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Velikyan, I., Haack, T., Bossart, M., Evers, A., Laitinen, I., Larsen, P., . . . Eriksson, O. (2019). First-in-class positron emission tomography tracer for the glucagon receptor. EJNMMI Research, 9, Article ID 17.
Åpne denne publikasjonen i ny fane eller vindu >>First-in-class positron emission tomography tracer for the glucagon receptor
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2019 (engelsk)Inngår i: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 9, artikkel-id 17Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The glucagon receptor (GCGR) is emerging as an important target in anti-diabetic therapy, especially as part of the pharmacology of dual glucagon-like peptide-1/glucagon (GLP-1/GCG) receptor agonists. However, currently, there are no suitable biomarkers that reliably demonstrate GCG receptor target engagement.

Methods: Two potent GCG receptor peptide agonists, S01-GCG and S02-GCG, were labeled with positron emission tomography (PET) radionuclide gallium-68. The GCG receptor binding affinity and specificity of the resulting radiopharmaceuticals [68Ga]Ga-DO3A-S01-GCG and [68Ga]Ga-DO3A-S02-GCG were evaluated in HEK-293 cells overexpressing the human GCG receptor and on frozen hepatic sections from human, non-human primate, and rat. In in vivo biodistribution, binding specificity and dosimetry were assessed in rat.

Results: [68Ga]Ga-DO3A-S01-GCG in particular demonstrated GCG receptor-mediated binding in cells and liver tissue with affinity in the nanomolar range required for imaging. [68Ga]Ga-DO3A-S01-GCG binding was not blocked by co-incubation of a GLP-1 agonist. In vivo binding in rat liver was GCG receptor specific with low non-specific binding throughout the body. Moreover, the extrapolated human effective doses, predicted from rat biodistribution data, allow for repeated PET imaging potentially also in combination with GLP-1R radiopharmaceuticals.

Conclusion: [68Ga]Ga-DO3A-S01-GCG thus constitutes a first-in-class PET tracer targeting the GCG receptor, with suitable properties for clinical development. This tool has potential to provide direct quantitative evidence of GCG receptor occupancy in humans.

Emneord
Glucagon, GCG, GLP-1 receptor, Dual agonist, Type 2 diabetes
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-378994 (URN)10.1186/s13550-019-0482-0 (DOI)000459043900002 ()30771019 (PubMedID)
Tilgjengelig fra: 2019-03-19 Laget: 2019-03-19 Sist oppdatert: 2019-03-19bibliografisk kontrollert
Eriksson, O. (2019). GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass. Current Diabetes Reports, 19(8), Article ID 49.
Åpne denne publikasjonen i ny fane eller vindu >>GPR44 as a Target for Imaging Pancreatic Beta-Cell Mass
2019 (engelsk)Inngår i: Current Diabetes Reports, ISSN 1534-4827, E-ISSN 1539-0829, Vol. 19, nr 8, artikkel-id 49Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Purpose of Review Quantitative markers for beta-cell mass (BCM) in human pancreas are currently lacking. Medical imaging using positron emission tomography (PET) markers for beta-cell restricted targets may provide an accurate and non-invasive measurement of BCM, to assist diagnosis and treatment of metabolic disease. GPR44 was recently discovered as a putative marker for beta cells and this review summarizes the developments so far. Recent Findings Several small molecule binders targeting GPR44 have been radiolabeled for PET imaging and evaluated in vitro and in small and large animal models. C-11-AZ12204657 and C-11-MK-7246 displayed a dose-dependent and GPR44-mediated binding to beta cells both in vitro and in vivo, with negligible uptake in exocrine pancreas. Summary GPR44 represents an attractive target for visualization of BCM. Further progress in radioligand development including clinical testing is expected to clarify the role of GPR44 as a surrogate marker for BCM in humans.

