Synthesis of [2‐{(4‐chlorophenyl) (4‐[ 125 I]iodophenyl)} methoxyethyl]‐1‐piperidine‐3‐carboxylic acid, [ 125 I]CIPCA: A potential radiotracer for GABA uptake sites

The synthesis of racemic [2‐{(4‐Chlorophenyl) (4‐iodophenyl)} methoxyethyl]‐1‐piperidine‐3‐carboxylic acid, (CIPCA) and its radioiodinated analog [ 125ß I]CIPCA is described. CIPCA was synthesized from 4‐iodobenzoyl chloride in five steps in 16% overall yield. Ammonium sulfate catalyzed solid‐state isotopic exchange of CIPCA with Na 125 I provided [ 125 I]CIPCA in 34% isolated radiochemical yield at a specific activity of 118 Ci/mmol. [ 125 ICIPCA] demonstrated moderate brain extraction and good in vivo radiostability in preliminary biodistribution studies conducted in CD‐1 mice. [ 125 I]CIPCA is a potentially useful radiotracer for study of the GABA uptake system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90161/1/2580361008_ftp.pd

Fungi and lichens recorded during the Cryptogam Symposium on Natural Beech Forests, Slovakia 2011

In September 2011, an international team of cryptogam experts visited seven national nature reserves in five mountain areas of Slovakia: Havešová and Stužica in the Poloniny Mts., Vihorlat in the Vihorlatské vrchyMts., Oblík in the Slanské vrchyMts., Dobročský prales and Klenovský Vepor in the Veporské vrchy Mts. and Badínsky prales in the Kremnické vrchy Mts. The reserves were selected to represent examples of the best protected old-growth beech forests in the country. The aim was to study the diversity of wood-inhabiting fungi on fallen beech logs and epiphytic lichens on standing beech trees. In total, 215 fungal species and 128 lichens were recorded on beech wood and bark, and 27 fungi and 26 lichens on additional substrates. The site of the highest conservation value is Stužica with 126 fungi and 79 lichens recorded on beech, of which 12 fungi and 19 lichens are indicators of high nature conservation value. Combined with historical records, a total of 19 non-lichenised fungal indicators are now reported from the site, making it the highest ranked natural beech forest in Europe. The second most important reserve for fungal diversity is Havešová with 121 species, including 14 indicator species recorded on beech wood. For lichens, the second most important reserve is Klenovský Vepor with 69 species including 18 lichen indicators recorded on beech. Nine fungus species are here reported as new to Slovakia: Asterostroma medium, Entoloma hispidulum, E. pseudoparasiticum, Gloeohypochnicium analogum, Hohenbuehelia valesiaca, Hymenochaete ulmicola, Hypocrea parmastoi, Melanomma spiniferum and Scutellinia colensoi. Lichen species Alyxoria ochrocheila is reported as new to Slovakia and Lecanographa amylacea, which was considered extinct in the Slovak Red list, was also recorded. This is the first list of wood-inhabiting fungi and epiphytic lichens of old-growth beech forests in Slovakia, and hence an important contribution to the exploration of biodiversity in Slovakia

Communities of wood-inhabiting bryophytes and fungi on dead beech logs in Europe - reflecting substrate quality or shaped by climate and forest conditions?

Aim: Fungi are drivers of wood decay in forested ecosystem, while bryophytes use dead wood as a platform for their autotrophic lifestyle. We tested the hypothesis that fungal communities on beech logs are mainly structured by substrate quality, while bryophyte communities are structured by climatic gradients. In addition, we tested whether community structure in both organism groups is altered along a gradient from nearly pristine forest to forests heavily affected by management and human disturbance in the past. Location: Europe. Methods: We surveyed 1207 fallen beech logs in 26 of the best-preserved forest stands across six European countries, representing a gradient in overall naturalness of the forest landscape. Recorded species were classified into ecological guilds. Indirect ordination and variation partitioning was used to analyse the relationship between species composition and environmental variables, recorded at log or site level. Results: In total, 10,367 bryophyte and 15,575 fungal records were made, representing 157 and 272 species, respectively. Fungal communities were more clearly structured by substrate quality than were bryophyte communities. In both groups a distinct turnover in species composition was evident along a longitudinal gradient from Central to Western Europe. Fungi specialized in trunk rot and specialized epixylic bryophytes were scarcely represented in Atlantic regions, and partly replaced by species belonging to less specialized guilds. Variables related to climate and forest conditions were confounded along this main geographical gradient in community composition. Main conclusions: We found that bryophyte and fungal communities co-occurring on fallen beech logs in European beech forest reserves differed in their responses to biogeographical drivers and local-scale habitat filters. Both groups responded to major gradients in climate and forest conditions, but the loss of specialist guilds in degraded forest landscapes points to a functionally important effect of forest landscape degradation at the European continental scale. © 2014 John Wiley & Sons Ltd

Synthesis of [ 18 F]phencyclidines for glutamate receptor mapping

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90096/1/25802601150_ftp.pd

Stereospecific inhibition of monoamine uptake transporters by meta-hydroxyephedrine isomers

