Françoise Vaufrey

Cea Leti, Grenoble, Rhône-Alpes, France

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Publications (34)65.01 Total impact

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    ABSTRACT: The glycolytic flux (cerebral metabolic rate of glucose CMRglc) and the TCA cycle flux (VTCA) were measured in the same monkeys by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 13C NMR spectroscopy, respectively. Registration of nuclear magnetic resonance (NMR) and PET data were used for comparison of CMRglc and VTCA in the exact same area of the brain. Both fluxes were in good agreement with literature values (CMRglc=0.23+/-0.03 micromol/g min, VTCA=0.53+/-0.13 micromol/g min). The resulting [CMRglc/VTCA] ratio was 0.46+/-0.12 (n=5, mean+/-s.d.), not significantly different from the 0.5 expected when glucose is the sole fuel that is completely oxidized. Our results provide a cross-validation of both techniques. Comparison of CMRglc with VTCA is in agreement with a metabolic coupling between the TCA cycle and glycolysis under normal physiologic conditions.
    Journal of Cerebral Blood Flow & Metabolism 12/2005; 25(11):1418-23. · 5.40 Impact Factor
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    ABSTRACT: We detected glutamate C4 and C3 labeling in the monkey brain during an infusion of [U-13C6]glucose, using a simple 1H PRESS sequence without 13C editing or decoupling. Point-resolved spectroscopy (PRESS) spectra revealed decreases in 12C-bonded protons, and increases in 13C-bonded protons of glutamate. To take full advantage of the simultaneous detection of 12C- and 13C-bonded protons, we implemented a quantitation procedure to properly measure both glutamate C4 and C3 enrichments. This procedure relies on LCModel analysis with a basis set to account for simultaneous signal changes of protons bound to 12C and 13C. Signal changes were mainly attributed to 12C- and 13C-bonded protons of glutamate. As a result, we were able to measure the tricarboxylic acid (TCA) cycle flux in a 3.9 cm3 voxel centered in the monkey brain on a whole-body 3 Tesla system (VTCA = 0.55 +/- 0.04 micromol x g(-1) x min(-1), N = 4). This work demonstrates that oxidative metabolism can be quantified in deep structures of the brain on clinical MRI systems, without the need for a 13C radiofrequency (RF) channel.
    Magnetic Resonance in Medicine 08/2004; 52(1):33-40. · 3.27 Impact Factor
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    ABSTRACT: We quantified putamen and prefrontal cortex metabolites in macaques with simian immunodeficiency virus infection and searched for virological and histological correlates. Fourteen asymptomatic macaques infected since 8-78 months (median: 38) were compared with eight uninfected ones. Absolute concentrations of acetate, alanine, aspartate, choline, creatine, GABA, glutamate, glutamine, lactate, myo-inositol, N-acetylaspartate, taurine and valine were determined by ex vivo proton magnetic resonance spectroscopy. Glutamate concentration in the CSF was determined by HPLC. Gliosis was assessed by glial fibrillary acidic protein and CD68 immunohistochemistry. Glutamate concentration was slightly increased in the prefrontal cortex (19%, p = 0.0152, t-test) and putamen (13%, p = 0.0354, t-test) of the infected macaques, and was unaffected in the CSF. Myo-inositol concentration was increased in the prefrontal cortex only (27%, p = 0.0136). The concentrations of glutamate and myo-inositol in the prefrontal cortex were higher in the animals with marked or intense microgliosis (p = 0.0114). The other studied metabolites, including N-acetylaspartate, were not altered. Glutamate concentration may thus increase in the cerebral parenchyma in asymptomatic animals, but is not accompanied by a detectable decrease in N-acetylaspartate concentration (neuronal dysfunction). Thus, there are probably compensatory mechanisms that may limit glutamate increase and/or counterbalance its effects.
