The melanin-concentrating hormone receptor 1 (MCHR1), which is highly expressed in the lateral hypothalamus, plays a key role in energy homeostasis, obesity and other endocrine diseases. Hence, there is a major interest in in vivo imaging of this receptor. A PET tracer would allow non-invasive in vivo visualization and quantification of the MCHR1. The aim of the study was the ex vivo evaluation of the MCHR1 ligand [18F]FE@SNAP as a potential PET tracer for the MCHR1.

Serotonergic neurotransmission is thought to underlie a dynamic interrelation between different key structures of the serotonin system. The serotonin transporter (SERT), which is responsible for the reuptake of serotonin from the synaptic cleft into the neuron, as well as the serotonin-1A (5-HT1A) and -1B (5-HT1B) receptors, inhibitory auto-receptors in the raphe region and projection areas, respectively, are likely to determine serotonin release. Thereby, they are involved in the regulation of extracellular serotonin concentrations and the extent of serotonergic effects in respective projection areas. Complex receptor interactions can be assessed in vivo with positron emission tomography (PET) and single-nucleotide-polymorphisms, which are thought to alter protein expression levels. Due to the complexity of the serotonergic system, gene × gene interactions are likely to regulate transporter and receptor expression and therefore subsequently serotonergic transmission. In this context, we measured 51 healthy subjects (mean age 45.5 ± 12.9, 38 female) with PET using [carbonyl-(11)C]WAY-100635 to determine 5-HT1A receptor binding potential (5-HT1A BPND). Genotyping for rs6296 (HTR1B) and 5-HTTLPR (SERT gene promoter polymorphism) was performed using DNA isolated from whole blood. Voxel-wise whole-brain ANOVA revealed a positive interaction effect of genotype groups (5-HTTLPR: LL, LS+SS and HTR1B: rs6296: CC, GC+GG) on 5-HT1A BPND with peak t-values in the bilateral parahippocampal gyrus. More specifically, highest 5-HT1A BPND was identified for individuals homozygous for both the L-allele of 5-HTTLPR and the C-allele of rs6296. This finding suggests that the interaction between two major serotonergic structures involved in serotonin release, specifically the SERT and 5-HT1B receptor, results in a modification of the inhibitory serotonergic tone mediated via 5-HT1A receptors.

The adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [18F]FE@SUPPY.

Purpose Since the adenosine A3 receptor (A3R) is considered to be of high clinical importance in the diagnosis and treatment of ischaemic conditions (heart and brain), glaucoma, asthma, arthritis, cancer and inflammation, a suitable and selective A3R PET tracer such as [ 18 F]FE@SUPPY would be of high clinical value for clinicians as well as patients. A3R was discovered in the late 1990s, but there is still little known regarding its distribution in the CNS and periphery. Hence, in autoradiographic experiments the distribution of A3R in human brain and rat tissues was investigated and the specific binding of the A3R antagonist FE@SUPPY and MRS1523 compared. Immunohistochemical staining (IHC) experiments were also performed to validate the autoradiographic findings. Methods For autoradiographic competition experiments human post-mortem brain and rat tissues were incubated with [ 125 I]AB-MECA and highly selective compounds to block the other adenosine receptor subtypes. Additionally, IHC was performed with an A3 antibody. Results Specific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0 % and 46.4 %), lung (44.5 % and 45.0 %), heart (39.9 % and 42.9 %) and testes (27.4 % and 29.5 %, respectively). Low amounts of A3R were found in rat brain tissues (5.9 % and 5.6 %, respectively) and human brain tissues (thalamus 8.0 % and 9.1 %, putamen 7.8 % and 8.2 %, cerebellum 6.0 % and 7.8 %, hippocampus 5.7 % and 5.6 %, caudate nucleus 4.9 % and 6.4 %, cortex 4.9 % and 6.3 %, respectively). The outcome of the A3 antibody staining experiments complemented the results of the autoradiographic experiments. Conclusion The presence of A3R protein was verified in central and peripheral tissues by autoradiography and IHC. The specificity and selectivity of FE@SUPPY was confirmed by direct comparison with MRS1523, providing further evidence that [ 18 F]FE@SUPPY may be a suitable A3 PET tracer for use in humans.

