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[68Ga]Exendin-4: Bench-to-Bedside: PET molecular imaging of the GLP-1 receptor for diabetes and cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes epidemic is underway. Beta cell dysfunction (BCF) and loss of beta cell mass (BCM) are known to be key events in its progression. Currently, there are no reliable techniques to estimate or follow the loss of BCM, in vivo. Non-invasive imaging and quantification of the whole BCM in the pancreas, therefore, has a great potential for understanding the progression of diabetes and the scope for early diagnosis for Type 2 diabetes.

Glucagon-like peptide-1 receptor (GLP-1R) is known to be selectively expressed on the pancreatic beta cells and overexpressed on the insulinoma, a pancreatic neuroendocrine tumor (PNET). Therefore, this receptor is considered to be a selective imaging biomarker for the beta cells and the insulinoma. Exendin-4 is a naturally occurring analog of GLP-1 peptide. It binds and activates GLP-1R with same the potency and engages in the insulin synthesis, with a longer biological half-life. In this thesis, Exendin-4 precursor, DO3A-VS-Cys40-Exendin-4 labeled with [68Ga], [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 ([68Ga]Exendin-4), was evaluated in different species models, namely, immune deficient nude mice, rats, pigs, non-human primate (NHP), and clinically in one insulinoma patient by positron emission tomography (PET), for its potential in beta cell imaging and its quantification as well as for visualizing the insulinoma. From internal dosimetry, the possible number of repetitive [68Ga]Exendin-4-PET/CT scans was estimated.

Pancreatic uptake and insulinoma tumor uptake of [68Ga]Exendin-4 were confirmed to be mediated by the specific binding to the GLP-1R. Pancreatic GLP-1R could be visualized and semi-quantified, for diabetic studies, except in rats. Nonetheless, we found conflicting results regarding the GLP-1R being a selective imaging biomarker for the beta cells. PET/CT scan of the patient with [68Ga]Exendin-4 has proven to be more sensitive than the clinical neuroendocrine tracer, [11C]5-HTP, as  it could reveal small metastatic tumors in liver. The kidney was the dose-limiting organ in the entire species model, from absorbed dose estimation. Before reaching a yearly kidney limiting dose of 150 mGy and a whole body effective dose of 10 mSv, 2–4 [68Ga]Exendin-4 PET/CT scans be performed in an adult human, which enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma, as well as in healthy volunteers enrolled in the early phase of anti-diabetic drug development studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 202
Keyword [en]
PET, [68Ga]Exendin-4, beta cell imaging, insulinoma, dosimetry
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-261629ISBN: 978-91-554-9323-3 (print)OAI: oai:DiVA.org:uu-261629DiVA: diva2:850859
Public defence
2015-10-23, Fåhraeussalen, Rudbecklaboratoriet (hus C5), Dag Hammarskjölds väg 20, 751 85, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-10-06 Created: 2015-09-02 Last updated: 2015-10-12
List of papers
1. In Vivo Imaging of the Glucagonlike Peptide 1 Receptor in the Pancreas with Ga-68-Labeled DO3A-Exendin-4
Open this publication in new window or tab >>In Vivo Imaging of the Glucagonlike Peptide 1 Receptor in the Pancreas with Ga-68-Labeled DO3A-Exendin-4
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2013 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 8, 1458-1463 p.Article in journal (Refereed) Published
Abstract [en]

The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on beta-cells in the Wets of Langerhans and is therefore an attractive target for imaging of the beta-cell mass. In the present study, Ga-68-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. Methods: Dose escalation studies of Ga-68-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. Results: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P < 0.0001) by coadministration of DO3A-exendin-4 at 100 mu g/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P < 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 mu g/kg ranged from 49% to 97%, as estimated by compartment modeling. Conclusion: These results strongly support the notion that Ga-68-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of beta-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native beta-cells.