    Journal of Neurochemistry 03/2004; 88(4):928-38. · 3.97 Impact Factor
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    ABSTRACT: Compared to homoaromatic and aliphatic nucleophilic radiofluorinations, only few references can be found in the literature describing nucleophilic substitutions with [18F]fluoride ion of heteroaromatic compounds such as pyridines and only reactions involving fluorination processes at the ortho-position (2-position) have been more intensively studied. In the present paper, the scope of the nucleophilic aromatic fluorinations at the meta- and para-position of the pyridine ring with no-carrier-added [18F]fluoride ion as its activated K[18F]F-K222 complex has been evaluated and compared to the nucleophilic aromatic fluorinations at the ortho-position in this pyridine series. The syntheses of 3- and 4-[18F]fluoropyridines were chosen as model reactions and compared to the radiosynthesis of 2-[18F]fluoropyridine. The parameters studied include the influence of the position of the leaving group at the pyridine ring, as well as the quantity of the precursor used, the type of activation (conventional heating, microwave irradiation), the solvent, the temperature and the reaction time. Using the corresponding nitro precursor, high yields were obtained at the 2-position (94% yield) using microwaves (100 W) for 2 min in DMSO. Good yields (up to 72%) were observed at the 4-position using the same conditions while practically no reaction was observed at the 3-position. About 60% yield was also obtained at both the 2- and 4-position using the corresponding nitro precursor at 145°C for 10 min in DMSO. Copyright © 2003 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 08/2003; 46(10):979 - 992.
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    ABSTRACT: In recent years, considerable effort has been spent on the design, synthesis and pharmacological characterization of radiofluorinated derivatives of the 5-HT(1A) receptor antagonist, WAY-100635, for the in vivo study of these receptors in human brain with PET. (Pyridinyl-6)-fluoro- and (pyridinyl-5)-fluoro-analogues of WAY-100635 (6-fluoro and 5-fluoro-WAY-100635, 5a/6a) were synthesized as well as the corresponding chloro-, bromo- and nitro-derivatives as precursors for labelling (5b-d and 6b-d). Comparative radiolabelling of these precursors with fluorine-18 (positron-emitting isotope, 109.8 min half-life) clearly demonstrated that only ortho-fluorination in this pyridine series, and not meta-fluorination, is of interest for the preparation of a radioligand by nucleophilic heteroaromatic substitution. 6-[(18)F]Fluoro-WAY-100635 ([(18)F]5a) can be efficiently synthesized in one step, either from the corresponding 6-bromo precursor (using conventional heating at 145 degrees C for 10 min) or from the corresponding 6-nitro precursor (using microwave activation at 100 W for 1 min). Typically, 15-25 mCi (0.55-0.92 GBq) of 6-[(18)F]fluoro-WAY-100635 ([(18)F]5a, 1-2 Ci/micromol or 37-72 GBq/micromol) were obtained in 50-70 min starting from a 100 mCi (3.7 GBq) aliquot of a batch of cyclotron-produced [(18)F]fluoride. This (18)F-labelled radioligand is now being evaluated in PET studies.
    Bioorganic & Medicinal Chemistry 08/2003; 11(13):2769-82. · 2.90 Impact Factor
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    ABSTRACT: Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro derivative has been designed for positron emission tomography (PET). The corresponding 5-iodo-, 5-bromo- and 5-chloro N-Boc-protected quipazines as labelling precursors, as well as 5-fluoro-6-nitroquipazine as a reference compound have been synthesized. 5-[(18)F]Fluoro-6-nitroquipazine has been radiolabelled with fluorine-18 (positron-emitting isotope, 109.8 min half-life) by nucleophilic aromatic substitution from the corresponding N-Boc protected 5-bromo- and 5-chloro-precursors using K[(18)F]F-K(222) complex in DMSO by conventional heating (145 degrees C, 2 min) or microwave activation (50 W, 30-45 s), followed by removal of the protective group with TFA. Typically, 15-25 mCi (5.5-9.2 GBq) of 5-[(18)F]fluoro-6-nitroquipazine (1-2 Ci/micromol or 37-72 GBq/micromol) could be obtained in 70-80 min starting from a 550-650 mCi (20.3-24.0 GBq) aliquot of a cyclotron [(18)F]F(-) production batch (2.7-3.8% non decay-corrected yield based on the starting [(18)F]fluoride). Ex vivo studies (biodistribution in rat), as well as PET imaging (in monkey) demonstrated that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) readily crossed the blood brain barrier and accumulated in the regions rich in 5-HT transporter (frontal- and posterial cortex, striata). However, the low accumulation of the tracer in the thalamus (rat and monkey) as well as the comparable displacement of the tracer observed with both citalopram, a -HT re-uptake inhibitor and maprotiline, a norepinephrine re-uptake inhibitor (rat), indicate that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) does not have the suggested potential for PET imaging of the serotin transporter (SERT).
