Argon blocks the expression of locomotor sensitization to amphetamine through antagonism at the vesicular monoamine transporter-2 and mu-opioid receptor in the nucleus accumbens.

We investigated the effects of the noble gas argon on the expression of locomotor sensitization to amphetamine and amphetamine-induced changes in dopamine release and mu-opioid neurotransmission in the nucleus accumbens. We found (1) argon blocked the increase in carrier-mediated dopamine release induced by amphetamine in brain slices, but, in contrast, potentiated the decrease in KCl-evoked dopamine release induced by amphetamine, thereby suggesting that argon inhibited the vesicular monoamine transporter-2; (2) argon blocked the expression of locomotor and mu-opioid neurotransmission sensitization induced by repeated amphetamine administration in a short-term model of sensitization in rats; (3) argon decreased the maximal number of binding sites and increased the dissociation constant of mu-receptors in membrane preparations, thereby indicating that argon is a mu-receptor antagonist; (4) argon blocked the expression of locomotor sensitization and context-dependent locomotor activity induced by repeated administration of amphetamine in a long-term model of sensitization. Taken together, these data indicate that argon could be of potential interest for treating drug addiction and dependence.

Radiosynthesis of [18F]Lu29-024: a potential PET ligand for brain imaging of the serotonergic 5-HT2 receptor.

In a previous work, Lu29-024 (2,5-dimethyl-3-(4-fluorophenyl)-1-(1-methyl-4-piperidinyl)-1H-indole), a selective 5-HT2A receptor antagonist with nanomolar affinity and high selectivity, was labeled with carbon-11 to evaluate its behavior as a potential PET ligand for the serotonergic 5-HT2A receptor in the central nervous system. Administration of this tracer to rats was followed by a good brain uptake, no brain labeled metabolites but no specific, regio-selective, binding at 20 and 40 min post injection. Despite this, the data noted at 20 and 40 min suggest that this tracer, if associated with a radioactive emitter with a longer half-life than that of carbon-11, could be useful for the quantification of 5HT2A receptors. For these reasons, we chose to label this compound, bearing a fluorine atom, with [18F]fluoride, in order to perform rat studies over a more prolonged time-scale. The precursor for the radiosynthesis of [18F]Lu29-024 was obtained in an overall yield of 20% by a multi-step synthesis including an acetonylation reaction followed by a Fisher indole reaction. The radiotracer was prepared by an aromatic substitution with activated [18F]fluoride followed by a decarbonylation reaction that employed Wilkinson's catalyst. The radiosynthesis of [18F]Lu29-024 required approximatively 110 min with an overall radiochemical yield of 20-35% and specific activities of 37GBq/micromol. Fluorine-labeled Lu29-024 may thus be envisaged as a potentially useful PET tracer that can be applied to a wide range of neurological and psychiatric diseases.

Radiosynthesis of [11C]Lu 29-024: a potential radiotracer for 5HT2 receptors PET studies.

For mapping 5-HT2 receptors in the central nervous system with positron emission tomography (PET), 2,5-dimethyl-3-(4-fluorophenyl)-1-(1-[11C]methyl-4-piperidinyl)-1H-indol e ([11C]Lu29-024) has been prepared. The precursor for the radiosynthesis of [11C]Lu29-024 was obtained in an overall yield of 53% by a convenient five-step synthesis; its reaction with [11C]methyl iodide afforded [11C]Lu29-024 in 35-50% radiochemical yield (decay corrected) in 45 to 50 min with a specific radioactivity ranging from 11 to 15 GBq/micromol. Following i.v. injections into rats, the analysis of plasma samples showed that the metabolism of [11C]Lu29-024 was rapid and extensive (60% of the original tracer was metabolized at 40 min). In contrast, only unmetabolized [11C]Lu29-024 could be detected in brain tissue. These biological results suggest that labeled metabolites have no access to brain tissue and further propose [11C]Lu29-024 as an interesting tool for PET studies of brain 5HT2 receptors.

Synthesis and biological investigations of [18F]MR18445, a 5-HT3 receptor partial agonist.

