Géza Horváth

A new, convenient method for the preparation of 4-[18F]fluorobenzyl halides

A convenient method suitable for automated preparation of 4-[18F]fluorobenzyl halides from no-carrier-added [18F]fluoride has been developed. 4-[18F]Fluorobenzaldehyde, synthesized from [18F]fluoride by aromatic nucleophilic substitution on 4-trimethylammoniumbenzaldehyde triflate, was first retained on a C18 cartridge and there efficiently reduced to 4-[18F]fluorobenzyl alcohol simply by flowing an aqueous solution of NaBH4. The conversion of 4-[18F]fluorobenzyl alcohol to 4-[18F]fluorobenzyl halide was investigated using PBr3, PI3, P2I4, Ph3PBr2 and Ph3PI2 in CH2Cl2. 4-[18F]Fluorobenzyl halides were purified by passing through a disposable silica cartridge. The conversion rapidly proceeded in radiochemical yields of nearly 90% at 40 degrees C with P2I4 and almost quantitatively at room temperature with Ph3PBr2. With this last reagent 4-[18F]fluorobenzyl bromide was obtained in overall radiochemical yields of 50-60% within 30 min from EOB.

Right prefrontal activation produced by arterial baroreceptor stimulation: a PET study.

This study was performed to test the hypothesis of greater right hemispheric involvement in the processing of baroreceptor stimuli. Carotid sinus baroreceptors were stimulated by rhythmically decreasing air pressure in a neck chamber, and under control conditions the thorax was stimulated in a similar manner. Changes in regional cerebral blood flow (rCBF) were measured by PET. Baroreceptor stimulation resulted in rCBF increase in the right anterior–inferior prefrontal cortex (Brodmann areas (BA) 10/44/47) and bilaterally in BA 6/8. We conclude that in at least some stages of baroreceptor information processing the right hemisphere plays a greater role than the left hemisphere.

Synthesis of 3‐[1H‐imidazol‐4‐yl]propyl 4‐[18F]fluorobenzyl ether ([18F]fluoroproxyfan): a potential radioligand for imaging histamine H3 receptors

3-[1H-Imidazol-4-yl]propyl 4-fluorobenzyl ether (fluoroproxyfan), a potential histamine H 3 receptor ligand, was labeled with 18 F for clinical PET studies. The synthesis involved the O-alkylation of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol with 4-[ 18 F]fluorobenzyl bromide in the presence of silver triflate and a non-nucleophilic amine base. 4-[18F]Fluoroproxyfan was obtained within 100 min from the end of bombardment (EOB) in 10% radiochemical yield (decay corrected to EOB) with a radiochemical purity >99% and a specific activity >150 GBq/μmol.

Synthesis of 5'-N-(2-[18F]Fluoroethyl)-carboxamidoadenosine: A promising tracer for investigation of adenosine receptor system by PET technique

5′-N-(2-[18F]Fluoroethyl)-carboxamidoadenosine ([18F]FNECA), a promising 18F-labelled adenosine agonist has been prepared by two different synthetic routes. In the first, [18F]fluoride was reacted with 5′-N,N-ethylene-2,′,3′-O-isopropylidenecarboxamido-adenosine and after removing the protective group [18F]FNECA was obtained in a low radiochemical yield (1±1%, means±sd, n=7, decay corrected). In the second, 2-[18F]fluoro-ethylamine was synthesised according to the literature and reacted with 2′,3′-O-isopropylideneadenosine-5′-uronic acid in the presence of a coupling agent. The following hydrolysis step provided the [18F]FNECA with a modest radiochemical yield (24±9%, n=17, based on [18F]fluoride-activity). After purification by preparative reverse phase HPLC 18·9–166·5 MBq (0·51–4·5 mCi) [18F]FNECA was obtained with a specific activity of 2·35±1·14 TBq/mmol (63·5±30·9 Ci/mmol, n-3). The total synthesis took 200 min and the decay corrected radiochemical yield based on [18F]F− activity was 17±9% (n=5) with more than 99·9% radiochemical purity. This second route provides sufficient [18F]FNECA for the subsequent biological evaluation using PET-technique. Copyright

On the mechanism of cogenotoxic action between ingested amphibole asbestos fibres and benzo[a]pyrene : II. Tissue specificity studies using comet assay

Epidemiological data seem to be equivocal on the probable increase in cancer incidence in populations exposed to asbestos-fibre contaminated drinking water. Although animal experiments failed to demonstrate carcinogenicity of oral asbestos exposure, the large surface area of the fibres, however, creates the possibility of cogenotoxic action with adsorbed water-borne organics. In our animal model, rats were gavaged with untreated UICC crocidolite and anthophyllite fibres and fibres that had been allowed to adsorb benzo[a]pyrene molecules from aqueous solutions. Peritoneal macrophages and intestine, parietal peritoneum and omentum samples were obtained from the animals after 24 h. The alkaline single-cell microgel electrophoresis assay (comet assay) was performed on cells isolated from the solid tissues. Tail moment was applied as a basis of evaluation following image analysis. Our results indicate high levels of DNA strand breaks in the cells prepared from the omentum and intestine. We could also demonstrate a significant potentiating effect of the adsorbed carcinogen on the induction of DNA damage in the omentum. The parietal peritoneum and macrophages were not involved in the early genotoxic alterations under study. Our results support the molecular model of asbestos cocarcinogenesis, including both asbestos-induced deletions and mutations caused by a mutagen carried by the same fibres.

