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Marton J.,ABX Advanced Biochemical Compounds Biomedizinische Forschungsreagenzien GmbH | Henriksen G.,Norsk Medisinsk Syklotronsenter AS | Henriksen G.,University of Oslo
Molecules | Year: 2012

The semisynthetic oripavine derivative phenethyl orvinol (PEO), a full agonist at opioid receptors (OR), is an attractive structural motif for developing 18F-labeled PET tracers with a high degree of sensitivity for competition between endogenous and exogenous OR-ligands. The target cold reference compound 6-O-(2-fluoroethyl)-6-O-desmethylphenylethyl orvinol (FE-PEO) was obtained via two separate reaction routes. A three-step synthesis was developed for the preparation of a tosyloxyethyl precursor (TE-TDPEO), the key precursor for a direct, nucleophilic radiofluorination to yield [ 18F]FE-PEO. The developed radiosynthesis provides the target compound in relevantly high yield and purity, and is adaptable to routine production. © 2012 by the authors; licensee MDPI, Basel, Switzerland.

Lien V.T.,University of Oslo | Lien V.T.,Norsk Medisinsk Syklotronsenter AS | Riss P.J.,University of Oslo | Riss P.J.,Norsk Medisinsk Syklotronsenter AS
BioMed Research International | Year: 2014

The present paper is concerned with radiochemical methodology to furnish the trifluoromethyl motif labelled with 18F. Literature spanning the last four decades is comprehensively reviewed and radiochemical yields and specific activities are discussed. © 2014 V. T. Lien and P. J. Riss.

Kristian A.,University of Oslo | Riss P.,University of Oslo | Riss P.,Norsk Medisinsk Syklotronsenter AS | Qu H.,University of Oslo | And 6 more authors.
Acta Oncologica | Year: 2014

Background. Breast carcinomas (BC) can have abnormal choline (Cho) metabolism. Earlier studies indicated that Cho uptake can differ between different subtypes of BC. The purpose of this study was to investigate uptake of 2-[18F]-fluoroethyl-choline ([18F]FECh) in three different patient-derived breast cancer xenografts (BCXs) using dynamic positron emission tomography (dPET). Material and methods. Nine athymic nude mice bearing bilateral MAS98.12 (basal-like), HBCx34 or MAS98.06 (both luminal B) BCXs were subjected to a 90-minute dPET scan following a bolus injection of 10 MBq of [18F]FECh. A Patlak Plot analysis and a well-established two-tissue compartment model were fitted to the uptake curves of the whole tumors, providing estimates of transfer rates between the vascular, non-metabolized and metabolized compartments. Patlak slope KP and intercept V, the rate constants k1, k2, k3, the intravascular fraction vb and MR[ 18F]FECh were estimated. Additionally, analyses of terminal blood samples and tumor cell suspension incubated with [18F]FECh were performed. Results. [18F]FECh uptake in all BCXs was similar to surrounding normal tissue, thus creating no image contrast. The average liver uptake was 10 times higher than the tumor uptake. The uptake in MAS98.12 was higher than in the other two BCXs during the whole course of the acquisition, and was significantly higher than in HBCx34 at 10-30 minutes after injection. No significant differences were found for k1, MR[18F]FECh and intravascular fraction vb. Patlak slope KP, k2 and k3 were significantly lower for the MAS98.12 xenograft, in line with in vitro results. KP was correlated with both MR[18F]FECh and k3. Conclusions. dPET demonstrated that different subtypes of breast cancer have different uptake of [ 18F]FECh. Differences in rate constants and KP were in line with in vitro uptake in cell suspensions and earlier spectroscopy and gene expression analysis. © 2014 Informa Healthcare.

Olberg D.E.,Norsk Medisinsk Syklotronsenter AS | Hausner S.H.,University of California at Davis | Bauer N.,University of California at Davis | Klaveness J.,University of Oslo | And 6 more authors.
MedChemComm | Year: 2015

Gonadotropin releasing hormone (GnRH) is recognized as an important neuromodulator affecting behavior and has been associated with the progression of Alzheimer's disease. The peptide has been shown to have a bidirectional transport through the blood-brain-barrier (BBB), which may account for the cognitive effects of systemically administered GnRH. In this study, four novel 18F-GnRH peptide analogues were synthesized and their in vitro and in vivo characteristics studied in male rats. GnRH peptides were assembled by solid-phase peptide synthesis, either as the full length d-Lys6-GnRH (pyroGlu1-His2-Trp3-Ser4-Tyr5-d-Lys6-Leu7-Arg8-Pro9-Gly10-NH2) or as d-Lys6-desGly10-GnRH-NHEt. In all, four GnRH peptide analogues were synthesized and reacted with N-succinimidyl-4-fluorobenzoate (SFB) to yield the fluorinated versions. Binding affinities of the analogues were determined in a competitive binding assay for both human and rat GnRH receptors. Ki-values for the GnRH peptides were found to be subnanomolar, with d-Lys6(FBA)-desGly10-GnRH-NHEt (7) being most potent with a Ki-value of around 50 pM for GnRH receptor species. Radiolabeling was performed using N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) in 33.3 ± 12.8% isolated decay corrected (d.c.) yield within 1.5-2 h. Rat serum stability over 2 h revealed minor degradation (≤5%). For in vivo studies, 18F-peptides (4-30 MBq) were injected intravenously via the tail vein into rats and brain uptake was evaluated by means of dynamic PET (2 h) followed by biodistribution studies. PET showed limited or no uptake in brain for the 18F-peptides which predominantly cleared rapidly by renal excretion. Specific binding in the pituitary gland was confirmed for the 18F-peptide, 7, by blocking with the GnRH agonist buserelin. This journal is © The Royal Society of Chemistry 2015.

Ruhl T.,University of Oslo | Rafique W.,University of Oslo | Lien V.T.,Norsk Medisinsk Syklotronsenter AS | Riss P.J.,University of Oslo | Riss P.J.,Norsk Medisinsk Syklotronsenter AS
Chemical Communications | Year: 2014

This report is concerned with an efficient, CuI-mediated method for the radiosynthesis of [18F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Three 18F-labelled radiotracer candidates were synthesised from [18F]fluoride ions as proof of principle. The new protocol is widely applicable for the synthesis of novel radiotracers in high radiochemical yields. © the Partner Organisations 2014.

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