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The imaging of σ1 receptors in the brain by fluorinated radiotracers will be used for the validation of σ1 receptors as drug targets as well as for differential diagnosis of diseases in the central nervous system. The biotransformation of four homologous fluorinated PET tracers 1′-benzyl-3-(ω-fluoromethyl to ω-fluorobutyl)-3H-spiro[2]benzofuran-1,4′-piperidine] ([18F]1–4) was investigated. In silico studies using fast metabolizer (FAME) software, electrochemical oxidations, in vitro studies with rat liver microsomes, and in vivo metabolism studies after application of the PET tracers [18F]1–4 to mice were performed. Combined liquid chromatography and mass spectrometry (HPLC–MS) analysis allowed structural identification of non-radioactive metabolites. Radio-HPLC and radio-TLC provided information about the presence of unchanged parent radiotracers and their radiometabolites. Radiometabolites were not found in the brain after application of [18F]2–4, but liver, plasma, and urine samples contained several radiometabolites. Less than 2 % of the injected dose of [18F]4 reached the brain, rendering [18F]4 less appropriate as a PET tracer than [18F]2 and [18F]3. Compounds [18F]2 and [18F]3 possess the most promising properties for imaging of σ1 receptors in the brain. High σ1 affinity (Ki=0.59 nm), low lipophilicity (logD7.4=2.57), high brain penetration (4.6 % of injected dose after 30 min), and the absence of radiometabolites in the brain favor the fluoroethyl derivative [18F]2 slightly over the fluoropropyl derivative [18F]3 for human use.

Erstmalig wurden für den Saale-Elbe-Raum — als geologisch gut erschlossenes Untersuchungsgebiet Mitteleuropas — systematisch gesammelte Proben durch Radiokarbon datiert. Somit ist es möglich, das weichseiszeitliche Alter der intakten und gekappten Niederterrasse zu bestätigen sowie die stark differenzierte holozäne Flußdynamik chronostratigraphisch zu erfassen. Die in der nacheiszeitlichen Flußgeschichte innerhalb eines komplexen Wirkungsgefüges ablaufenden Sedimentationsprozesse wurden in bestimmten Einzugsgebieten durch mittelbare anthropogene Eingriffe bereits seit neolithischer Zeit stark beeinflußt. Dies zeigt sich vor allem im Beginn und Verlauf der Auelehmakkumulation. Durch die radiometrische Datierung subfossiler Hölzer aus holozänen Flußschottern konnte ebenfalls für den mitteldeutschen Raum die Verdrängung der Kiefer durch die Eiche aus den Flußtälern bereits für das Boreal (ältestes 14C-Datum 8790 ± 140 BP) festgestellt werden. Dies stimmt gut mit Befunden aus anderen Flußgebieten vor allem des südlichen Mitteleuropas überein., research

Both enantiomers of the epibatidine analogue flubatine display high affinity towards the α4β2 nicotinic acetylcholine receptor (nAChR) in vitro, accompanied by negligible interactions with diverse off-target proteins. Extended single dose toxicity studies in rodent indicated a NOEL (No Observed Effect Level) of 6.2μg/kg for (-)-flubatine and 1.55μg/kg for (+)-flubatine. We developed syntheses for both flubatine enantiomers and their corresponding precursors for radiolabeling. The newly synthesized trimethylammonium precursors allowed for highly efficient (18)F-radiolabelling in radiochemical yields >60% and specific activities >750GBq/μmol, thus making the radioligands practical for clinical investigation.