Meta-hydroxyephedrine (HED) comprises four stereoisomers consisting of two enantiomeric pairs related to ephedrine and pseudoephedrine. HED is transported into adrenergic neurons and radiolabeled HED has been employed in positron emission tomography (PET) to image adrenergic neurons in vivo. To extend structure-activity analyses of binding sites within monoamine transporters and to determine which stereoisomer displayed the best selectivity for PET imaging applications, we tested the HED compounds for their abilities to inhibit [ 3 H]neurotransmitter uptake into platelets, transfected cells, and chromaffin vesicles. We hypothesized that the HED compounds would be most potent at the norepinephrine transporter (NET) compared to the serotonin or dopamine transporters and that the 1R diastereomers would be more effective than 1S diastereomers. Supporting the hypotheses, all stereoisomers were most potent at the NET and the 1R,2S stereoisomer was the most potent inhibitor overall. However, the 1S,2R isomer may be preferred for PET applications because of better selectivity among the transporters and reduced neuronal recycling.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42456/1/702-109-10-1229_21091229.pd

Iodine-125 and fluorine-18 labeled aryl-1,4-dialkylpiperazines: Potential radiopharmaceuticals for in vivo study of the dopamine uptake system

A series of fluorine-18 and iodine-125 labeled aryl-1,4-dialkylpiperazine analogs, derivatives of GBR 12935, were synthesized as radiotracers for positron emission tomography or single photon emission computerized tomography imaging of the brain based on their affinity for the presynaptic dopamine reuptake system. High specific activity fluorine-18 tracers were prepared by nucleophilic aromatic substitution reactions; iodine-125 tracers were prepared by isotopic exchange reactions. In vitro competitive binding studies demonstrated that iodine substitution is tolerated in the 4-position of the phenyl ring of the phenalkylpiperazine group. In vivo regional brain biodistribution studies in mice indicated no selectivity of the radioiodinated ligands for the dopamine reuptake site, with striatum/cerebellum concentration ratios of 1. Similar negative results with the new fluorine-18 derivatives demonstrated that in vivo selectivity for the dopamine reuptake site appears to be critically dependent on the carbon chain length between the piperazine ring and the solitary aromatic ring. These studies suggest that development of new radiopharmaceuticals based on the GBR 12935 structure cannot be based solely on considerations of in vitro binding affinities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30090/1/0000461.pd

NMDA receptor channels: Labeling of MK-801 with iodine-125 and fluorine-18

Methods for labeling the glutamate channel blocking agent MK-801 with iodine-125 (125I) and fluorine-18 (18F) are described. Radioiodine was incorporated in the 1- or 3-positions of the aromatic ring of (+/-)MK-801 by solid-state halogen exchange techniques. Attachment of the [18F]fluoromethyl group to the bridgehead methyl position was achieved by reaction of [18F]fluoride with the triflamide alcohol 8 or the novel cyclic sulfamate 9 recently reported by Merck chemists. Radiochemical yields of (+/-)13-[18F]- fluoromethyl-MK-801 were >72%, EOB; radiochemical purity >99%. In competitive binding studies using rat brain homogenates, (+/-)3-bromo-MK-801 showed greater affinity than (+/-)MK-801 for the glutamate-linked channel. The experimental log P (2.1 +/- 0.1) of MK-801 is optimal for transit of the blood-brain barrier. These preliminary findings support further testing of 3-[123I]iodo-MK-801 and (+/-)13-[18F]fluoromethyl-MK-801 as possible agents for in vivo mapping of the glutamate receptor complex.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27605/1/0000649.pd

Synthesis and Investigation of a Radioiodinated F3 Peptide Analog as a SPECT Tumor Imaging Radioligand

A radioiodinated derivative of the tumor-homing F3 peptide, (N-(2-{3-[125I]Iodobenzoyl}aminoethyl)maleimide-F3Cys peptide, [125I]IBMF3 was developed for investigation as a SPECT tumor imaging radioligand. For this purpose, we custom synthesized a modified F3 peptide analog (F3Cys) incorporating a C-terminal cysteine residue for site-specific attachment of a radioiodinated maleimide conjugating group. Initial proof-of-concept Fluorescence studies conducted with AlexaFluor 532 C5 maleimide-labeled F3Cys showed distinct membrane and nuclear localization of F3Cys in MDA-MB-435 cells. Additionally, F3Cys conjugated with NIR fluorochrome AlexaFluor 647 C2 maleimide demonstrated high tumor specific uptake in melanoma cancer MDA-MB-435 and lung cancer A549 xenografts in nude mice whereas a similarly labeled control peptide did not show any tumor uptake. These results were also confirmed by ex vivo tissue analysis. No-carrier-added [125I]IBMF3 was synthesized by a radioiododestannylation approach in 73% overall radiochemical yield. In vitro cell uptake studies conducted with [125I]IBMF3 displayed a 5-fold increase in its cell uptake at 4 h when compared to controls. SPECT imaging studies with [125I]IBMF3 in tumor bearing nude mice showed clear visualization of MDA-MB-435 xenografts on systemic administration. These studies demonstrate a potential utility of F3 peptide-based radioligands for tumor imaging with PET or SPECT techniques

Early inhaled budesonide for the prevention of bronchopulmonary dysplasia

BACKGROUND Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P = 0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P = 0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P = 0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P = 0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P = 0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality

Search for Axionlike Particles Produced in e⁺ e⁻ Collisions at Belle II

International audienceWe present a search for the direct production of a light pseudoscalar a decaying into two photons with the Belle II detector at the SuperKEKB collider. We search for the process e+e-→γa, a→γγ in the mass range 0.2