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Publications (10 of 58) Show all publications
Rokka, J., Fang, X. T., Hultqvist, G., Faresjö, R., Olberg, D., Antoni, G., . . . Eriksson, J. (2019). Journal of Labelled Compounds and Pharmaceuticals: Neurosciences session. In: ISRS 2019: . Paper presented at 23rd International Symposium on Radiopharmaceutical Sciences, 26-31, May, 2019, Beijing, China (pp. S78-S79). Wiley Online Library, 62
Open this publication in new window or tab >>Journal of Labelled Compounds and Pharmaceuticals: Neurosciences session
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2019 (English)In: ISRS 2019, Wiley Online Library , 2019, Vol. 62, p. S78-S79Conference paper, Oral presentation with published abstract (Refereed)
Place, publisher, year, edition, pages
Wiley Online Library, 2019
National Category
Medicinal Chemistry Neurosciences
Identifiers
urn:nbn:se:uu:diva-393156 (URN)10.1002/jlcr.3724 (DOI)
Conference
23rd International Symposium on Radiopharmaceutical Sciences, 26-31, May, 2019, Beijing, China
Available from: 2019-09-16 Created: 2019-09-16 Last updated: 2020-05-12Bibliographically approved
Jonasson, M., Wall, A., Chiotis, K., Leuzy, A., Eriksson, J., Antoni, G., . . . Lubberink, M. (2019). Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET. NeuroImage: Clinical, 22, Article ID 101681.
Open this publication in new window or tab >>Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET
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2019 (English)In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 22, article id 101681Article in journal (Refereed) Published
Abstract [en]

[F-18]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R-1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 +/- 4 min for AD patients and in putamen at 20 +/- 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R-1 with 40 min scan duration.

Keywords
Alzheimer’s disease, PET, Parametric images, Supervised clustering, Tau imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-341785 (URN)10.1016/j.nicl.2019.101681 (DOI)000470123000005 ()30710871 (PubMedID)
Funder
Swedish Research Council, 05817The Swedish Brain FoundationStockholm County CouncilThe Karolinska Institutet's Research FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla TjänarinnorSwedish Foundation for Strategic Research
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2020-05-15Bibliographically approved
Schembri, L. S., Eriksson, J. & Odell, L. R. (2019). Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylsulfonamides via Regioselective Acylation. Journal of Organic Chemistry, 84(11), 6970-6981
Open this publication in new window or tab >>Palladium(0)-Catalyzed Carbonylative Synthesis of N-Acylsulfonamides via Regioselective Acylation
2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 11, p. 6970-6981Article in journal (Refereed) Published
Abstract [en]

N-Acylsulfonamides represent an important bioisostere of carboxylic acids that allow for greater molecular elaboration and enhanced hydrogen bonding capabilities. Herein, we present a mild and convenient palladium(0)-catalyzed synthesis of N-acylsulfonamides via the carbonylative coupling of sulfonyl azides and electron-rich heterocycles. The reaction proceeds via in situ generation of a sulfonyl isocyanate followed by regioselective acylation of an indole or pyrrole nucleophile. This approach has been used to synthesize 34 indole- and pyrrole-substituted N-acylsulfonamides in yields of up to 95%. Importantly, this process is ligand-free and compatible with an ex situ solid CO source and requires only slightly elevated temperatures, making it a highly attractive method for the preparation of this important class of compounds. This study further investigated the possibility of labeling N-acylsulfonamides with carbon-11 to facilitate biological evaluation and in vivo studies with positron emission tomography.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-389596 (URN)10.1021/acs.joc.9b00740 (DOI)000471212000042 ()31064177 (PubMedID)
Funder
Swedish Research Council, 2018-05133
Available from: 2019-07-24 Created: 2019-07-24 Last updated: 2019-07-24Bibliographically approved
Heurling, K., Ashton, N. J., Leuzy, A., Zimmer, E. R., Blennow, K., Zetterberg, H., . . . Schöll, M. (2019). Synaptic vesicle protein 2A as a potential biomarker in synaptopathies. Molecular and Cellular Probes, 97, 34-42
Open this publication in new window or tab >>Synaptic vesicle protein 2A as a potential biomarker in synaptopathies
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2019 (English)In: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 97, p. 34-42Article in journal (Refereed) Published
Abstract [en]

