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Synthesis and in vitro evaluation of 18F-β-carboline alkaloids as PET ligands
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi. (Bengt Långström)
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
Visa övriga samt affilieringar
2008 (Engelska)Ingår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 51, nr 6, s. 277-282Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A one-step 18F-labelling strategy was used to prepare four 18F-labelled analogues of 7-methoxy-1-methyl-9H-β-carboline (harmine): 7-(2-[18F]fluoroethoxy)-1-methyl-9H-β-carboline (5), 7-(3-[18F]fluoro-propoxy)-1-methyl-9H-β-carboline (6), 7-[2-(2-[18F]fluoroethoxy)ethoxy]-1-methyl-9H-β-carboline (7), and 7-{2-[2-(2-[18F]fluoroethoxy)ethoxy]-ethoxy}-1-methyl-9H-β-carboline (8). These were synthesized as potential PET ligands for monoamine oxidase A. A solution of pure labelled compound in buffer was obtained in < 70 min from end of radionuclide production, with a decay-corrected yield of up to 23%. The average specific binding to MAO-A in rat brain, determined by autoradiography experiments, was highest for compounds 7 and 8 (89 ± 2 and 96 ± 1% respectively), which was obtained at < 1 nM radioligand concentration.

Ort, förlag, år, upplaga, sidor
2008. Vol. 51, nr 6, s. 277-282
Nyckelord [en]
Harmine anologues, nucleophilic 18F-fluorination, one-step labelling, b-carboline alkaloids, MAO-A
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-106708DOI: 10.1002/jlcr.1519ISI: 000257341900032OAI: oai:DiVA.org:uu-106708DiVA, id: diva2:236743
Tillgänglig från: 2009-09-24 Skapad: 2009-06-29 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. Development of 18F- and 68Ga-Labelled Tracers: Design Perspectives and the Search for Faster Synthesis
Öppna denna publikation i ny flik eller fönster >>Development of 18F- and 68Ga-Labelled Tracers: Design Perspectives and the Search for Faster Synthesis
2009 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2009. s. 48
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 678
Nyckelord
PET, nucleophilic 18F-fluorination, perfluoro, F-SPE, molecular design, 68Ga, chelators, DOTA, NOTA, microwave, halogen exchange, harmine, biotin, RGD, VEGF, CRP
Nationell ämneskategori
Kemi
Forskningsämne
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-108629 (URN)978-91-554-7626-7 (ISBN)
Disputation
2009-11-26, C8:305, BMC, Husargatan 3, 751 23 Uppsala, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2009-11-05 Skapad: 2009-09-24 Senast uppdaterad: 2011-03-03Bibliografiskt granskad

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Blom, ElisabethEriksson, OlofHall, HåkanLångström, Bengt

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Institutionen för biokemi och organisk kemiInstitutionen för onkologi, radiologi och klinisk immunologi
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