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68Ga-Labeling of Biotin Analogues and their Characterization
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Bengt Långström)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
2009 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 20, no 6, 1146-1151 p.Article in journal (Refereed) Published
Abstract [en]

Biotin- and Ga-68-based tracers have been suggested as tools that could be used to monitor the survival of avidin-coated islets of Langerhans isolated from pancreas and used in transplantation, i.e., to liver. Three biotin analogues with various alkyl and poly(ethylene glycol) (PEG) chains coupled to DOTA were synthesized and labeled with Ga-68. The Ga-68 labeling was studied at room temperature as well as elevated temperature using either conventional or microwave heating. Radioactivity incorporation reached 95% within 5 and 2 min using the, respectively, conventional and microwave heating modes. The specific activity of the tracers was improved by preconcentration and purification of the generator eluate. The binding of the labeled and nonlabeled conjugates to avidin in solution was compared to the binding of native biotim. All compounds maintained good affinity for avidin, though introducing the linkers and chelator, especially the PEG-groups, somewhat decreased the binding affinity. The extent of binding of the labeled compounds to avidin was 54-91% after 5 min. Blocking experiments were performed confirming the specificity of the binding of biotin analogues to avidin. The stability of the three labeled compounds in human serum was studied. The stability of the biotin analogue 8 (65% within 30 min) and avidin-biotin complex (80% within 120 min) might be sufficient for the monitoring of the islets of Langerhans. The tracers will be evaluated in in vitro experiments of avidin-coated islets of Langerhans and in transplantation models in vivo.

Place, publisher, year, edition, pages
2009. Vol. 20, no 6, 1146-1151 p.
National Category
Chemical Sciences
URN: urn:nbn:se:uu:diva-106715DOI: 10.1021/bc800538sISI: 000267117600008PubMedID: 19453100OAI: oai:DiVA.org:uu-106715DiVA: diva2:236741
Available from: 2009-09-24 Created: 2009-06-29 Last updated: 2011-03-04Bibliographically approved
In thesis
1. Development of 18F- and 68Ga-Labelled Tracers: Design Perspectives and the Search for Faster Synthesis
Open this publication in new window or tab >>Development of 18F- and 68Ga-Labelled Tracers: Design Perspectives and the Search for Faster Synthesis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the design of 18F- and 68Ga-labelled positron emission tomography (PET) tracers and the development of technologies that enable faster and simpler preparation with high specific radioactivity. Techniques like microwave heating and reducing the concentrations of the precursor were investigated with this perspective. A few applications were explored using molecular design perspectives.

A nucleophilic 18F-labelling strategy using perfluoro-containing leaving groups was explored. We observed that [18F]fluoride was interacting with the perfluoro alkyl chains of the substrate, preventing the nucleophilic substitution from taking place. When a perfluoroaryl group was instead used in the leaving group, the substitution took place and purification by fluorous solid-phase extraction was possible.

18F-Labelled analogues of the monoamine oxidase-A inhibitor harmine were prepared by one-step nucleophilic fluorinations and evaluated by in vitro autoradiography, showing high specific binding.

Biotin analogues labelled with 18F and 68Ga were prepared and their binding to avidin evaluated. All analogues retained their binding ability and will be further evaluated in transplantation models with avidin-coated islets of Langerhans.

Peptide design perspectives were used in some examples where the Arg-Gly-Asp (RGD) sequence and a single-chain version of vascular endothelial growth factor (VEGF) protein functionalized with 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) or 2,2',2''-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA) as chelators were labelled with 68Ga. The RGD motif and VEGF have high affinity for, respectively, αvβ3 integrin and VEGFR-2 receptor that are overexpressed in angiogenesis process. The 68Ga-labelled scVEGF maintained its functional activity in vitro.

A polypeptide conjugate containing phosphocholine, which has affinity for the C-reactive protein released during the inflammatory process, was labelled with 68Ga for the development of an imaging agent for inflammation in vivo.

Finally [18F]/19F exchange in fluorine-containing compounds was studied in order to investigate whether the exchange reaction can be of practical use for labelling.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 48 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 678
PET, nucleophilic 18F-fluorination, perfluoro, F-SPE, molecular design, 68Ga, chelators, DOTA, NOTA, microwave, halogen exchange, harmine, biotin, RGD, VEGF, CRP
National Category
Chemical Sciences
Research subject
Organic Chemistry
urn:nbn:se:uu:diva-108629 (URN)978-91-554-7626-7 (ISBN)
Public defence
2009-11-26, C8:305, BMC, Husargatan 3, 751 23 Uppsala, Uppsala, 13:15 (English)
Available from: 2009-11-05 Created: 2009-09-24 Last updated: 2011-03-03Bibliographically approved

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