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Åberg, Ola
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Publications (10 of 21) Show all publications
Hellström-Lindahl, E., Åberg, O., Ericsson, C., O'Mahony, G., Johnström, P., Skrtic, S. & Eriksson, O. (2017). Toward molecular imaging of the free fatty acid receptor 1. Acta Diabetologica, 54(7), 663-668
Open this publication in new window or tab >>Toward molecular imaging of the free fatty acid receptor 1
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2017 (English)In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 54, no 7, p. 663-668Article in journal (Refereed) Published
Abstract [en]

Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.

Place, publisher, year, edition, pages
SPRINGER-VERLAG ITALIA SRL, 2017
Keywords
FFAR1, GPR40, Beta cell imaging, Islet imaging, Drug development
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-329002 (URN)10.1007/s00592-017-0989-7 (DOI)000403508100006 ()28409274 (PubMedID)
Funder
Swedish Child Diabetes FoundationSwedish Diabetes AssociationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2017-09-06 Created: 2017-09-06 Last updated: 2017-09-06Bibliographically approved
Stevens, M. Y., Chow, S. Y., Estrada, S., Eriksson, J., Asplund, V., Orlova, A., . . . Odell, L. R. (2016). Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO. ChemistryOpen, 5(6), 566-573
Open this publication in new window or tab >>Synthesis of C-11-labeled Sulfonyl Carbamates through a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols, and [C-11]CO
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2016 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 5, no 6, p. 566-573Article in journal (Refereed) Published
Abstract [en]

We describe the development of a new methodology focusing on C-11-labeling of sulfonyl carbamates in a multicomponent reaction comprised of a sulfonyl azide, an alkyl alcohol, and [C-11] CO. A number of C-11-labeled sulfonyl carbamates were synthesized and isolated, and the developed methodology was then applied in the preparation of a biologically active molecule. The target compound was obtained in 24 +/- 10% isolated radiochemical yield and was evaluated for binding properties in a tumor cell assay; in vivo biodistribution and imaging studies were also performed. This represents the first successful radiolabeling of a non-peptide angiotensin II receptor subtype 2 agonist, C21, currently in clinical trials for the treatment of idiopathic pulmonary fibrosis.

Keywords
AT(2)R agonists, multicomponent reactions, radiochemistry, sulfonyl azides, sulfonyl carbamates
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-316971 (URN)10.1002/open.201600091 (DOI)000393071500012 ()28032026 (PubMedID)
Funder
Carl Tryggers foundation , CTS13:333 CTS14:356Swedish Cancer Society, 2014/474Swedish Research Council, 2015-02509
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-01-13Bibliographically approved
Eriksson, J., Åberg, O., Selvaraju, R. K., Antoni, G., Johansson, L. & Eriksson, O. (2014). 5-Hydroxy-L-[beta-C-11]-tryptophan Deuterium Isotopologue Shows Increased Retention In Neuro-endocrine Cells Due To Secondary Kinetic Isotope Effect. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN. European Journal of Nuclear Medicine and Molecular Imaging, 41(S2), S261-S261, Article ID OP466.
Open this publication in new window or tab >>5-Hydroxy-L-[beta-C-11]-tryptophan Deuterium Isotopologue Shows Increased Retention In Neuro-endocrine Cells Due To Secondary Kinetic Isotope Effect
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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, p. S261-S261, article id OP466Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247690 (URN)000348841900328 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN
Available from: 2015-04-08 Created: 2015-03-23 Last updated: 2017-12-04Bibliographically approved
Eriksson, J., Åberg, O., Selvaraju, R. K., Antoni, G., Johansson, L. & Eriksson, O. (2014). Strategy to develop a MAO-A-resistant 5-hydroxy-L-[beta-C-11]tryptophan isotopologue based on deuterium kinetic isotope effects. EJNMMI Research, 4(1), Article ID 62.
Open this publication in new window or tab >>Strategy to develop a MAO-A-resistant 5-hydroxy-L-[beta-C-11]tryptophan isotopologue based on deuterium kinetic isotope effects
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2014 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, no 1, article id 62Article in journal (Refereed) Published
Abstract [en]

Background

The serotonin precursor 5-hydroxy-L-[β-11C]tryptophan ([11C]HTP) is in clinical use for localization of neuroendocrine tumors and has been suggested as a proxy marker for pancreatic islet cells. However, degradation by monoamine oxidase-A (MAO-A) reduces retention and the contrast to non-endocrine tissue.

