhorst, A.D. Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines. Ann. Nucl. Med., 2018, 32(3), 236-238.
[] [PMID: 29423765]
Quality_Control_Module Human Heatlh Campus (IAEA).,
Langille, S.E. Particulate matter in injectable drug products. PDA J. Pharm. Sci. Technol., 2013, 67(3), 186-200.
[] [PMID: 23752747]
Gallium (68Ga) Edotreotide (monograph 2482). In: European Pharmacopoeia; 1062-1064.

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy