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

Optogenetic activation of cholinergic neurons in the PPT or LDT induces REM sleep

Rapid eye movement (REM) sleep is an important component of the natural sleep/wake cycle, yet the mechanisms that regulate REM sleep remain incompletely understood. Cholinergic neurons in the mesopontine tegmentum have been implicated in REM sleep regulation, but lesions of this area have had varying effects on REM sleep. Therefore, this study aimed to clarify the role of cholinergic neurons in the pedunculopontine tegmentum (PPT) and laterodorsal tegmentum (LDT) in REM sleep generation. Selective optogenetic activation of cholinergic neurons in the PPT or LDT during non-REM (NREM) sleep increased the number of REM sleep episodes and did not change REM sleep episode duration. Activation of cholinergic neurons in the PPT or LDT during NREM sleep was sufficient to induce REM sleep.National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant TR01-GM104948)National Institutes of Health (U.S.) (Grant T32-HL07901)Massachusetts General Hospital (Executive Committee on Research Fellowship)Massachusetts General Hospital. Dept. of Anesthesia, Critical Care, and Pain Medicin

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

Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse

This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, do not provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description is of importance for stereological, neuronal tracing, and physiological, molecular and neuroimaging studies in which a precise parcellation of the prefrontal cortex (PFC) is required. The present study describes and illustrates: the medial prefrontal areas, i.e., the infralimbic, prelimbic, dorsal and ventral anterior cingulate and Fr2 area; areas of the lateral PFC, i.e., the dorsal agranular insular cortical areas and areas of the ventral PFC, i.e., the lateral, ventrolateral, ventral and medial orbital areas. Each cytoarchitectonically defined boundary is corroborated by one or more chemoarchitectonic stainings, i.e., acetylcholine esterase, SMI32, SMI311, dopamine, parvalbumin, calbindin and myelin staining

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