Measuring synaptic density in vivo using positron emission tomography (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clinical applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathology and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic density, the potential role of fluid-based biomarkers for SV2A, and related future perspectives.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Biomarkers, Position emission tomography, SV2A, Synaptopathies
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-382939 (URN)10.1016/j.mcn.2019.02.001 (DOI)000472239000004 ()30796959 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationMagnus Bergvall FoundationSwedish Research CouncilEU, European Research Council
Available from: 2019-05-07 Created: 2019-05-07 Last updated: 2019-08-07Bibliographically approved
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
Open this publication in new window or tab >>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 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed) 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.

National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-381559 (URN)10.1016/j.nucmedbio.2019.04.002 (DOI)000475837000001 ()
Funder
Swedish Research Council, 2018-05133Knut and Alice Wallenberg FoundationSwedish Child Diabetes FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2019-04-11 Created: 2019-04-11 Last updated: 2019-09-13Bibliographically approved
Nordeman, P., Yngve, U., Wilking, H., Gustavsson, S. Å., Eriksson, J. & Antoni, G. (2018). Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS). Journal of labelled compounds & radiopharmaceuticals, 61(14), 1106-1109
Open this publication in new window or tab >>Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS)
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2018 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 61, no 14, p. 1106-1109Article in journal (Refereed) Published
Abstract [en]

The radiosynthesis and GMP validation of [11 C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [11 C]CO2 ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.

Keywords
[11C]AMT, automation, methyl iodide, positron emission tomography, tracer production system
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-368809 (URN)10.1002/jlcr.3648 (DOI)000453709100011 ()29902836 (PubMedID)
Available from: 2018-12-07 Created: 2018-12-07 Last updated: 2019-01-15Bibliographically approved
Odell, L. R., Åkerbladh, L., Schembri, L. S., Nordeman, P., Roslin, S. & Eriksson, J. (2018). Carbonylations beyond aryl-X: Development of new multicomponent reactions. Paper presented at 255th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nexus of Food, Energy, and Water, MAR 18-22, 2018, New Orleans, LA. Abstract of Papers of the American Chemical Society, 255
Open this publication in new window or tab >>Carbonylations beyond aryl-X: Development of new multicomponent reactions
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2018 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal, Meeting abstract (Other academic) Published
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-367232 (URN)000435539901514 ()
Conference
255th National Meeting and Exposition of the American-Chemical-Society (ACS) - Nexus of Food, Energy, and Water, MAR 18-22, 2018, New Orleans, LA
Available from: 2018-12-06 Created: 2018-12-06 Last updated: 2018-12-06Bibliographically approved
Eriksson, J., Fang, X. T., Hultqvist, G., Olberg, D. E., Antoni, G., Lannfelt, L., . . . Syvänen, S. (2018). [F-18]Tetrazine-trans-cyclooctene mediated labelling of antibodies for PET imaging of amyloid-beta. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S643-S643
Open this publication in new window or tab >>[F-18]Tetrazine-trans-cyclooctene mediated labelling of antibodies for PET imaging of amyloid-beta
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S643-S643Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372958 (URN)000449266206054 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
Verbeek, J., Eriksson, J., Syvänen, S., Huisman, M., Schuit, R. C., Molthoff, C. F., . . . Windhorst, A. D. (2018). Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression.. EJNMMI radiopharmacy and chemistry, 3, Article ID 11.
Open this publication in new window or tab >>Synthesis and preliminary preclinical evaluation of fluorine-18 labelled isatin-4-(4-methoxyphenyl)-3-thiosemicarbazone ([18F]4FIMPTC) as a novel PET tracer of P-glycoprotein expression.
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2018 (English)In: EJNMMI radiopharmacy and chemistry, ISSN 2365-421X, Vol. 3, article id 11Article in journal (Refereed) Published
Abstract [en]

Background: Several P-glycoprotein (P-gp) substrate tracers are available to assess P-gp function in vivo, but attempts to develop a tracer for measuring expression levels of P-gp have not been successful. Recently, (Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide was described as a potential selective P-gp inhibitor that is not transported by P-gp. Therefore, the purpose of this study was to radiolabel two of its analogues and to assess their potential for imaging P-gp expression using PET.