Methods

A synthesis method was developed for 5-hydroxy-L-[β-11C2H]tryptophan ([11C]DHTP), an isotopologue of [11C]HTP, labeled with 11C and 2H at the β-position adjacent to the carbon involved in MAO-A decarboxylation. MAO-A-mediated degradation of [11C]DHTP was evaluated and compared to non-deuterated [11C]HTP.

Results

[11C]DHTP was synthesized with a radiochemical purity of >98%, radioactivity of 620 ± 190 MBq, and deuterium (2H or 2H2) incorporation at the β-position of 22% ±5%. Retention and resistance to MAO-A-mediated degradation of [11C]DHTP were increased in cells but not in non-human primate pancreas.

Conclusions

Partial deuteration of the β-position yields improved resistance to MAO-A-mediated degradation in vitro but not in vivo.

National Category
Medicinal Chemistry Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-237937 (URN)10.1186/s13550-014-0062-2 (DOI)000358052300001 ()
Available from: 2014-12-08 Created: 2014-12-08 Last updated: 2018-01-11Bibliographically approved
Kaliszczak, M., Trousil, S., Åberg, O., Perumal, M., Nguyen, Q.-D. & Aboagye, E. O. (2013). A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.. British Journal of Cancer, 108(2), 342-50
Open this publication in new window or tab >>A novel small molecule hydroxamate preferentially inhibits HDAC6 activity and tumour growth.
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2013 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 2, p. 342-50Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: This study investigates whether a histone deacetylase subtype 6 (HDAC6) inhibitor could be used in the treatment of solid tumours.

METHODS: We evaluated the effect of a novel inhibitor, C1A, on HDAC6 biochemical activity and cell growth. We further examined potential of early noninvasive imaging of cell proliferation by [(18)F]fluorothymidine positron emission tomography ([(18)F]FLT-PET) to detect therapy response.

RESULTS: C1A induced sustained acetylation of HDAC6 substrates, α-tubulin and HSP90, compared with current clinically approved HDAC inhibitor SAHA. C1A induced apoptosis and inhibited proliferation of a panel of human tumour cell lines from different origins in the low micromolar range. Systemic administration of the drug inhibited the growth of colon tumours in vivo by 78%. The drug showed restricted activity on gene expression with <0.065% of genes modulated during 24 h of treatment. C1A treatment reduced tumour [(18)F]FLT uptake by 1.7-fold at 48 h, suggesting that molecular imaging could provide value in future studies of this compound.

CONCLUSION: C1A preferentially inhibits HDAC6 and modulates HDAC6 downstream targets leading to growth inhibition of a diverse set of cancer cell lines. This property together with the favourable pharmacokinetics and efficacy in vivo makes it a candidate for further pre-clinical and clinical development.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-202006 (URN)10.1038/bjc.2012.576 (DOI)23322205 (PubMedID)
Available from: 2013-06-18 Created: 2013-06-18 Last updated: 2017-12-06
Åberg, O., Varasteh, Z., Lindeberg, G., Larhed, M., Tolmachev, V. & Orlova, A. (2013). (AlF)-F-18-labelling of NOTA-P2-RM26 and its evaluation as a PET ligand for GRPR/BB2. Paper presented at 20th International Symposium on Radiopharmaceutical Sciences; 12-17 May 2013; ICC JEJU, Jeju, Korea. Journal of labelled compounds & radiopharmaceuticals, 56(S1), S404-S404
Open this publication in new window or tab >>(AlF)-F-18-labelling of NOTA-P2-RM26 and its evaluation as a PET ligand for GRPR/BB2
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2013 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, no S1, p. S404-S404Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203006 (URN)000318694100405 ()
Conference
20th International Symposium on Radiopharmaceutical Sciences; 12-17 May 2013; ICC JEJU, Jeju, Korea
Available from: 2013-07-02 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved
Eriksson, J., Åberg, O. & Antoni, G. (2013). Automation of the 'xenon method' and comparative study on C-11-carbonylation at ambient pressure versus high solvent pressure. Paper presented at 20th International Symposium on Radiopharmaceutical Sciences; 12-17 May 2013; ICC JEJU, Jeju, Korea. Journal of labelled compounds & radiopharmaceuticals, 56(S1), S96-S96
Open this publication in new window or tab >>Automation of the 'xenon method' and comparative study on C-11-carbonylation at ambient pressure versus high solvent pressure
2013 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 56, no S1, p. S96-S96Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203009 (URN)000318694100097 ()
Conference
20th International Symposium on Radiopharmaceutical Sciences; 12-17 May 2013; ICC JEJU, Jeju, Korea
Available from: 2013-07-02 Created: 2013-07-01 Last updated: 2017-12-06Bibliographically approved
Trousil, S., Carroll, L., Kalusa, A., Åberg, O., Kaliszczak, M. & Aboagye, E. O. (2013). Design of symmetrical and nonsymmetrical N,N-dimethylaminopyridine derivatives as highly potent choline kinase alpha inhibitors. MedChemComm, 4(4), 693-696
Open this publication in new window or tab >>Design of symmetrical and nonsymmetrical N,N-dimethylaminopyridine derivatives as highly potent choline kinase alpha inhibitors
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2013 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 4, no 4, p. 693-696Article in journal (Refereed) Published
Abstract [en]