BackgroundWomen are two times more likely to be diagnosed with depression than men. Sex hormones modulating serotonergic transmission are proposed to partly underlie these epidemiologic findings. Here, we used the cross-sex steroid hormone treatment of transsexuals seeking sex reassignment as a model to investigate acute and chronic effects of testosterone and estradiol on serotonin reuptake transporter (SERT) binding in female-to-male and male-to-female transsexuals.MethodsThirty-three transsexuals underwent [11C]DASB positron emission tomography before start of treatment, a subset of which underwent a second scan 4 weeks and a third scan 4 months after treatment start. SERT nondisplaceable binding potential was quantified in 12 regions of interest. Treatment effects were analyzed using linear mixed models. Changes of hormone plasma levels were correlated with changes in regional SERT nondisplaceable binding potential.ResultsOne and 4 months of androgen treatment in female-to-male transsexuals increased SERT binding in amygdala, caudate, putamen, and median raphe nucleus. SERT binding increases correlated with treatment-induced increases in testosterone levels, suggesting that testosterone increases SERT expression on the cell surface. Conversely, 4 months of antiandrogen and estrogen treatment in male-to-female transsexuals led to decreases in SERT binding in insula, anterior, and mid-cingulate cortex. Increases in estradiol levels correlated negatively with decreases in regional SERT binding, indicating a protective effect of estradiol against SERT loss.ConclusionsGiven the central role of the SERT in the treatment of depression and anxiety disorders, these findings may lead to new treatment modalities and expand our understanding of the mechanism of action of antidepressant treatment properties.

The serotonergic system modulates brain functions that are considered to underlie affective states, emotion and cognition. Several lines of evidence point towards a strong lateralization of these mental processes, which indicates similar asymmetries in associated neurotransmitter systems. Here, our aim was to investigate a potential asymmetry of the serotonin transporter distribution using positron emission tomography and the radioligand [(11)C]DASB in vivo. As brain asymmetries may differ between sexes, we further aimed to compare serotonin transporter asymmetry between females, males and male-to-female (MtF) transsexuals whose brains are considered to be partly feminized. Voxel-wise analysis of serotonin transporter binding in all groups showed both strong left and rightward asymmetries in several cortical and subcortical structures including temporal and frontal cortices, anterior cingulate, hippocampus, caudate and thalamus. Further, male controls showed a rightward asymmetry in the midcingulate cortex, which was absent in females and MtF transsexuals. The present data support the notion of a lateralized serotonergic system, which is in line with previous findings of asymmetric serotonin-1A receptor distributions, extracellular serotonin concentrations, serotonin turnover and uptake. The absence of serotonin transporter asymmetry in the midcingulate in MtF transsexuals may be attributed to an absence of brain masculinization in this region.

BACKGROUND:The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) may impact on the in-vivo binding of important serotonergic structures such as the serotonin transporter (5-HTT) and the serotonin-1A (5-HT1A) receptor. Previous positron emission tomography (PET) studies on the association between Val66Met and 5-HTT and 5-HT1A binding potential (BPND) have demonstrated equivocal results.METHODS:We conducted an imaging genetics study investigating the effect of Val66Met genotype on 5-HTT or 5-HT1A BPND in 92 subjects. Forty-one subjects (25 healthy subjects and 16 depressive patients) underwent genotyping for Val66Met and PET imaging with the 5-HTT specific radioligand [11C]DASB. Additionally, in 51 healthy subjects Val66Met genotypes and 5-HT1A binding with the radioligand [carbonyl-11C]WAY-100635 were ascertained. Voxel-wise and region of interest-based analyses of variance were used to examine the influence of Val66Met on 5-HTT and 5-HT1A BPND.RESULTS:No significant differences of 5-HTT nor 5-HT1A BPND between BDNF Val66Met genotype groups (val/val vs. met-carrier) were detected. There was no interaction between depression and Val66Met genotype status.CONCLUSION:In line with previous data, our work confirms an absent effect of BDNF Val66Met on two major serotonergic structures. These results could suggest that altered protein expression associated with genetic variants, might be compensated in vivo by several levels of unknown feedback mechanisms. In conclusion, Val66Met genotype status is not associated with changes of in-vivo binding of 5-HTT and 5-HT1A receptors in human subjects.