Results: [18F]2-(4-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]5) and [18F]2-(6-fluoro-2-oxoindolin-3-ylidene)-N-(4-methoxyphenyl)hydrazine-carbothioamide ([18F]6) were synthesized and both their biodistribution and metabolism were evaluated in rats. In addition, PET scans were acquired in rats before and after tariquidar (P-gp inhibitor) administration as well as in P-gp knockout (KO) mice.Both [18F]5 and [18F]6 were synthesized in 2-3% overall yield, and showed high brain uptake in ex vivo biodistribution studies. [18F]6 appeared to be metabolically unstable in vivo, while [18F]5 showed moderate stability with limited uptake of radiolabelled metabolites in the brain. PET studies showed that transport of [18F]5 across the blood-brain barrier was not altered by pre-treatment with the P-gp inhibitor tariquidar, and uptake was significantly lower in P-gp KO than in wild-type animals and indeed transported across the BBB or bound to P-gp in endothelial cells.

Conclusion: In conclusion, [18F]5 and [18F]6 were successfully and reproducibly synthesized, albeit with low radiochemical yields. [18F]5 appears to be a radiotracer that binds to P-gp, as showed in P-gp knock-out animals, but is not a substrate for P-gp.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
P-glycoprotein, P-gp inhibitor, Radiofluorination, [18F]-fluorisatin, [18F]4FIMPTC
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-368808 (URN)10.1186/s41181-018-0046-z (DOI)30294663 (PubMedID)
Available from: 2018-12-07 Created: 2018-12-07 Last updated: 2020-04-14Bibliographically approved
Fang, X. T., Eriksson, J., Antoni, G., Yngve, U., Cato, L., Lannfelt, L., . . . Syvänen, S. (2017). Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting. Neuropharmacology, 113(Pt A), 293-300, Article ID S0028-3908(16)30459-2.
Open this publication in new window or tab >>Brain mGluR5 in mice with amyloid beta pathology studied with in vivo [(11)C]ABP688 PET imaging and ex vivo immunoblotting
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2017 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 113, no Pt A, p. 293-300, article id S0028-3908(16)30459-2Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [(11)C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning. In order to convey these neurotoxic effects, Aβo requires interaction with the metabotropic glutamate 5 receptor (mGluR5). The aim was to investigate in vivo mGluR5 changes in an Aβ pathology model using PET. Wild type C57/BL6 (wt) and AβPP transgenic mice (tg-ArcSwe), 4, 8, and 16 months old, were PET scanned with [(11)C]ABP688, which is highly specific to mGluR5, to investigate changes in mGluR5. Mouse brains were extracted postscan and mGluR5 and Aβ protofibril levels were assessed with immunoblotting and ELISA respectively. Receptor-dense brain regions (hippocampus, thalamus, and striatum) displayed higher [(11)C]ABP688 concentrations corresponding to mGluR5 expression pattern. Mice had similar uptake levels of [(11)C]ABP688 regardless of genotype or age. Immunoblotting revealed general decline in mGluR5 expression and elevated levels of mGluR5 in 16 months old tg-ArcSwe compared with wt mice. [(11)C]ABP688 could visualize mGluR5 in the mouse brain. In conclusion, mGluR5 levels were found to decrease with age and tended to be higher in tg-ArcSwe compared with wt mice, however these changes could not be quantified with PET.

Keywords
Alzheimer's disease, PET, [(11)C]ABP688, mGluR5
National Category
Geriatrics Radiology, Nuclear Medicine and Medical Imaging Neurology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-317721 (URN)10.1016/j.neuropharm.2016.10.009 (DOI)000390502200028 ()27743932 (PubMedID)
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0241-092X

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