Choline kinase alpha is hyperactivated in many solid tumours and regulates malignant progression, making it a promising cancer drug target. The successful design and synthesis of novel inhibitors with high cellular activity are described.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-202007 (URN)10.1039/C3MD00068K (DOI)
Available from: 2013-06-18 Created: 2013-06-18 Last updated: 2017-12-06
Varasteh, Z., Åberg, O., Lindberg, G., Antoni, G., Velikyan, I., Sandström, M., . . . Orlova, A. (2013). GRPR antagonist NOTA-P2-RM26 labeled with fluorine-18: radiochemistry, in vitro and in vivo evaluation. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM); OCT 19-23, 2013; Lyon, FRANCE. European Journal of Nuclear Medicine and Molecular Imaging, 40(Suppl. 2), S247-S248
Open this publication in new window or tab >>GRPR antagonist NOTA-P2-RM26 labeled with fluorine-18: radiochemistry, in vitro and in vivo evaluation
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2013 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, p. S247-S248Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211603 (URN)000325853400520 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM); OCT 19-23, 2013; Lyon, FRANCE
Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
Varasteh, Z., Åberg, O., Velikyan, I., Lindeberg, G., Sörensen, J., Larhed, M., . . . Orlova, A. (2013). In Vitro and In Vivo Evaluation of a F-18-Labeled High Affinity NOTA Conjugated Bombesin Antagonist as a PET Ligand for GRPR-Targeted Tumor Imaging. PLoS ONE, 8(12), e81932
Open this publication in new window or tab >>In Vitro and In Vivo Evaluation of a F-18-Labeled High Affinity NOTA Conjugated Bombesin Antagonist as a PET Ligand for GRPR-Targeted Tumor Imaging
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81932-Article in journal (Refereed) Published
Abstract [en]

Expression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to 1,4,7-triazacyclononane-N,N',N ''-triacetic acid (NOTA) via a diethylene glycol (PEG(2)) spacer (NOTA-P2-RM26) labeled with Ga-68 and In-111. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a F-18-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with F-18 using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50) of the [F-nat]AlF-NOTA-P2-RM26 was compared to that of the Ga-nat-loaded peptide using I-125-Tyr(4)-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with F-18 within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/mu mol). The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [F-nat]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4 +/- 0.8 nM). The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [F-18]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p. i. was 5.5 +/- 0.7 % ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87 +/- 42, 159 +/- 47, 38 +/- 16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p. i. The initial biological results suggest that [F-18]AlF-NOTA-P2-RM26 is a promising candidate for PET imaging of GRPR in vivo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-214023 (URN)10.1371/journal.pone.0081932 (DOI)000327947800069 ()
Available from: 2014-01-07 Created: 2014-01-07 Last updated: 2017-12-06Bibliographically approved
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