    Bioorganic & Medicinal Chemistry 09/2002; 10(8):2611-23. · 2.90 Impact Factor
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    ABSTRACT: Understanding brain disorders, the neural processes implicated in cognitive functions and their alterations in neurodegenerative pathologies, or testing new therapies for these diseases would benefit greatly from combined use of an increasing number of rodent models and neuroimaging methods specifically adapted to the rodent brain. Besides magnetic resonance (MR) imaging and functional MR, positron-emission tomography (PET) remains a unique methodology to study in vivo brain processes. However, current high spatial-resolution tomographs suffer from several technical limitations such as high cost, low sensitivity, and the need of restraining the animal during image acquisition. We have developed a beta(+)-sensitive high temporal-resolution system that overcomes these problems and allows the in vivo quantification of cerebral biochemical processes in rodents. This beta-MICROPROBE is an in situ technique involving the insertion of a fine probe into brain tissue in a way very similar to that used for microdialysis and cell electrode recordings. In this respect, it provides information on molecular interactions and pathways, which is complementary to that produced by these technologies as well as other modalities such as MR or fluorescence imaging. This study describes two experiments that provide a proof of concept to substantiate the potential of this technique and demonstrate the feasibility of quantifying brain activation or metabolic depression in individual living rats with 2-[(18)F]fluoro-2-deoxy-d-glucose and standard compartmental modeling techniques. Furthermore, it was possible to identify correctly the origin of variations in glucose consumption at the hexokinase level, which demonstrate the strength of the method and its adequacy for in vivo quantitative metabolic studies in small animals.
    Proceedings of the National Academy of Sciences 09/2002; 99(16):10807-12. · 9.81 Impact Factor
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    ABSTRACT: Inhibition of succinate dehydrogenase (SDH) by the mitochondrial toxin 3-nitropropionic acid (3-NP) has gained acceptance as an animal model of Huntington's disease. In this study 13C NMR spectroscopy was used to measure the tricarboxylic acid (TCA) cycle rate in the rat brain after 3-NP treatment. The time course of both glutamate C4 and C3 13C labelling was monitored in vivo during an infusion of [1-13C]glucose. Data were fitted by a mathematical model to yield the TCA cycle rate (Vtca) and the exchange rate between alpha-ketoglutarate and glutamate (Vx). 3-NP treatment induced a 18% decrease in Vtca from 0.71 +/- 0.02 micro mol/g/min in the control group to 0.58 +/- 0.02 micro mol/g/min in the 3-NP group (p < 0.001). Vx increased from 0.88 +/- 0.08 micro mol/g/min in the control group to 1.33 +/- 0.24 micro mol/g/min in the 3-NP group (p < 0.07). Fitting the C4 glutamate time course alone under the assumption that Vx is much higher than Vtca yielded Vtca=0.43 micro mol/g/min in both groups. These results suggest that both Vtca and Vx are altered during 3-NP treatment, and that both glutamate C4 and C3 labelling time courses are necessary to obtain a reliable measurement of Vtca.
