Norsk Medisinsk Syklotronsenter AS

Oslo, Norway

Norsk Medisinsk Syklotronsenter AS

Oslo, Norway
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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.

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.

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.

Olberg D.E.,Norsk medisinsk syklotronsenter AS | Olberg D.E.,University of Oslo | Bauer N.,University of California at Davis | Andressen K.W.,University of Oslo | And 7 more authors.
Nuclear Medicine and Biology | Year: 2016

Introduction The gonadotropin releasing hormone receptor (GnRH-R) has a well-described neuroendocrine function in the anterior pituitary. However, little is known about its function in the central nervous system (CNS), where it is most abundantly expressed in hippocampus and amygdala. Since peptide ligands based upon the endogenous decapetide GnRH do not pass the blood–brain-barrier, we are seeking a high-affinity small molecule GnRH-R ligand suitable for brain imaging by positron emission tomography. We have previously reported the radiosynthesis and in vitro evaluation of two novel [18F]fluorinated GnRH-R ligands belonging to the furamide class of antagonists, with molecular weight less than 500 Da. We now extend this work using palladium coupling for the synthesis of four novel radioligands, with putatively reduced polar surface area and hydrophilicity relative to the two previously described compounds, and report the uptake of these 18F-labeled compounds in brain of living rats. Methods We synthesized reference standards of the small molecule GnRH-R antagonists as well as mesylate precursors for 18F-labeling. The antagonists were tested for binding affinity for both human and rat GnRH-R. Serum and blood stability in vitro and in vivo were studied. Biodistribution and PET imaging studies were performed in male rats in order to assess brain penetration in vivo. Results A palladium coupling methodology served for the synthesis of four novel fluorinated furamide GnRH receptor antagonists with reduced heteroatomic count. Radioligand binding assays in vitro revealed subnanomolar affinity of the new fluorinated compounds for both human and rat GnRH-R. The 18F-GnRH antagonists were synthesized from the corresponding mesylate precursors in 5–15% overall radiochemical yield. The radiolabeled compounds demonstrated good in vivo stability. PET imaging with the 18F-radiotracers in naive rats showed good permeability into brain and rapid washout, but absence of discernible specific binding in vivo. Conclusions The novel small molecule 18F-fluorinated GnRH-R antagonist compounds show high receptor affinity in vitro, and may prove useful for quantitative autoradiographic studies in vitro. The compounds were permeable to the blood–brain barrier, but nonetheless failed to reveal significant specific binding in brain of living rats. Nonetheless, our approach may serve as a foundation for designing PET ligands suitable to image the GnRH-R distribution in brain. © 2016 Elsevier Inc.

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.

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.

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