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Rosenström, Ulrika
Publications (10 of 28) Show all publications
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.
Open this publication in new window or tab >>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 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 748Article in journal (Refereed) 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.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-342327 (URN)10.1038/s41598-017-18855-0 (DOI)000422637200007 ()29335487 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-02-28Bibliographically approved
Velikyan, I., Rosenström, U. & Eriksson, O. (2017). Fully automated GMP production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 for clinical use. American Journal of Nuclear Medicine and Molecular Imaging, 7(3), 111-125
Open this publication in new window or tab >>Fully automated GMP production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 for clinical use
2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 3, p. 111-125Article in journal (Refereed) Published
Abstract [en]

[Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4/PET-CT targeting glucagon like peptide-1 receptor (GLP-1R) has previously demonstrated its potential clinical value for the detection of insulinomas. The production and accessibility of this radiopharmaceutical is one of the critical factors in realization of clinical trials and routine clinical examinations. Previously, the radiopharmaceutical was prepared manually, however larger scale of clinical trials and healthcare requires automation of the production process in order to limit the operator radiation dose as well as improve tracer manufacturing robustness and on-line documentation for enhanced good manufacturing practice (GMP) compliance. A method for Ga-68-labelling of DO3A-VS-Cys(40)-Exendin-4 on a commercially available synthesis platform was developed. Equipment such as Ge-68/Ga-68 generator, synthesis platform, and disposable cassettes for Ga-68-labelling used in the study was purchased from Eckert & Ziegler. DO3A-VS-Cys(40)-Exendin-4 was synthesized in-house. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, pH, product purification step were investigated and optimised. Reproducible and GMP compliant automated production of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 was developed. Exendin-4 comprising methionine amino acid residue was prone to oxidation which was strongly influenced by the elevated temperature, radioactivity amount, and precursor concentration. The suppression of the oxidative radiolysis was achieved by addition of ethanol, dihydroxybenzoic acid and ascorbic acid to the reaction buffer as well as by optimizing heating temperature. The non-decay corrected radiochemical yield was 43 +/- 2% with radiochemical purity of over 90% wherein the individual impurity signals in HPLC chromatogram did not exceed 5%. Automated production and quality control methods were established for paving the pathway for broader clinical use of [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4.

Keywords
Exendin-4, Insulinoma, GLP-1, GMP, Gallium-68, automation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-335532 (URN)000409370800002 ()28721305 (PubMedID)
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-08Bibliographically approved
Mitran, B., Thisgaard, H., Rosenström, U., Dam, J. H., Larhed, M., Tolmachev, V. & Orlova, A. (2017). High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26. Contrast Media & Molecular Imaging, Article ID UNSP 6873684.
Open this publication in new window or tab >>High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26
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2017 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id UNSP 6873684Article in journal (Refereed) Published
Abstract [en]

High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a Co-55-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with Co-57 and Co-55, stability, binding specificity, and in vitro and in vivo characteristics of Co-57-NOTA-PEG(2)-RM26 were studied. NOTA-PEG(2)-RM26 was successfully radiolabeled with Co-57 and Co-55 with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. Co-57-NOTA-PEG(2)-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG(2)-RM26 translated into high contrast preclinical PET/CT (using Co-55) and SPECT/CT (using Co-57) images of PC-3 xenografts. The initial biological results suggest that Co-55-NOTA-PEG(2)-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

Keywords
Positron-Emission-Tomography, Receptor-Positive Tumors, In-Vivo Evaluation, Radiolabeled Peptides, Analog; Agonists, Visualization, Proteins, Affinity, Therapy.
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-334114 (URN)10.1155/2017/6873684 (DOI)000408099300001 ()
Funder
Swedish Cancer Society, CAN2014/474; CAN2015/350Swedish Research Council, 2015-02509; 2015-02353Knut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2017-11-24Bibliographically approved
Eriksson, O., Rosenström, U., Selvaraju, R. K., Eriksson, B. & Velikyan, I. (2017). Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4. Acta Diabetologica, 54(11), 1039-1045
Open this publication in new window or tab >>Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4
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2017 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 11, p. 1039-1045Article in journal (Refereed) Published
Abstract [en]

AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed.

METHODS: -Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment.

RESULTS: -Exendin4.

CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.

Keywords
Animal models, Beta cell imaging, Beta cell mass, Exendin4, GLP-1R, Positron emission tomography
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-342527 (URN)10.1007/s00592-017-1046-2 (DOI)000413142300008 ()28891030 (PubMedID)
Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-02-23Bibliographically approved
Diwakarla, S., Nylander, E., Grönbladh, A., Reddy Vanga, S., Shamsudin Khan, Y., Gutierrez-de-Teran, H., . . . Hallberg, M. (2016). Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density. Molecular Pharmacology, 89(4), 413-424
Open this publication in new window or tab >>Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
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2016 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed) Published
Abstract [en]

Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-275166 (URN)10.1124/mol.115.102533 (DOI)000370935700003 ()26769413 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-01-31 Created: 2016-01-31 Last updated: 2018-03-20
Velikyan, I., Rosenström, U., Eriksson, O. & Antoni, G. (2016). Ga-68/PET imaging and quantification of fibrosis using peptide-based tracers. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 15-19, 2016, Barcelona, SPAIN. European Journal of Nuclear Medicine and Molecular Imaging, 43, S73-S73
Open this publication in new window or tab >>Ga-68/PET imaging and quantification of fibrosis using peptide-based tracers
2016 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S73-S73Article in journal (Refereed) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-316227 (URN)000391801600167 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 15-19, 2016, Barcelona, SPAIN
Available from: 2017-02-27 Created: 2017-02-27 Last updated: 2017-11-29Bibliographically approved
Engen, K., Rosenström, U., Axelsson, H., Konda, V., Dahllund, L., Otrocka, M., . . . Larhed, M. (2016). Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening. Assay and drug development technologies, 14(3), 180-193
Open this publication in new window or tab >>Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening
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2016 (English)In: Assay and drug development technologies, ISSN 1540-658X, E-ISSN 1557-8127, Vol. 14, no 3, p. 180-193Article in journal (Refereed) Published
Abstract [en]

Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.

National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-297122 (URN)10.1089/adt.2016.708 (DOI)000374641700005 ()27078680 (PubMedID)
Funder
The Karolinska Institutet's Research FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council
Available from: 2016-06-22 Created: 2016-06-21 Last updated: 2018-01-10Bibliographically approved
Mitran, B., Varasteh, Z., Selvaraju, R. K., Lindeberg, G., Sörensen, J., Larhed, M., . . . Orlova, A. (2016). Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26.. International journal of oncology, 48(5), 2124-2134
Open this publication in new window or tab >>Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26.
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2016 (English)In: International journal of oncology, ISSN 1791-2423, Vol. 48, no 5, p. 2124-2134Article in journal (Refereed) Published
Abstract [en]

Bombesin (BN) analogs bind with high affinity to gastrin-releasing peptide receptors (GRPRs) that are up-regulated in prostate cancer and can be used for the visualization of prostate cancer. The aim of this study was to investigate the influence of radionuclide-chelator complexes on the biodistribution pattern of the 111In-labeled bombesin antagonist PEG2-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (PEG2-RM26) and to identify an optimal construct for SPECT imaging. A series of RM26 analogs N-terminally conjugated with NOTA, NODAGA, DOTA and DOTAGA via a PEG2 spacer were radiolabeled with 111In and evaluated both in vitro and in vivo. The conjugates were successfully labeled with 111In with 100% purity and retained binding specificity to GRPR and high stability. The cellular processing of all compounds was characterized by slow internalization. The IC50 values were in the low nanomolar range, with lower IC50 values for positively charged natIn-NOTA-PEG2-RM26 (2.6±0.1 nM) and higher values for negatively charged natIn-DOTAGA-PEG2-RM26 (4.8±0.5 nM). The kinetic binding studies showed KD values in the picomolar range that followed the same pattern as the IC50 data. The biodistribution of all compounds was studied in BALB/c nu/nu mice bearing PC-3 prostate cancer xenografts. Tumor targeting and biodistribution studies displayed rapid clearance of radioactivity from the blood and normal organs via kidney excretion. All conjugates showed similar uptake in tumors at 4 h p.i. The radioactivity accumulation in GRPR-expressing organs was significantly lower for DOTA- and DOTAGA-containing constructs compared to those containing NOTA and NODAGA. 111In-NOTA-PEG2-RM26 with a positively charged complex showed the highest initial uptake and the slowest clearance of radioactivity from the liver. At 4 h p.i., DOTA- and DOTAGA-coupled analogs showed significantly higher tumor-to-organ ratios compared to NOTA- and NODAGA-containing variants. The NODAGA conjugate demonstrated the best retention of radioactivity in tumors, and, at 24 h p.i., had the highest contrast to blood, muscle and bones.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-281358 (URN)10.3892/ijo.2016.3429 (DOI)000372568600037 ()26983776 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2016-03-23 Created: 2016-03-23 Last updated: 2016-04-28Bibliographically approved
Mitran, B., Varasteh, Z., Rosenström, U., Tolmachev, V., Lindeberg, G., Larhed, M. & Orlova, A. (2015). Development of radiocobalt-labeled GRPR antagonist NOTA-PEG2-RM26.. Paper presented at 28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 10-14, 2015, Hamburg, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 42(S1), S142-S142
Open this publication in new window or tab >>Development of radiocobalt-labeled GRPR antagonist NOTA-PEG2-RM26.
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2015 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, p. S142-S142Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-269141 (URN)000363013201248 ()
Conference
28th Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 10-14, 2015, Hamburg, GERMANY
Note

Meeting Abstract: OP340

Available from: 2015-12-18 Created: 2015-12-14 Last updated: 2017-12-01Bibliographically approved
Velikyan, I., Rosenström, U., Bulenga, T., Eriksson, O. & Antoni, G. (2015). Extrapolated dosimetry of two novel Ga-68-labelled imaging agents for fibrosis: feasibility of multiple examinations. Journal of labelled compounds & radiopharmaceuticals, 58, S96-S96
Open this publication in new window or tab >>Extrapolated dosimetry of two novel Ga-68-labelled imaging agents for fibrosis: feasibility of multiple examinations
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2015 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, p. S96-S96Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-284897 (URN)000369950200097 ()
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
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