Sharpless asymmetric dihydroxylation of styrene derivative 6 afforded chiral triols (R)-7 and (S)-7, which were cyclized with tosyl chloride in the presence of Bu2SnO to provide 2-benzopyrans (R)-4 and (S)-4 with high regioselectivity. The additional hydroxy moiety in the 4-position was exploited for the introduction of various substituents. Williamson ether synthesis and replacement of the Boc protective group with a benzyl moiety led to potent σ1 ligands with high σ1/σ2-selectivity. With exception of the ethoxy derivative 16, the (R)-configured enantiomers represent eutomers with eudismic ratios of up to 29 for the ester (R)-18. The methyl ether (R)-15 represents the most potent σ1 ligand of this series of compounds, with a Ki value of 1.2 nM and an eudismic ratio of 7. Tosylate (R)-21 was used as precursor for the radiosynthesis of [18F]-(R)-20, which was available by nucleophilic substitution with K[18F]F K222 carbonate complex. The radiochemical yield of [18F]-(R)-20 was 18%–20%, the radiochemical purity greater than 97% and the specific radioactivity 175–300 GBq/µmol. Although radiometabolites were detected in plasma, urine and liver samples, radiometabolites were not found in brain samples. After 30 min, the uptake of the radiotracer in the brain was 3.4% of injected dose per gram of tissue and could be reduced by coadministration of the σ1 antagonist haloperidol. [18F]-(R)-20 was able to label those regions of the brain, which were reported to have high density of σ1 receptors.

(−)-[18F]flubatine is a promising agent for visualization by PET of cerebral α4β2 nicotinic acetylcholine receptors (nAChRs), which are implicated in psychiatric and neurodegenerative disorders. Here, we describe a substantially improved two-step radiosynthesis strategy for (−)-[18F]flubatine, based on the nucleophilic radiofluorination of an enantiomerically pure precursor followed by deprotection of the intermediate. An extensive leaving group/protecting group library of precursors was tested. Application of a trimethylammonium-iodide precursor with a Boc-protecting group provided the best results: labeling efficiencies of 80–95%, RCY of 60±5%, radiochemical purity of >98%, and a specific activity of >350 GBq/μmol. The radiosynthesis is easily transferable to an automated synthesis module.

The imaging of σ

To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [18F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs). Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [18F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg·kg−1 bolus + 1 mg·kg−1·h−1 continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time–radioactivity curves was performed, and parametric maps were calculated relative to arterial input. Plasma [18F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUVmax was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUVmax 1.53 ± 0.32). Administration of NS6740 significantly decreased [18F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BPND. The baseline BPND ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BPND in regions with high [18F]NS10743 binding (temporal lobe −29%, p = 0.01; midbrain: −35%, p = 0.02), without significantly altering the BPND in low binding regions (cerebellum: −16%, p = 0.2). This study confirms the potential of [18F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET.

Alzheimer’s disease (AD), the most common form of sporadic or late-onset dementia, is characterized by progressive cognitive and functional impairment. Although the clinical tests currently performed are rather accurate, a definitive diagnosis can still only be made by examining the brain tissue after death. Post-mortem diagnosis of AD relies in part on the accurate detection of senile plaques (SPs) and neurofibrillary tangles (NFTs), the two major defining neuropathological features of AD.

A series of various N-substituted 3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidines] (7) has been synthesized. In receptor binding studies, the N-benzyl derivative 7a (WMS-1813) revealed extraordinarily high sigma(1) receptor affinity (K(i) = 1.4 nM) and excellent sigma(1)/sigma(2) selectivity (600 fold). In vitro biotransformation of 7a with rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7 g). The PET tracer [(18)F]7a was synthesized by nucleophilic substitution of the tosylate 13 with K[(18)F]F-K222-carbonate complex. The decay corrected radiochemical yield of [(18)F]7a was 35-48% with a radiochemical purity of99.5% and a specific activity of 150-238 GBq/micromol. The radiotracer properties were evaluated in female CD-1 mice by organ distribution and ex vivo brain autoradiography. The radiotracer uptake in the brain was fast and sufficient, with values of approximately 4% injected dose per gram. Target specificity of [(18)F]7a was validated in blocking studies by preapplication of haloperidol, and significant reduction in the uptake of radioactivity was observed in the brain and peripheral organs expressing sigma(1) receptors.

The 7 m thick sediment profile at Plinz in northern Thuringia (central Germany) covering the time span between 10,000 and at least 8000 14C years BP (about 11,600–9000 cal BP) was studied using radiocarbon, stable isotopes and pollen analysis. The results reflect the very fast climatic transition from the Late Glacial to the Holocene as a change from cold and dry to warmer and wetter conditions. A short climatic deterioration during the Preboreal oscillation (PBO) at around 9800 14C years BP is clearly reflected by a sharp drop in the Pinus concentration accompanied by a considerable increase in Betula, Salix, various herbs and the distinct occurrence of aquatic plants. During the Preboreal stable isotopes of biogenic carbonate show several episodes with altered levels of atmospheric moisture. Continuous climatic improvement without any oscillations can be suggested for the period covering the end of Preboreal and the Boreal.