Suffering from anhedonia, patients with major depressive disorder (MDD) exhibit alterations in several parts of the serotonergic neurotransmitter system, which are in turn involved in reward processing. However, previous investigations of the serotonin transporter (SERT) focused on regional differences with varying results depending on the clinical syndrome. Here, we aimed to describe the serotonergic system of MDD patients on a network level by evaluating SERT associations across brain regions. Twenty medication free patients with major depression and 20 healthy controls underwent positron emission tomography using the radioligand [(11) C]DASB. SERT binding potentials (BPND ) were quantified voxel-wise with the multilinear reference tissue model 2. In addition, SERT BPND was extracted from the dorsal raphe nucleus (DRN) as an indicator of midbrain serotonergic neurotransmission. Whole-brain linear regression analysis was applied to evaluate the association of DRN SERT bindings to those in projection areas, which was followed by ANCOVA to assess differences in interregional relationships between patients and controls. Although both groups showed widespread positive correlations, group differences were restricted to decreased SERT associations between the DRN and the ventral striatum (right and left respectively: t=5.85, P<0.05 corrected and t=5.07, P<0.1 corrected) when comparing MDD patients (R(2)=0.11 and 0.24) to healthy subjects (R(2)=0.72 and 0.66, P<0.01 and 0.05 corrected). Adjusting for age and sex did not change these findings. This study indicates a disturbed regulation between key regions involved in reward processing via the SERT. Our interregional approach highlights the importance of evaluating pathophysiological alterations on a network level to gain complementary information in addition to regional investigations.

The MCHR1 is an interesting pharmacological and pharmaceutical target, due to its involvement in pathologies as diabetes, gut inflammation and adiposity. in vivo PET-studies of the MCHR1 in energy homeostasis and diabetes could be of great value for deeper understanding of endocrinological hormone status and consequential pharmacological interactions. Furthermore, PET-tracers would facilitate compound dose selection of MCHR1 antagonists for treatment. Therefore, we developed two potential PET-tracers, [11C]SNAP-7941 and [18F]FE@SNAP, for the in vivo visualization of this receptor. Aim of this study was a preclinical in vitro evaluation of both unlabeled ligands. Therefore, a comparative autoradiographic investigation on CNS (coronal rat brain and 4 different human brain regions) and peripheral tissues (rat tongue as target and rat testes as non-target region) was conducted. Competition experiments, using the two radioligands [125I]-MCH and [125I]-S36057, were performed with selective and specific MCHR1 ligands as PMC-3886, a MCHR1 agonist, SNAP-7941 and FE@SNAP, two MCHR1 antagonists. Additionally, immunohistochemical staining with a specific MCHR1 antibody was performed. Specific binding was found in all tissues known to express the MCHR1 as human and rat CNS and peripheral rat tongue tissue. No specific binding was found in the non-target region of rat testes. MCHR1 antibody staining complemented the outcome of the autoradiographic experiments. The compounds SNAP-7941 and FE@SNAP were generally comparable with PMC-3886. Hence, the in vitro autoradiographic study of the unlabeled compounds SNAP-7941 and FE@SNAP further qualifies the potential of the PET-tracers [11C]SNAP-7941 and [18F]FE@SNAP as useful MCHR1 PET-tracers.

