68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET
Insulinomas are neuroendocrine tumours derived from pancreatic β-cells. The glucagon-like peptide 1 receptor (GLP-1R) is expressed with a high incidence (>90%) and high density in insulinomas. Glucagon-like peptide 1 (GLP-1), the natural ligand of GLP-1R, is rapidly degraded in vivo. A more stable agonist of GLP-1R is exendin-3. We investigated imaging of insulinomas with DOTA-conjugated exendin-3 labelled with 68Ga.
Targeting of insulinomas with [Lys40(DOTA)]exendin-3 labelled with either 111In or 68Ga was investigated in vitro using insulinoma tumour cells (INS-1). [Lys40(111In-DTPA)]Exendin-3 was used as a reference in this study. In vivo targeting was investigated in BALB/c nude mice with subcutaneous INS-1 tumours. PET imaging was performed using a preclinical PET/CT scanner.
In vitro exendin-3 specifically bound and was internalized by GLP-1R-positive cells. In BALB/c nude mice with subcutaneous INS-1 tumours a high uptake of [Lys40(111In-DTPA)]exendin-3 in the tumour was observed (33.5 ± 11.6%ID/g at 4 h after injection). Uptake was specific, as determined by coinjection of an excess of unlabelled [Lys40]exendin-3 (1.8 ± 0.1%ID/g). The pancreas also exhibited high and specific uptake (11.3 ± 1.0%ID/g). High uptake was also found in the kidneys (144 ± 24%ID/g) and this uptake was not receptor-mediated. In this murine tumour model optimal targeting of the GLP-1R expressing tumour was obtained at exendin doses ≤0.1 µg. Remarkably, tumour uptake of 68Ga-labelled [Lys40(DOTA)]exendin-3 was lower (8.9 ± 3.1%ID/g) than tumour uptake of 111In-labelled [Lys40(DTPA)]exendin-3 (25.4 ± 7.2%ID/g). The subcutaneous tumours were clearly visualized by small-animal PET imaging after injection of 3 MBq of [Lys40(68Ga-DOTA)]exendin-3.
[Lys40(68Ga-DOTA)]Exendin-3 specifically accumulates in insulinomas, although the uptake is lower than that of [Lys40(111In-DTPA)]exendin-3. Therefore, [Lys40(68Ga-DOTA)]exendin-3 is a promising tracer to visualize insulinomas with PET.
- Modlin, IM, Tang, LH (1997) Approaches to the diagnosis of gut neuroendocrine tumors: the last word (today). Gastroenterology 112: pp. 583-590 CrossRef
- Krenning, EP, Kwekkeboom, DJ, Bakker, WH, Breeman, WA, Kooij, PP, Oei, HY (1993) Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20: pp. 716-731 CrossRef
- Joseph, K, Stapp, J, Reinecke, J, Skamel, HJ, Hoffken, H, Benning, R (1993) Receptor scintigraphy using 111In-pentetreotide in endocrine gastroenteropancreatic tumors. Nuklearmedizin 32: pp. 299-305
- Abboud, B, Boujaoude, J (2008) Occult sporadic insulinoma: localization and surgical strategy. World J Gastroenterol 14: pp. 657-665 CrossRef
- Jackson, JE (2005) Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 19: pp. 229-239 CrossRef
- 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: pp. 781-793
- Gotthardt, M, Fischer, M, Naeher, I, Holz, JB, Jungclas, H, Fritsch, HW (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: pp. 597-606 CrossRef
- Singh, G, Eng, J, Raufman, JP (1994) Use of 125I-[Y39]exendin-4 to characterize exendin receptors on dispersed pancreatic acini and gastric chief cells from guinea pig. Regul Pept 53: pp. 47-59 CrossRef
- Hassan, M, Eskilsson, A, Nilsson, C, Jonsson, C, Jacobsson, H, Refai, E (1999) In vivo dynamic distribution of 131I-glucagon-like peptide-1 (7-36) amide in the rat studied by gamma camera. Nucl Med Biol 26: pp. 413-420 CrossRef
- Gotthardt, M, Boermann, OC, Behr, TM, Behe, MP, Oyen, WJ (2004) Development and clinical application of peptide-based radiopharmaceuticals. Curr Pharm Des 10: pp. 2951-2963 CrossRef
- Goke, R, Larsen, PJ, Mikkelsen, JD, Sheikh, SP (1995) Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 7: pp. 2294-2300 CrossRef
- Wild, D, Behe, M, Wicki, A, Storch, D, Waser, B, Gotthardt, M (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: pp. 2025-2033
- Gotthardt, M, Lalyko, G, Eerd-Vismale, J, Keil, B, Schurrat, T, Hower, M (2006) A new technique for in vivo imaging of specific GLP-1 binding sites: first results in small rodents. Regul Pept 137: pp. 162-167 CrossRef
- Wicki, A, Wild, D, Storch, D, Seemayer, C, Gotthardt, M, Behe, M (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: pp. 3696-3705 CrossRef
- Wild, D, Macke, H, Christ, E, Gloor, B, Reubi, JC (2008) Glucagon-like peptide 1-receptor scans to localize occult insulinomas. N Engl J Med 359: pp. 766-768 CrossRef
- Asfari, M, Janjic, D, Meda, P, Li, G, Halban, PA, Wollheim, CB (1992) Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinology 130: pp. 167-178 CrossRef
- Laverman, P, Roosenburg, S, Gotthardt, M, Park, J, Oyen, WJ, Jong, M (2008) Targeting of a CCK(2) receptor splice variant with (111)In-labelled cholecystokinin-8 (CCK8) and (111)In-labelled minigastrin. Eur J Nucl Med Mol Imaging 35: pp. 386-392 CrossRef
- Kauhanen, S, Seppanen, M, Minn, H, Gullichsen, R, Salonen, A, Alanen, K (2007) Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients. J Clin Endocrinol Metab 92: pp. 1237-1244 CrossRef
- Buchmann, I, Henze, M, Engelbrecht, S, Eisenhut, M, Runz, A, Schafer, M (2007) Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging 34: pp. 1617-1626 CrossRef
- Kowalski, J, Henze, M, Schuhmacher, J, Macke, HR, Hofmann, M, Haberkorn, U (2003) Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe(1)-Tyr(3)-octreotide in comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol 5: pp. 42-48 CrossRef
- van Dalen JA, Visser EP, Laverman P, Vogel WV, Oyen WJG, Corstens FHM, et al. Effect of the positron range on the spatial resolution of a new generation pre-clinical PET using fluorine-18, gallium-68, zirconium-89 and iodine-124. Eur J Nucl Med Mol Imaging 2007;34:S228-S.
- Reubi, JC, Schar, JC, Waser, B, Wenger, S, Heppeler, A, Schmitt, JS (2000) Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 27: pp. 273-282 CrossRef
- Antunes, P, Ginj, M, Zhang, H, Waser, B, Baum, RP, Reubi, JC (2007) Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?. Eur J Nucl Med Mol Imaging 34: pp. 982-993 CrossRef
- Breeman, WA, Jong, M, Blois, E, Bernard, BF, Konijnenberg, M, Krenning, EP (2005) Radiolabelling DOTA-peptides with 68Ga. Eur J Nucl Med Mol Imaging 32: pp. 478-485 CrossRef
- Brom, M, Baumeister, P, Melis, M, Laverman, P, Joosten, L, Behe, M (2009) Determination of the beta-cell mass by SPECT imaging with In-111-DTPA-Exendin-3 in rats. J Nucl Med 50: pp. 147
- 68Ga-labelled exendin-3, a new agent for the detection of insulinomas with PET
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