Keyword
beta-cell imaging, beta-cell mass, GLP-1R
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-206991 (URN)10.2967/jnumed.112.114066 (DOI)000322692400061 ()
Available from: 2013-09-09 Created: 2013-09-09 Last updated: 2017-12-06Bibliographically approved
2. Positron Emission Tomography imaging of the glucagon like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs
Open this publication in new window or tab >>Positron Emission Tomography imaging of the glucagon like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs
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2014 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, S394-S394 p., P128Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247701 (URN)000348841901124 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN
Available from: 2015-03-31 Created: 2015-03-23 Last updated: 2017-12-04Bibliographically approved
3. Pre-clinical evaluation of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 for imaging of insulinoma
Open this publication in new window or tab >>Pre-clinical evaluation of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 for imaging of insulinoma
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2014 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 41, no 6, 471-476 p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma.

METHODS: [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficient mice at two different doses of peptide: 2.5μg/kg (baseline) and 100μg/kg (block). In vivo imaging of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP).

RESULTS: GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 showed significant uptake (p≤0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [(11)C]5-HTP.

CONCLUSION: [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-225057 (URN)10.1016/j.nucmedbio.2014.03.017 (DOI)000336946400005 ()24857864 (PubMedID)
Available from: 2014-05-27 Created: 2014-05-27 Last updated: 2017-12-05Bibliographically approved
4. Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report
Open this publication in new window or tab >>Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 -: a case report
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2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 5, 1519-1524 p.Article in journal (Refereed) Published
Abstract [en]

Context:

Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.

Objective:

To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.

Design:

Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.

Setting:

Uppsala University Hospital, Uppsala, Sweden.

Patients:

A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic insulinoma was suspected and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found and a distal pancreatic resection (plus splenectomy) and removal of lymph node was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.

Interventions:

The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.

Main Outcome Measures:

N/A

Results:

The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT which confirmed several small GLP-1R positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.

Conclusion:

The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-218879 (URN)10.1210/jc.2013-3541 (DOI)000342339800030 ()24512490 (PubMedID)
Available from: 2014-02-19 Created: 2014-02-19 Last updated: 2017-12-06Bibliographically approved
5. Dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rodents, pigs, non-human primates and human - repeated scanning in human is possible.
Open this publication in new window or tab >>Dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rodents, pigs, non-human primates and human - repeated scanning in human is possible.
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2015 (English)In: American journal of nuclear medicine and molecular imaging, ISSN 2160-8407, Vol. 5, no 3, 259-69 p.Article in journal (Refereed) Published
Abstract [en]

Quantitative PET imaging with [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has potential use in diabetes and cancer. However, the radiation dose to the kidneys has been a concern for the possibility of repeated imaging studies in humans. Therefore, we investigated the dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 based on the biodistribution data in rats, pigs, non-human primates (NHP) and a human.Organ distribution of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rats (Male Lewis; n=12; 30, 60, and 80 min) was measured ex vivo. The dynamic uptake of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in the abdomen was assessed by PET/CT scanning of pigs (male; n = 4, 0-60 min), NHP (Female; cynomolgus; n=3; 0-90 min), and human (female; n=1; 0-40, 100, 120 min).The organ distribution data in each species were extrapolated to those of a human, assuming similar distribution between the species. Residence times were assessed by trapezoidal approximation of the kinetic data. Organ doses (mGy/MBq) and the whole body effective dose (mSv/MBq), was extrapolated by using the OLINDA/EXM 1.1 software. The extrapolated human whole body effective dose was 0.017 ± 0.004 (rats), 0.014 ± 0.004 (pigs), 0.017 ± 0.004 (NHP), and 0.016 (human) mSv/MBq. The absorbed dose to the kidneys was limiting:0.33 ± 0.06 (rats), 0.28±0.05 (pigs), 0.65 ± 0.11 (NHP), and 0.28 (human) mGy/MBq, which corresponded to the maximum yearly administered amounts of 455 (rat), 536 (pig), 231 (NHP), and 536 (human) MBq before reaching the yearly kidney limiting dose of 150 mGy. More than 200 MBq of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 can be administered yearly in a human, allowing for repeated (2-4 times) scanning. This potentially enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma.

National Category
Radiology, Nuclear Medicine and Medical Imaging Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-255245 (URN)26069859 (PubMedID)
Available from: 2015-06-15 Created: 2015-06-15 Last updated: 2016-02-24

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