    Journal of Neurochemistry 08/2002; 82(4):857-66. · 3.97 Impact Factor
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    ABSTRACT: Inhibition of succinate dehydrogenase (SDH) by the mitochondrial toxin 3-nitropropionic acid (3-NP) has gained acceptance as an animal model of Huntington's disease. In this study 13C NMR spectroscopy was used to measure the tricarboxylic acid (TCA) cycle rate in the rat brain after 3-NP treatment. The time course of both glutamate C4 and C3 13C labelling was monitored in vivo during an infusion of [1-13C]glucose. Data were fitted by a mathematical model to yield the TCA cycle rate (Vtca) and the exchange rate between α-ketoglutarate and glutamate (Vx). 3-NP treatment induced a 18% decrease in Vtca from 0.71 ± 0.02 µmol/g/min in the control group to 0.58 ± 0.02 µmol/g/min in the 3-NP group (p < 0.001). Vx increased from 0.88 ± 0.08 µmol/g/min in the control group to 1.33 ± 0.24 µmol/g/min in the 3-NP group (p < 0.07). Fitting the C4 glutamate time course alone under the assumption that Vx is much higher than Vtca yielded Vtca=0.43 µmol/g/min in both groups. These results suggest that both Vtca and Vx are altered during 3-NP treatment, and that both glutamate C4 and C3 labelling time courses are necessary to obtain a reliable measurement of Vtca.
    Journal of Neurochemistry 07/2002; 82(4):857 - 866. · 3.97 Impact Factor
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    ABSTRACT: The α2-adrenergic receptor antagonist atipamezole has been labelled with carbon-11 using [11C]formaldehyde and 2-ethyl-2-oxoacetylindane. Various routes are proposed for the synthesis of the latter: oxidation of 2-acetyl-2-ethylindane, hydrolysis of 2-diethoxy-2-indane and oxidation of 2-diazoacetyl-2-ethylindane. The average radiochemical yield of [11C]atipamezole was 24% based on [11C]formaldehyde, and the synthesis time, including HPLC purification and formulation, was 45 min. Copyright © 2002 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 01/2002; 45(1).
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    ABSTRACT: The lead compound of a new series of azabicyclic carbamates described by Astra Laboratories as ligands for the α7 nicotinic acetylcholine receptor subtype, namely N-(4-bromophenyl)carbamic acid quinuclidin-3-yl ester, has been labelled with carbon-11 using no-carrier-added [11C]phosgene and the isocyanate pathway. Typically, 25–35 mCi (0.92–1.29 GBq) of the tracer was obtained within 30 min of radiosynthesis (HPLC purification included) with specific radioactivities ranging from 500 to 800 mCi/µmol (18.5–29.6 GBq/µmol). Biodistribution studies demonstrated a relatively good brain uptake of the compound (0.8–1.2% I.D./g tissue in various brain regions), but without preferential concentration in brain regions rich in α7-subtype nicotinic receptor (e.g. hippocampus, pons and colliculi). No specific binding could be demonstrated in pre-saturation studies performed with both the cold compound and nicotine. Therefore, this ligand is not suitable for further exploration in PET imaging. Copyright © 2001 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 07/2001; 44(11):785 - 795.
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    ABSTRACT: Me-QNB (N-methyl-quinuclidin-3-yl benzilate or N-methyl-quinuclidin-3-yl diphenylhydroxy acetate) is a hydrophilic, non-metabolized and highly specific muscarinic acetylcholinergic antagonist. Using this quaternary ammonium derivative of QNB, labelled with carbon-11, a positron-emitting isotope (half-life : 20.4 minutes), the potential for quantification of myocardial muscarinic receptors in vivo using the high-resolution, sensitive and quantitative imaging technique PET (positron emission tomography) was previously demonstrated in dogs and validated in humans. In this paper, the radiosynthesis of carbon-11-labelled Me-QNB is investigated and oriented towards the preparation of multi milliCuries of radiotracer. Typically, using no-carrier-added [11C]methyl triflate as the alkylating agent and 0.64 mg (1.89 µmol) of QNB as precursor for labelling at 100°C for 1 minute lead to a 48.5% +/−10% (15 runs) decay-corrected radiochemical yield (based on [11C]methyl triflate). 183 mCi (+/−39) of [11C]Me-QNB ([11C]-1) could be synthesized in only 27 to 28 minutes after EOB and occasionally, up to 340 mCi of [11C]Me-QNB ([11C]-1) were obtained, corresponding to a 85% decay-corrected yield. The associated decay-corrected specific radioactivities obtained were 2658 mCi/µmol (+/−971) at EOB. Copyright © 2001 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 05/2001; 44(5):337 - 345.