Several 3H-spiro[[2]benzofuran-1,4'-piperidines] bearing a p-fluorobenzyl residue at the N-atom and various substituents in position 3 of the benzofuran system were synthesized. The crucial reaction steps are the addition of a lithiated benzaldehyde derivative to the p-fluorobenzylpiperidone 5 and the BF(3).OEt(2) catalyzed substitution of the methoxy group of 2a by various nucleophiles. Structure-affinity relationship studies revealed that compounds with two protons (2d), a methoxy group (2a), and a cyano group (2e) in position 3 possess subnanomolar sigma(1) affinity (K(i)=0.18 nM, 0.79 nM, 0.86 nM) and high selectivity against the sigma(2) subtype. The metabolites of 2a, 2d, and 2e, which were formed upon incubation with rat liver microsomes, were identified. Additionally, the rate of metabolic degradation of 2a, 2d, and 2e was determined and compared with the degradation rate of the non-fluorinated spirocyclic compound 1. For the synthesis of the potential PET tracers [(18)F]2a and [(18)F]2e two different radiosynthetic approaches were followed.

The outstanding diversity of cellular properties mediated by neuronal and nonneuronal alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) points to the diagnostic potential of quantitative nuclear molecular imaging of alpha7 nAChR in neurology and oncology. It was our goal to radiolabel the alpha7 nAChR agonist 4-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane (NS10743) and to assess the selectivity of [(18)F]NS10743 binding site occupancy in animal experiments.[(18)F]NS10743 was synthesized by nucleophilic substitution of the nitro precursor. In vitro receptor affinity and selectivity were assessed by radioligand competition and autoradiography. The radiotracer properties were evaluated in female CD-1 mice by brain autoradiography and organ distribution. Target specificity was validated after treatment with SSR180711 (10 mg/kg, intraperitoneal), and metabolic stability was investigated using radio-HPLC.The specific activity of [(18)F]NS10743 exceeded 150 GBq/micromol at a radiochemical purity99%. In vitro, NS10743 and [(18)F]NS10743 showed high affinity and specificity towards alpha7 nAChR. The brain permeation of [(18)F]NS10743 was fast and sufficient with values of 4.83 and 1.60% injected dose per gram and brain to plasma ratios of 3.83 and 2.05 at 5 and 60 min after radiotracer administration. Brain autoradiography and organ distribution showed target-specific accumulation of [(18)F]NS10743 in brain substructures and various alpha7 nAChR-expressing organs. The radiotracer showed a high metabolic stability in vivo with a single polar radiometabolite, which did not cross the blood-brain barrier.The good in vitro and in vivo features of [(18)F]NS10743 make this radioligand a promising candidate for quantitative in vivo imaging of alpha7 nAChR expression and encourage further investigations.

The design of radioligands selective for particular GABAA receptor isoforms is challenging because of their great potential for the diagnostic imaging of neuropsychiatric diseases such as epilepsy and sleep disorders. A subtype specificity higher than that of the classical benzodiazepines makes the novel pyrazolopyrimidine indiplon an attractive candidate structure. In the present work, N-(3-[18F]fluoro-propyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine- 7-yl]-phenyl}-acetamide ([18F]fluoro-propyl-indiplon; [18F]FPI) was characterized and validated as a candidate tracer for positron emission tomography imaging of α1-GABAA receptors. In vitro, receptor affinity and autoradiography of [18F]FPI were assessed in cerebellar homogenates and sagittal brain slices of rats, respectively. The regional brain and organ uptake was investigated in NMRI mice at various times after i.v. application of [18F]FPI by ex vivo autoradiography and dissection, respectively. Radiometabolites of [18F]FPI were determined in blood, brain, and urine samples by highperformance liquid chromatography. [18F]FPI binds to cerebellar receptors with high affinity (KD 2.93 nM), and the in vitro labelling pattern appears to be more selective for α1-containing GABAA receptors than [3H]flunitrazepam. Intravenous application of [18F]FPI revealed (i) a strong biotransformation, (ii) low brain-to-plasma ratios of 18F ( < 0.4 at all times after tracer injection), (iii) homogenous and non-specific 18F distribution in the rat brain, and (iv) high radioactivity uptake in liver and femur. Thus, despite the promising results obtained by in vitro evaluation, [18F]FPI is excluded from further development as PET tracer.

