[en] In order to develop radiotracers for the Positron Emission Tomography (PET), we labelled both the mecamylamine and SIB-1553A with carbon-11 to study the nicotinic cholinergic receptors (nAChRs). The radiosynthesis of [¹¹C]-t-PA_stop and the labelling with tritium of one analogue were realized for cerebral ischemia PET studies. The [¹¹C]-mecamylamine, a non-competitive and non-selective nAChRs antagonist was synthesized in 45 min via a N-[¹¹C]-methylation reaction. In the rat brain, the ex vivo studies showed no radio-metabolite 45 min after the injection of [¹¹C]-mecamylamine. The uptake kinetics in the rat brain or in vivo by PET in the anesthetized baboon or in the conscious monkey, reached a plateau around 45-50 min after injection. However, the saturation or displacement experiments did not permit to exhibit nor a significant difference of labelling between the different cerebral regions nor a specific uptake. In consequence, the [¹¹C]-mecamylamine was not an appropriate radioligand for nAChRs PET study. The labelling of [¹¹C]-SIB 1553A, a selective agonist for the nicotinic β4 subunit, required the synthesis in 5 steps (56% overall yield) of precursor for the incorporation of carbon-11. The radiosynthesis was performed in 36 min by a N-[¹¹C]-methylation reaction (yield: 75%). The [¹¹C]-t-PA_stop was obtained from [¹¹C]-KCN with yields from 80 to 90%. For the first time with carbon-11, the formation of an amidine group was realized from a nitrile group. The labelling by isotopic exchange of hydrogen by tritium of the t-PA_stop did not permit to obtain the [³H]-t-PA_stop but a tritiated analogue. This compound will be used to study its vectorization by micro-encapsulation. (author)

[en] Imaging the N-methyl-D-aspartate receptors (NMDARs) in the living human brain by positron emission tomography (PET) or single photon emission computed tomography (SPECT) would provide useful information on the role of these receptors in ischemia and in various neurological disorders such as degenerative diseases, epilepsy or schizophrenia. To assess NMDAR radiotracer development and to propose perspectives, we overviewed the PET and SPECT candidate radioligands developed until now. Labelled molecules of interest were classified in three groups according to their binding site: intra-channel pore site blockers, glycine site inhibitors and NR2B selective subunit antagonists. (authors)

[en] In order to perform in vivo imaging of the NR2B NMDA receptor system by positron emission tomography, a NR2B selective NMDA receptor antagonist has been labelled with carbon-11 (half-life: 20 min). N-[4-(4-fluorobenzyl)piperidin-1-yl]-N0- (2-oxo-1, 3-dihydrobenzimidazol-5-yl)oxamide has been described demonstrating high affinity and selectivity for the NR2B receptors (IC₅₀ of 5 nM in [³H]Ro-25, 6981 binding assay). The labelling precursor and the reference compound were synthesized by coupling the 4-(4-fluorobenzyl)piperidine with the corresponding oxalamic acid. The reaction of [¹¹C]phosgene with phenylenediamine precursor led the formation of the [¹¹C]benzimid-azolone ring present on the ligand. The labelling occurred in THF or acetonitrile and the decay corrected radiochemical yield was 30-40% from the produced [¹¹C]methane. HPLC purification and formulation led to 2.6-3.7 GBq (70-100 mCi) of radioligand within 30-35 min. The specific radioactivity was 72-127 GBq/μmol (2-3.4 Ci/μmol) at the end of synthesis. (authors)

[en] The hydrogen isotope exchange of Brefeldin-A with tritium gas (T₂) in 1,4-dioxane was studied over a commercial palladium catalyst supported on diatomaceous earth (5% metallic weight). The effect of the gas phase was studied. Addition of air in the gas phase led to an increase of the catalytic activity. Moreover, exchange was enhanced when the air/T₂ ratio reached a value of 4. This latter result is interpreted, principally, in terms of a strongly poisoning of the metallic particles together with an effect of the T₂ partial pressure. Through the comparison with Pd(II) oxide, the role of the support is also shown. The specific activities ranged up to 2.8 Ci/mMoles. The labelled product was analyzed by ³H NMR. Possible mechanisms for tritium incorporation are discussed and two different adsorbed species, on the catalyst surface, are involved. (author)

[en] The synthesis and improved purification procedures of two photoactivatable ligands ³H-A and ³H-A are presented. Particular attention was given to the use of resolutive reversed-phase HPLC conditions which were found to be essential for the characterization and the elimination of contaminating products and for the obtention of pure diazonium probes at high specific radioactivity (up to 50 Ci/mmol). (author)

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[en] The palladium-catalyzed cross-coupling reactions between a (trimethylstannyl)arene and [¹¹C]methyl iodide (Stille reaction) or between an aryl halide and a [¹¹C]monomethyltin reagent issued from Lappert's stannylene, were developed for the synthesis of polyfunctional [¹¹C]methyl quinolines and quinoline-imides as potential tracers for positron emission tomography (PET). (authors)

[en] Two potent and selective 5-HT₄ ligands, [³H]-5-[(N-propylpiperidin-4-yl)methoxy]-1, 2, 3, 4-tetrahydrobenzo[ h][1, 6] naphthyridine (1a) and [³H]-1-methyl-5-[(N-propylpiperidin-4-yl)methoxy]pyrrolo[1, 2- a]thieno[2, 3-e]pyrazine (2a) were radiolabelled with tritium. Radioactive labelling was achieved by simultaneous tritium reduction of a mixture of both propargylic precursors (1c-2c). The two tritiated ligands thus obtained were radiochemically pure and possessed high radioactive specific activities. These tritiated 5-HT₄ ligands will allow for binding characterization as an essential tool for their further development. (authors)

[en] In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radio-fluorination followed by a reduction of the para-position carbonyl function. Radiotracers [¹⁸F]1a, [¹⁸F]2a or the pattern 4-(4-[¹⁸F]-fluorobenzyl)piperidine ([¹⁸F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radio-defluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [¹⁸F]1a or [¹⁸F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration.We also argue for a cautious use of the radiolabeled pattern, 4-(4-[¹⁸F]-fluorobenzyl)piperidine, to develop PET radiotracers. (authors)