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    ABSTRACT: Fluorine-18- (t(1/2) 109.8 min) and carbon-11 (t(1/2) 20.4 min)-labeled norepinephrine analogues have been found previously to be useful positron-emission-tomography (PET) radioligands to map adrenergic nerve terminals of the heart. Metaraminol ((1R,2S)-2-amino-1-(3-hydroxyphenyl)-1-propanol) is a metabolically stable structural analogue of norepinephrine and possesses high affinity towards the norepinephrine transporter and the vesicular monoamine transporter. This paper presents the radiosynthesis of new positron-emission-tomography halogeno analogues of metaraminol labeled with high specific radioactivity. Firstly, fluorine-18-labeled 4-fluorometaraminol (4-[18F]FMR or (1R,2S)-2-amino-1-(4-[18F]fluoro-3-hydroxyphenyl)-1-propanol) and its three other stereoisomers were prepared based on the following key steps: (a) condensation of the corresponding no-carrier-added labeled fluorobenzaldehyde with nitroethane, and (b) HPLC (C18 and chiral) resolution of the diastereomeric product mixture into the four individual enantiomers. Secondly, the corresponding 6-fluoro analogues, fluorine-18-labeled 6-fluorometaraminol (6-[18F]FMR or (1R,2S)-2-amino-1-(2-[18F]fluoro-5-hydroxyphenyl)-1-propanol) and its three other enantiomers, were prepared in an analogous way. Typically, 0.48-0.55 GBq of 4-[18F]FMR and 0.14-0.15 GBq of 6-[18F]FMR could be obtained after 120-160 min total synthesis time, with a specific radioactivity of 56-106 GBq/micromol. Furthermore, the synthesis of racemic 4-fluorometaraminol and 6-fluorometaraminol as reference compounds was performed. as well as independent chiral syntheses of the optically active (1R,2S) enantiomers. For the chiral syntheses, the key step was an electrophilic fluorination with acetyl hypofluorite of (1R,2S)-configurated organometallic derivatives of metaraminol. Tissue distribution studies in rats suggested that both 4-[18F]FMR and 6-[18F]FMR display similar affinity towards the presynaptic adrenergic nerve terminal in the heart. From a practical point of view, 4-[18F]FMR appeared to be the more attractive candidate for future PET investigations, due to higher radiochemical yields.
    Bioorganic & Medicinal Chemistry 04/2001; 9(3):677-94. · 2.90 Impact Factor
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    ABSTRACT: The α‐2 antagonist Atipamezole has been labelled with carbon‐11 using [11C]CH2O and the corresponding α‐ketoaldehyde 1. For the synthesis of 1 two routes are proposed. The radiochemical yield of [11C]Atipamezole was 24% relative to [11C]CH2O and the synthesis time, including HPLC purification, was 30 minutes.
    Journal of Labelled Compounds and Radiopharmaceuticals 01/2001; 44. · 1.24 Impact Factor
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    ABSTRACT: A new scheme is proposed to edit separately glutamate C(3) and C(4) resonances of (1)H bound to (13)C, in order to resolve these two signals which overlap at intermediate magnetic fields (1.5 T-3 T), commonly available for human brain studies. The two edited spectra are obtained by combining the individual acquisitions from a four-scan measurement in two different ways. The four acquisitions correspond to the two steps of the classical POCE scheme combined with another two-scan module, where the relative phases of the C(3) and C(4) (1)H resonances are manipulated using zero quantum and double quantum coherence pathways. This new technique exhibits the same sensitivity as POCE and allows the (13)C labeling of C(3) and C(4) glutamate from [1-(13)C]glucose to be monitored separately in the rat brain at 3 T.