sted, utgiver, år, opplag, sider
Springer, 2019
Emneord
Beta-cell imaging, Islet imaging, Beta-cell mass, GPR44, PET, Diabetes
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-390420 (URN)10.1007/s11892-019-1164-z (DOI)000473164900004 ()31250117 (PubMedID)
Tilgjengelig fra: 2019-08-12 Laget: 2019-08-12 Sist oppdatert: 2019-08-12bibliografisk kontrollert
Elksnis, A., Martinell, M., Eriksson, O. & Espes, D. (2019). Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass. Frontiers in Physiology, 10, Article ID 107.
Åpne denne publikasjonen i ny fane eller vindu >>Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass
2019 (engelsk)Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 10, artikkel-id 107Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Type 2 diabetes (T2D) is a complex and heterogeneous disease which affects millions of people worldwide. The classification of diabetes is at an interesting turning point and there have been several recent reports on sub-classification of T2D based on phenotypical and metabolic characteristics. An important, and perhaps so far underestimated, factor in the pathophysiology of T2D is the role of oxidative stress and reactive oxygen species (ROS). There are multiple pathways for excessive ROS formation in T2D and in addition, beta-cells have an inherent deficit in the capacity to cope with oxidative stress. ROS formation could be causal, but also contribute to a large number of the metabolic defects in T2D, including beta-cell dysfunction and loss. Currently, our knowledge on beta-cell mass is limited to autopsy studies and based on comparisons with healthy controls. The combined evidence suggests that beta-cell mass is unaltered at onset of T2D but that it declines progressively. In order to better understand the pathophysiology of T2D, to identify and evaluate novel treatments, there is a need for in vivo techniques able to quantify beta-cell mass. Positron emission tomography holds great potential for this purpose and can in addition map metabolic defects, including ROS activity, in specific tissue compartments. In this review, we highlight the different phenotypical features of T2D and how metabolic defects impact oxidative stress and ROS formation. In addition, we review the literature on alterations of beta-cell mass in T2D and discuss potential techniques to assess beta-cell mass and metabolic defects in vivo.

sted, utgiver, år, opplag, sider
Frontiers Media S.A., 2019
Emneord
type 2 diabetes, diabetes classification, oxygen stress, reactive oxygen species, beta-cell, beta-cell mass, imaging, positron emission tomography
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-378233 (URN)10.3389/fphys.2019.00107 (DOI)000458732800001 ()
Forskningsfinansiär
Swedish Child Diabetes FoundationSwedish Society for Medical Research (SSMF)Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceErnfors FoundationSwedish Diabetes AssociationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Tilgjengelig fra: 2019-03-15 Laget: 2019-03-15 Sist oppdatert: 2019-03-15bibliografisk kontrollert
Espes, D., Manell, E., Rydén, A., Carlbom, L., Weis, J., Jensen-Waern, M., . . . Eriksson, O. (2019). Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI. Acta Diabetologica, 56(10), 1113-1120
Åpne denne publikasjonen i ny fane eller vindu >>Pancreatic perfusion and its response to glucose as measured by simultaneous PET/MRI
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2019 (engelsk)Inngår i: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 56, nr 10, s. 1113-1120Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

AIMS: Perfusion of the pancreas and the islets of Langerhans is sensitive to physiological stimuli and is dysregulated in metabolic disease. Pancreatic perfusion can be assessed by both positron emission tomography (PET) and magnetic resonance imaging (MRI), but the methods have not been directly compared or benchmarked against the gold-standard microsphere technique.

METHODS: Pigs (n = 4) were examined by [15O]H2O PET and intravoxel incoherent motion (IVIM) MRI technique simultaneously using a hybrid PET/MRI scanner. The pancreatic perfusion was measured both at basal conditions and after intravenous (IV) administration of up to 0.5 g/kg glucose.

RESULTS: Pancreatic perfusion increased by 35%, 157%, and 29% after IV 0.5 g/kg glucose compared to during basal conditions, as assessed by [15O]H2O PET, IVIM MRI, and microspheres, respectively. There was a correlation between pancreatic perfusion as assessed by [15O]H2O PET and IVIM MRI (r = 0.81, R2 = 0.65, p < 0.01). The absolute quantification of pancreatic perfusion (ml/min/g) by [15O]H2O PET was within a 15% error of margin of the microsphere technique.