Preparation and primary evaluation of [11C]CSC as a possible tracer for mapping adenosine A2A receptors by PET

A 11C labeled selective adenosine A2A antagonist, (E)-8-(3-chlorostyryl)-1,3-dimethyl-7-[11C]methylxanthine [11C]CSC) was prepared by the reaction of (E)-8-(3-chlorostyryl)-1,3-dimethylxanthine and [11C]methyl iodide. The decay-corrected radiochemical yield was 32.3% with a radiochemical purity of 99%, a specific activity of 1.85-5.55 GBq/mumol and a preparation time of 1 h. A primary evaluation of [11C]CSC as a potential tracer for mapping adenosine A2A receptors by positron emission tomography (PET) is also presented. Biodistribution and autoradiographic studies were carried out on Swiss mice and domestic rabbits. In mice the lung showed the highest uptake at 10 min after i.v. injection, followed by the liver, kidney, heart and brain. Inside the brain a high level of radioactivity accumulated in the striatum, in accordance with previous findings on the specific spatial distribution of A2A adenosine receptors and also in the medulla oblongata. Dynamic PET studies on rabbits showed a fast brain uptake of CSC, reaching a maximum in less then 2 min. On the basis of competition experiments with the unlabeled ligand [11C]CSC proves to bind specifically to the appropriate receptor.

Changes in brain activation caused by caloric stimulation in the case of cochleovestibular denervation - PET study

There are a number of well-known stimulation methods for the investigation of the central projection of the vestibular system. In addition to optokinetic, galvanic and neck vibration tests, the most widespread method is caloric stimulation. These listed methods cause not only vestibular, but also other effects on the central nervous system (CNS) (acoustic, tactile and nociceptive). In this paper, positron emission tomography (PET) was used to investigate whether caloric stimulation contains a non-vestibular (extravestibular) component, which would cause a distortion in the cortical activity and therefore in the vestibular effect on the CNS. Caloric stimulation was carried out in six patients who had been operated on due to cerebello-pontine angle tumour. These patients suffered post-operatively from a complete lesion of the vestibular system and anacusis on the operated side. Ipsilaterally activated areas were the inferior pole of the post-central gyrus and temporoparietal junction, caudal part of the post-central gyrus (SI, SII), inferior parietal lobule and medial frontal gyrus. Contralaterally activated areas were the anterior cingulate gyrus, medial frontal gyrus, posterior part of the insula, post-central gyrus and temporoparietal junction (SII). Ipsilaterally deactivated areas were the caudal and cranial part of the medial occipital gyrus (V2, V3, V4, V5). Contralaterally deactivated areas were the lingual gyrus, inferior occipital gyrus (V2, V3) and fusiform gyrus. On the basis of these data, it was postulated that, during caloric stimulation, extravestibular reaction also occurs, which corresponds to the subjective feeling of heat and pain. The deactivation of the occipital cortex due to an extravestibular effect was demonstrated. This is the first observation to suggest the possibility of nociceptivevisual interaction.

Synthesis of 5'-deoxy-5'-[18F]fluoro-adenosine by radiofluorination of 5'-deoxy-5'-haloadenosine derivatives

Abstract5′-Deoxy-5′-[18F]fluoro-adenosine was synthesised by nucleophilic radiofluorination reactions of 5′-deoxy-5′-haloadenosines. The homogeneous isotope exchange in 5′-deoxy-5′-fluoro-adenosine was also investigated. The conversion of these reactions was found to be rather low and depends on the strength of the halogen-carbon bond: 0.248% for chloride-, 0.488% for bromide- and 1.070% for iodide-derivative; there was no reaction observed in the case of fluoro-compound.

In vivo studies on genotoxicity and cogenotoxicity of ingested UICC anthophyllite asbestos

Early cytogenetic action of oral exposure to UICC anthophyllite, an amphibole type of asbestos, was studied in Fischer-344 rats. The animals were gavaged with a suspension of untreated fibres (50 mg/kg) and fibres which had been allowed to adsorb benzo[alpha]pyrene molecules from aqueous solutions of 0.25-2.5 micrograms/ml. HPLC measurements indicated effective adsorption of the benzo[alpha]pyrene molecules on the fibres. The authors consider this system a suitable model for the drinking of water containing asbestos fibres and organic micropollutants. The formation of micronuclei and sister chromatid exchanges was studied in bone marrow samples taken from animals 24 h after oral administration of suspensions. Whereas anthophyllite fibres failed to induce cytogenetic alterations, fibres pretreated with the polycyclic aromatic solutions caused dose-dependent increase in the sister chromatid exchange frequencies. The observed cytogenetic impact can be explained by a local action of carcinogen molecules accumulated and subsequently transported. The results support the hypothesis that epidemiological evidence of carcinogenicity of asbestos in potable water may rather be explained by cogenotoxic action of the asbestos fibres and biologically active organic micropollutants adsorbed on their surface.

Alternative proof of the Lyndon-Schützenberger theorem

Some observations on products of primitive words are discussed. By these results, alternative proof is given for the Lyndon-Schutzenberger Theorem, which says that every solution of the equation ambn = ck over σ* is trivial.