18F Labelled MR18445 (4-[4-(4-[18F]fluorobenzyl)piperazino]-7-methoxypyrrolo++ +[1,2-alpha] quinoxaline), a selective 5-HT3 receptor partial agonist with nanomolar affinity, was synthesized and examined as a potential radioligand for PET imaging of brain 5HT3 receptors. Radiotracer was prepared by N-alkylation of the MR18491 precursor with 4-[18F]fluorobenzyl iodide. This latter was synthesized in a three-step procedure from 4-[18F]fluorobenzaldehyde obtained by 18F-nucleophilic displacement of 4-nitrobenzaldehyde, subsequently reduced to 4-[18F]fluorobenzyl alcohol and converted into reactive 4-[18F]fluorobenzyl iodide. The reduction step was performed on a column filled with NaBH4/Al2O3 and 4-[18F]fluorobenzyl alcohol was obtained with high reproducible yield (82-93% from 4-[18F]fluorobenzaldehyde) if there were traces of water in the system. The radiosynthesis of [18F]MR18445 required approximately 120 min. Semi-preparative HPLC purification followed by formulation gave injectable solutions of [18F]MR18445 with a radiochemical purity > 99%. The overall yield of the synthesis was mainly dependent upon the first step efficiency of aromatic incorporation of 18F- and varied from 12% to 29%. All the synthetic procedure was realized on a ZYMARK robotic system. Biological in vivo studies in rats showed that uptake of [18F]MR18445 in brain was rapid and high. No evidence of radiolabeled metabolites could be observed in the brain as late as 40 min after injection, despite the rapid appearance of metabolites in the plasma. However, neither phosphorimaging autoradiographic studies in rats nor PET experiments in baboons revealed specific binding of the radiotracer in brain, suggesting [18F]MR18445 is not suitable for 5-HT3 receptors PET studies.

[11C]S21007, a putative partial agonist for 5-HT3 receptors PET studies. Rat and primate in vivo biological evaluation.

We recently labeled with carbon-11, a high affinity, selective, 5-HT3 receptor (5-HT3R) ligand, S21007, for potential positron emission tomography (PET) applications. To evaluate the in vivo binding properties of [11C]S21007, its brain regional distribution, tissue and plasma pharmacokinetics and plasma metabolisation were characterized. To circumvent the problem of highly discrete brain localization of the 5-HT3R (area postrema, hippocampus), we designed an original approach combining high-resolution imaging techniques (ex vivo phosphor plate autoradiography and MRI-guided coronal PET in the rat and baboon, respectively). After i.v. injection of trace amounts of [11C]S21007 to rats, phosphorimager autoradiography failed to reveal in vivo specific binding to, nor selectivity for 5-HT3R-rich areas. PET studies in the baboon showed consistent results, i.e., there was no selective accumulation of [11C]S21007 in the area postrema or hippocampus, and neither displacement nor presaturation with cold S21007 resulted in significant changes in tissue distribution or kinetics of [11C]S21007.

In vitro dissolution of uranium oxide by baboon alveolar macrophages.

In vitro cellular dissolution tests for insoluble forms of uranium oxide are technically difficult with conventional methodology using adherent alveolar macrophages. The limited number of cells per flask and the slow dissolution rate in a large volume of nutritive medium are obvious restricting factors. Macrophages in suspension cannot be substituted because they represent different and poorly reproducible functional subtypes with regard to activation and enzyme secretion. Preliminary results on the dissolution of uranium oxide using immobilized alveolar macrophages are promising because large numbers of highly functional macrophages can be cultured in a limited volume. Cells were obtained by bronchoalveolar lavages performed on baboons (Papio papio) and then immobilized after the phagocytosis of uranium octoxide (U3O8) particles in alginate beads linked with Ca2+. The dissolution rate expressed as percentage of initial uranium content in cells was 0.039 +/- 0.016%/day for particles with a count median geometric diameter of 3.84 microns(sigma g = 1.84). A 2-fold increase in the dissolution rate was observed when the same number of particles was immobilized without macrophages. These results, obtained in vitro, suggest that the U3O8 preparation investigated should be assigned to inhalation class Y as recommended by the International Commission on Radiological Protection. Future experiments are intended to clarify this preliminary work and to examine the dissolution characteristics of other particles such as uranium dioxide. It is recommended that the dissolution rate should be measured over an interval of 3 weeks, which is compatible with the survival time of immobilized cells in culture and may reveal transformation states occurring with aging of the particles.