CONCLUSION: Pancreatic perfusion by [15O]H2O PET was in agreement with the microsphere technique assessment. The IVIM MRI method has the potential to replace [15O]H2O PET if the pancreatic perfusion is sufficiently large, but not when absolute quantitation is required.

sted, utgiver, år, opplag, sider
Springer, 2019
Emneord
Diabetes, Hybrid scanner, PET/MRI scanner, Pancreas perfusion
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-383433 (URN)10.1007/s00592-019-01353-2 (DOI)000486160600003 ()31028528 (PubMedID)
Forskningsfinansiär
Ernfors FoundationGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Diabetes AssociationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in SwedenScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Tilgjengelig fra: 2019-05-14 Laget: 2019-05-14 Sist oppdatert: 2019-10-31bibliografisk kontrollert
Eriksson, J., Roy, T., Sawadjoon, S., Bachmann, K., Sköld, C., Larhed, M., . . . Odell, L. R. (2019). Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass. Nuclear Medicine and Biology, 71, 1-10
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
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2019 (engelsk)Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, s. 1-10Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-381559 (URN)10.1016/j.nucmedbio.2019.04.002 (DOI)000475837000001 ()
Forskningsfinansiär
Swedish Research Council, 2018-05133Knut and Alice Wallenberg FoundationSwedish Child Diabetes FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Tilgjengelig fra: 2019-04-11 Laget: 2019-04-11 Sist oppdatert: 2019-09-13bibliografisk kontrollert
Kang, N.-Y., Soetedjo, A. A., Amirruddin, N. S., Chang, Y.-T., Eriksson, O. & Teo, A. K. (2019). Tools for Bioimaging Pancreatic beta Cells in Diabetes. Trends in Molecular Medicine, 25(8), 708-722
Åpne denne publikasjonen i ny fane eller vindu >>Tools for Bioimaging Pancreatic beta Cells in Diabetes
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2019 (engelsk)Inngår i: Trends in Molecular Medicine, ISSN 1471-4914, E-ISSN 1471-499X, Vol. 25, nr 8, s. 708-722Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

When diabetes is diagnosed, the majority of insulin-secreting pancreatic beta cells are already dysfunctional or destroyed. This beta cell dysfunction/destruction usually takes place over many years, making timely detection and clinical intervention difficult. For this reason, there is immense interest in developing tools to bioimage beta cell mass and/or function noninvasively to facilitate early diagnosis of diabetes as well as to assist the development of novel antidiabetic therapies. Recent years have brought significant progress in beta cell imaging that is now inching towards clinical applicability. We explore here the need to bioimage human beta cells noninvasively in various types of diabetes, and we discuss current and emerging tools for bioimaging beta cells. Further developments in this field are expected to facilitate beta cell imaging in diabetes.

sted, utgiver, år, opplag, sider
Elsevier, 2019
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-391427 (URN)10.1016/j.molmed.2019.05.004 (DOI)000477707700007 ()31178230 (PubMedID)
Forskningsfinansiär
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Tilgjengelig fra: 2019-10-03 Laget: 2019-10-03 Sist oppdatert: 2019-10-03bibliografisk kontrollert
Lahesmaa, M., Eriksson, O., Gnad, T., Oikonen, V., Bucci, M., Hirvonen, J., . . . Nuutila, P. (2018). Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue. Diabetes, 67(7), 1226-1236
Åpne denne publikasjonen i ny fane eller vindu >>Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue
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2018 (engelsk)Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, nr 7, s. 1226-1236Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [F-18]FMPEP-d(2) and measured BAT activation in parallel with the glucose analog [F-18]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, 3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans.