This study aimed to demonstrate that patients who exhibit a tumor metabolic response to first-line chemotherapy seen on FDG-PET and computed tomography (CT) would survive longer than those who did not show such a response, comparing this evaluation with the morphologic response seen on CT.Images were acquired in 22 consecutive patients with advanced non–small-cell lung cancer (NSCLC) randomized to receive carboplatin/paclitaxel/sorafenib or placebo. FDG-PET was performed within 4 weeks before (PET1) and 2 weeks after starting treatment (PET2). Similarly, CT (CT1) was performed at baseline and then every 2 cycles (6 weeks) during treatment (CT2). Responders and nonresponders were identified with FDG-PET, and metabolic response was then compared with morphologic changes detected by spiral CT.Twenty-one of 22 patients completed this study. In terms of progression-free survival (PFS) (45 vs. 22.2 weeks) and overall survival (OS) (77 vs. 47.7 weeks), we observed a trend that was not statistically significant for patients whose response after 2 weeks of treatment was seen on FDG-PET (P = .22 for PFS; P = .15 for OS).Patients with advanced NSCLC who had a positive outcome, as evidenced by prolonged survival, were those who showed a tumor metabolic response seen on FDG-PET.

Aim of this work was the implementation of a generalized in-loop synthesis for (11)C-carboxylations and subsequent (11)C-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-(11)C]WAY-100635 and, for the first time, [(11)C]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-(11)C]WAY-100635 and [(11)C]-(+)-PHNO were prepared with high reliability and satisfying outcome.

Aim of this work was the implementation of a generalized in-loop synthesis for C-11-carboxylations and subsequent C-11-acylations on the TRACERlab FxC Pro platform. The set-up was tested using [carbonyl-C-11] WAY-100635 and, for the first time, [C-11]-(+)-PHNO. Its general applicability could be demonstrated and both [carbonyl-C-11]WAY-100635 and [C-11]-(+)-PHNO were prepared with high reliability and satisfying outcome. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

The debate on the optimal exchange-rate regime has been rekindled by the arrival of the euro and the rash of crises in Latin America and elsewhere. This paper reviews the key issues and assesses the state of play in the debate. This provides the context for the other papers in the group, prepared for a conference on “ Monetary union: Theory, EMU experience, and prospects for Latin America,” which took place in Vienna in April 2002 and which was co-sponsored by the Banco de Chile, the Oesterreichische Nationalbank, and the University of Vienna. The papers selected for this issue deal with exchange-rate problems in the Western Hemisphere, and Latin America and the Caribbean (LAC), in particular. After assessing the debate over floating rates versus currency union, the paper examines the issue in the context of monetary relations between the U.S. and Canada. It concludes with an empirical measure of convergence among the countries in the hemisphere.

Introduction: The norepinephrine transporter (NET) is an important target for research in neurology and psychology and is involved in the pathophysiology of many neurodegenerative diseases such as Alzheimer's disease and attention deficient hyperactivity disorder. For visualization of NET abundance and deregulation, a novel PET tracer - [C-11]Me@APPI - has been developed.Methods: For precursor synthesis, a 4-step synthesis starting from N-phenyl-o-phenylenediamine was set up. Radiosynthesis was established and optimized using standard methods and subsequently automated in a GE TRACERlabFx C Pro synthesizer. Preclinical testing was performed comprising affinity and selectivity testing on human membranes as well as stability and blood-brain-barrier-penetration using in-vitro models.Results: Precursor molecule (APPI:0) and reference compound (Me@APPI) were synthesized with 26.5% and 21.4% overall yield, respectively. So far, 1.25 +/- 0.72 GBq [C-11]Me@APPI with 54.35 +/- 7.80 GBq/mu mol specific activity were produced (n=11). Affinity of reference compounds was determined as 8.08 +/- 1.75 nM for Me@APPI and 19.31 +/- 2.91 nM for APPI:0, respectively (n >= 9). IAM-chromatography experiments (n=3) revealed a Pm value of 1.51 +/- 0.34 for Me@APPI. Stability testing using human liver microsomes revealed that 99.5% of the tracer was found to be still intact after 60 minutes (n=4).Conclusion: Present data indicate that [C-11]Me@APPI has promising properties to become a clinically useful NET-PET-tracer. Further in-vitro and in-vivo evaluations are currently under way. (C) 2013 Elsevier Inc. All rights reserved.