A new family of molten salts is reported, based on the N-alkyl, N-alkyl pyrrolidinium cation and the bis-(trifluoromethane sulfonyl)imide anion. Some of the members of the family are molten at room temperature, while the smaller and more symmetrical members have melting points around 100°C. Of the room-temperature molten salt examples, the methyl butyl derivative exhibits the highest conductivity; at 2 × 10 -3 S/cm this is the highest molten salt conductivity observed to date at room temperature among the ammonium salts. This highly conductive behavior is rationalized in terms of the role of cation planarity. The salts also exhibit multiple crystalline phase behavior below their melting points and exhibit significant conductivity in at least their higher temperature crystal phase. For example, the methyl propyl derivative (mp ) 12°C) shows ion conductivity of 1 × 10 -6 S/cm at 0°C in its higher temperature crystalline phase.

Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. The primary sequence and structure of AhR 3 in different species have been highly conserved during the course of evolution, suggesting that this receptor, which belongs to the family of basic helix-loop-helix nuclear transcription factors, plays an important physiological role(s) in homeostatic processes (1, 2). However, despite intensive studies, this physiological role and the endogenous activators of the AhR remain to be elucidated (3). At the cellular level, activated AhR interacts with various signal transduction pathways; induces biotransformation enzymes; alters the cell cycle, cell adhesion, and migration; and causes apoptosis or aberrant cell growth (4 -7). In vivo, the AhR plays significant roles in connection with development, immunological and reproductive functions, and adaptive responses to light and xenobiotics (8 -11). Compounds of this nature exert carcinogenic and endocrinedisrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived fromThe AhR protein has been shown to bind the compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as well as similar highly lipophilic halogenated and non-halogenated hydrocarbons leading to cardiovascular, carcinogenic, and endocrine effects (12-16). Consequently, most studies designed to explore the functions of this receptor have been performed with TCDD. One remarkable feature of activation of AhR by dioxinlike compounds is sustained induction of both cytochromes P450 and other metabolizing enzymes, whereas other agonists cause only transient induction of these enzymes. It seems likely that for purposes of regulation, endogenous ligands of AhR are metabolized rapidly, so that the use of persistent xenobiotics such as dioxins to investigate this receptor might be inappropriate. A striking discrepancy between the effects of different types of AhR activators was made evident in two recent studies (17,18). The authors showed that FICZ, the suggested physiologic AhR ligand, boosted T H 17-cell differentiation and worsened the experimentally induced autoimmune encephalomyelitis, whereas TCDD increased levels of T reg and suppressed the pathological effects in myelin-immunized mice.* This work was supported by Swedish Research Council (Formas), the Swedish Radiation Safety Authority, Karolinska Institutet, and the Sven and Lily Lawskis Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertiseme...

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.

A number of novel organic ionic compounds based on the pyrrolidinium cation are described which have been found to be ion conductors in their solid states around room temperature. The properties of the compounds are consistent with their exhibiting plastic crystal phases. In order to understand some of the molecular origins of the plastic crystal behaviour and the ion conductivity that it promotes, a number of related compounds based on the imidazolium and ammonium cations are also described which have structural elements in common with the pyrrolidinium cation, but which do not show the plastic behaviour. It is found therefore that the nature of the cation is quite critical to the development of this behaviour. The alkyl methyl pyrrolidinium cation is found to produce plastic crystal phases when the alkyl chains are short, thereby preserving the ability of the cation to rotate with minimal steric hindrance. The ammonium and imidazolium cations of comparable size and structure are less able to produce these plastic phases, in many cases because the low temperature phase proceeds to melt rather than forming a stable rotator phase.

Here, we examined reproducibility of [ 11 C]PBR28 binding in healthy subjects as quantified on a regional and voxel-by-voxel basis. In addition, a preliminary analysis of diurnal changes in TSPO availability was performed. MethodsTwelve subjects were examined with HRRT PET and [ 11 C]PBR28, six in the morning and afternoon on the same day, and six in the morning of two separate days. Regional Volume of distribution (V T ) values were derived using a region-of-interest based two-tissue compartmental analysis (2TCM), as well as a parametric approach. Metabolite-corrected arterial plasma was used as input function. ResultsFor the whole sample, the mean absolute variability of V T in gray matter (GM) was 18.3 ± 12.7 %. Intraclass Correlation Coefficient values in GM regions ranged from 0.90 to 0.94. Reducing the time of analysis from 91 to 63 minutes yielded a variability of 16.9 ± 14.9%. There was a strong correlation between the parametric and 2TCM-derived GM values (r=0.99). A significant increase in GM V T was observed between morning and afternoon examinations when using secondary methods of quantification (p=0.028). For the subjects examined at the same time of the day, the absolute variability was 15.9 ± 12.2 % for the 91 minute 2TCM data. [15,16], the study was designed so that six subjects were examined in the morning and afternoon on the same day, and six subjects at the same time point on two different days. Conclusions Methods SubjectsThe study was conducted at the Karolinska University Hospital, Solna, Sweden and was approved by the regional Ethics Committee in Stockholm and the Radiation Safety Committee at the Karolinska University Hospital, Stockholm.Subjects were recruited by advertisement and provided written informed consent. They were healthy according to medical history, clinical examination and routine laboratory tests in blood and urine. All subjects were assessed by a senior psychiatrist (K.C.), using the Mini International Neuropsychiatric Interview (MINI) for psychiatric diagnoses. None of the subjects had previously been exposed to psychopharmacological medication. Furthermore, a negative illegal drug screening test was ascertained in all subjects, prior to PET examination. None of the subjects were on any medication at the time of the study. No brain abnormality was detected on magnetic resonance imaging (MRI), as evaluated by a neuroradiologist at the MR-centre, Karolinska University Hospital, Solna.As demonstrated both in vitro and in vivo, [ 11 C]PBR28 binding is influenced by an identified single point mutation in the TSPO gene [8,17]. At screening, a blood sample was collected and genotyping was performed according to the description below. In total, 15 subjects were recruited. Of these, one was a low affinity binder (LAB) and was therefore excluded from the analysis. Two additional subjects were excluded due to technical issues with the PET measurements. The remaining twelve subjects were six men and six women, with a mean age of 23.9 SD ± 3.1 years. Six were high affinity binders ...

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [C]PBR28. Gray matter (GM) volume of distribution (V) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [C]PBR28 binding, and gender. There was a significant reduction of [C]PBR28 V in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM V and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

The palladium‐catalyzed [11C]carbonylation of aryl halides and triflates was achieved at atmospheric pressure by employing xantphos as the supporting ligand. Aryl halides were converted into their corresponding [11C]amides in good to excellent yields. The conditions were also successfully employed in the radiolabeling of an [11C]ester, a [11C]carboxylic acid, an [11C]aldehyde, and a [11C]ketone.

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