sted, utgiver, år, opplag, sider
AMER DIABETES ASSOC, 2018
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-358271 (URN)10.2337/db17-1366 (DOI)000435927000003 ()29650773 (PubMedID)
Forskningsfinansiär
EU, FP7, Seventh Framework Programme, 278373German Research Foundation (DFG), GN 108/1-1German Research Foundation (DFG), RTG 1873
Tilgjengelig fra: 2018-08-29 Laget: 2018-08-29 Sist oppdatert: 2018-08-29bibliografisk kontrollert
Gotthardt, M., Eizirik, D. L., Aanstoot, H.-J., Korsgren, O., Mul, D., Martin, F., . . . Brom, M. (2018). Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer. Diabetologia, 61(12), 2516-2519
Åpne denne publikasjonen i ny fane eller vindu >>Detection and quantification of beta cells by PET imaging: why clinical implementation has never been closer
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2018 (engelsk)Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, nr 12, s. 2516-2519Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In this issue of Diabetologia, Alavi and Werner (10.1007/s00125-018-4676-1) criticise the attempts to use positron emission tomography (PET) for in vivo imaging of pancreatic beta cells, which they consider as futile'. In support of this strong statement, they point out the limitations of PET imaging, which they believe render beta cell mass impossible to estimate using this method. In our view, the Alavi and Werner presentation of the technical limitations of PET imaging does not reflect the current state of the art, which leads them to questionable conclusions towards the feasibility of beta cell imaging using this approach. Here, we put forward arguments in favour of continuing the development of innovative technologies enabling in vivo imaging of pancreatic beta cells and concisely present the current state of the art regarding putative technical limitations of PET imaging. Indeed, far from being a futile' effort, we demonstrate that beta cell imaging is now closer than ever to becoming a long-awaited clinical reality.

sted, utgiver, år, opplag, sider
SPRINGER, 2018
Emneord
Clinical diabetes, Imaging, Islets, PET imaging
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-369382 (URN)10.1007/s00125-018-4745-5 (DOI)000449290200005 ()30284016 (PubMedID)
Tilgjengelig fra: 2019-01-15 Laget: 2019-01-15 Sist oppdatert: 2019-01-15bibliografisk kontrollert
Eriksson, O., Johnström, P., Cselenyi, Z., Jahan, M., Selvaraju, R. k., Jensen-Waern, M., . . . Korsgren, O. (2018). In Vivo Visualization of beta-Cells by Targeting of GPR44. Diabetes, 67(2), 182-192
Åpne denne publikasjonen i ny fane eller vindu >>In Vivo Visualization of beta-Cells by Targeting of GPR44
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2018 (engelsk)Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, nr 2, s. 182-192Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

GPR44 expression has recently been described as highly beta-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C-11]AZ12204657, was evaluated for visualization of beta-cells in pigs and non-human primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess beta-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C-11]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C-11]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C-11]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C-11]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic beta-cells by targeting the protein GPR44.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-342900 (URN)10.2337/db17-0764 (DOI)000426034500003 ()29208633 (PubMedID)
Forskningsfinansiär
Swedish Research Council, K2015-54X-12219-19-4, K2013-64X-08268-26-3, K2013-55X-15043, 921-2014-7054Ernfors FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Child Diabetes FoundationSwedish Diabetes AssociationEXODIAB - Excellence of Diabetes Research in Sweden
Tilgjengelig fra: 2018-02-23 Laget: 2018-02-23 Sist oppdatert: 2018-05-09bibliografisk kontrollert
Monazzam, A., Lau, J., Velikyan, I., Li, S.-C., Razmara, M., Rosenström, U., . . . Skogseid, B. (2018). Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET. Scientific Reports, 8, Article ID 748.
Åpne denne publikasjonen i ny fane eller vindu >>Increased Expression of GLP-1R in Proliferating Islets of Men1 Mice is Detectable by [Ga-68]Ga-DO3A-VS-Cys(40)- Exendin-4/PET
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2018 (engelsk)Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 748Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment. Glucagon-like peptide 1 (GLP-1) pathway is essential in islet regeneration, i.e. inhibition of β-cell apoptosis and enhancement of β-cell proliferation, yet involvement of GLP-1 in MEN1 related P-NET has not yet been demonstrated. The objective of this work was to investigate if normal sized islets of Men1 heterozygous mice have increased Glucagon-like peptide-1 receptor (GLP-1R) expression compared to wild type islets, and if this increase is detectable in vivo with positron emission tomography (PET) using [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 (68Ga-Exendin-4). 68Ga-Exendin-4 showed potential for early lesion detection in MEN1 pancreas due to increased GLP1R expression.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-342327 (URN)10.1038/s41598-017-18855-0 (DOI)000422637200007 ()29335487 (PubMedID)
Forskningsfinansiär
Swedish Cancer Society
Tilgjengelig fra: 2018-02-20 Laget: 2018-02-20 Sist oppdatert: 2018-02-28bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-2515-8790