    Magnetic Resonance in Medicine 10/2000; 44(3):395-400. · 3.27 Impact Factor
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    ABSTRACT: A new scheme is proposed to edit separately glutamate C3 and C4 resonances of 1H bound to 13C, in order to resolve these two signals which overlap at intermediate magnetic fields (1.5 T-3 T), commonly available for human brain studies. The two edited spectra are obtained by combining the individual acquisitions from a four-scan measurement in two different ways. The four acquisitions correspond to the two steps of the classical POCE scheme combined with another two-scan module, where the relative phases of the C3 and C41H resonances are manipulated using zero quantum and double quantum coherence pathways. This new technique exhibits the same sensitivity as POCE and allows the 13C labeling of C3 and C4 glutamate from [1-13C]glucose to be monitored separately in the rat brain at 3 T. Magn Reson Med 44:395–400, 2000. © 2000 Wiley-Liss, Inc.
    Magnetic Resonance in Medicine 08/2000; 44(3):395 - 400. · 3.27 Impact Factor
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    ABSTRACT: Evaluation of oligonucleotides for biomedical applications requires different in vivo and in vitro approaches (pharmacokinetics, biodistribution, macro- and microimaging, metabolism, ...), that are performed with different radioisotopes according to the temporal and spatial resolution needed. A method to introduce radioactive isotopes of halogens (fluorine, bromine, and iodine) in a small and stable molecule has been developed. Radiosynthons can then be conjugated with any given oligonucleotide in one step to create the appropriate radiotracer. This general radiolabeling procedure for oligonucleotides is efficient to synthesize 18F-, 76Br-, and 125I-oligonucleotides for biological needs. Applications of the method to biodistribution, metabolism, in vivo and ex vivo imaging of 125I- and 18F-labeled oligonucleotides are reported.
    Bioconjugate Chemistry 08/2000; 11(5). · 4.58 Impact Factor
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    ABSTRACT: We have recently described the labeling of a natural deoxyribose phosphodiester oligonucleotide with fluorine-18 (t1/2 : 109·8 min) and demonstrated its potential for in vivo imaging in a primate PET study. We here report that the methodology employed can be reliably and routinely applied to the most popular chemical modifications: (a) full length internucleosidic phosphorothioate diester bonds deoxyribose oligonucleotides (the modification most favoured by industry for human antisense therapy), (b) hybrid methylphosphonate/phosphodiester internucleosidic bonds deoxyribose oligonucleotides and (c) 2′Methyl modified ribose oligonucleotides. The whole fluorine-18 labeling procedure allows us to obtain 15 to 21 mCi (0·55 to 0·74 GBq) of pure labeled oligonucleotides (regardless the modification of the sugar phosphate backbone) in 180 minutes with a specific radioactivity of 0·8 to 2 Ci/μmol (30 to 70 GBq/μmol) at the end of synthesis. Copyright © 2000 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 07/2000; 43(8):837 - 848.
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    ABSTRACT: [11C]FLB 457 is a high affinity dopamine D2 receptor radioligand that is used for visualisation and quantitation of extrastriatal dopamine D2 receptors with positron emission tomography (PET). In this study, we report a comparison regarding the specific radioactivity of [11C]FLB 457 obtained by two different methods of synthesising [11C]methyl iodide. In addition, the synthesis of unlabelled FLB 457 and the corresponding desmethyl-precursor, starting from commercially available material, is reported. The first method used for [11C]methyl iodide synthesis was reduction of [11C]CO2 with lithium aluminium hydride in tetrahydrofuran to [11C]CH3OH, followed by conversion into [11C]CH3I= with hydrogen iodide. The second, recently developed method uses gas phase halogenation of [11C]CH4 with iodine. [11C]FLB 457 was labelled with [11C]methyl triflate produced on-line from [11C]methyl iodide. With the first method a specific radioactivity for [11C]FLB 457 of 2100 Ci/mmol (78 GBq/μmol) (n=13) at 40 min after end of bombardment (EOB) was achieved. Using the gas phase method a specific radioactivity of 3400 Ci/mmol (126 GBq/μmol) (n=7) at 40 min EOB could be obtained. The use of the gas phase method also resulted in shorter time for set-up compared to the regular method since no wet chemistry is involved in the preparation of [11C]methyl iodide. Copyright © 2000 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 04/2000; 43(4):331 - 338.