The function of gamma-aminobutyric acid type A receptors (GABA(A) receptors) is enhanced by various clinically important drugs including benzodiazepines that act on an allosteric site formed at the interface between the alpha and gamma subunits. In contrast to classical benzodiazepines, the novel pyrazolopyrimidine indiplon (N-methyl-N-{3-[7-(thiophene-2-carbonyl)-1,5,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-2-yl]phenyl}acetamide; N-methyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide) demonstrates relative binding selectivity for the alpha1 subunit containing receptor subtypes, which are the most frequently expressed in the mammalian central nervous system. To investigate the pharmacological properties at GABA(A) receptors and to promote the development of alpha1 subunit selective radiotracers for positron emission tomography imaging, we have started with the evaluation of various fluorinated indiplon derivatives. Binding affinities were determined in homogenates from newborn and adult rats suggesting an alpha1 preference of the reference compounds indiplon, zaleplon as well as for all newly synthesized indiplon derivatives. In homogenated cerebellar tissue obtained from adult rat brain, known to primarily express alpha1 containing GABA(A) receptors, the high affinity of the basic indiplon structure was only slightly affected by an elongation of the alkyl substituent of the amide N from methyl (indiplon; K(i) 3.1 nM) via ethyl (2a, N-(2-fluoro-ethyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 5.4 nM) to propyl (2b, N-(3-fluoro-propyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 2.4 nM). Whole cell patch-clamp recordings at neuronal and recombinant GABA(A) receptors indicated that the fluorinated derivatives 2a and 2b have a high potency at alpha1beta3gamma2L isoforms comparable to indiplon (EC(50): 105, 158, and 81 nM, respectively), with 2b displaying the most pronounced efficacy at alpha3beta3gamma2L subtypes. In conclusion, the affinity profiles and functional properties of the newly synthesised fluorinated indiplon derivatives make compounds 2a and 2b suitable for the development of [(18)F]-labelled ligands at GABA(A) receptors containing the alpha1 subunit.

With the aim of producing selective radiotracers for in vivo imaging of the vesicular acetylcholine transporter (VAChT) using positron mission tomography (PET), here, we report synthesis and analysis of a new class of conformationally constrained vesamicol analogues with moderate lipophilicity. The sequential ring opening on trans -1,4-cyclohexadiene dioxide enabled an approach to synthesize 6-arylpiperidino-octahydrobenzo[1,4]oxazine-7-ols [morpholino vesamicols]. The radiosynthesis of the [ 18 F]fluoroacetyl-substituted derivative ([ 18 F]FAMV) was achieved starting from a corresponding bromo precursor [2-Bromo-1-[7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazin-4-yl]-ethanone] and using a modified commercial computer-controlled module system with a radiochemical yield of 27±4%, a high radiochemical purity (99%) and a specific activity of 35 GBq/μmol. In competitive binding assays using a PC12 cell line overexpressing VAChT and [ 3 H]-(−) vesamicol, 2-fluoro-1-[7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazin-4-yl]-ethanone (FAMV) demonstrated a high selectivity for binding to VAChT ( K i : 39.9±5.9 nM) when compared to its binding to sigma 1/2 receptors ( K i >1500 nM). The compound showed a moderate lipophilicity (logD (pH 7) =1.9) and a plasma protein binding of 49%. The brain uptake of [ 18 F]FAMV was about 0.1% injected dose per gram at 5 min after injection and decreased continuously with time. Notably, an increasing accumulation of radioactivity in the lateral brain ventricles was observed. After 1 h, the accumulation of [ 18 F]FAMV, expressed as ratio to the cerebellum, was 4.5 for the striatum, 2.0 for the cortical and 1.5 for the hippocampal regions, measured on brain slices using ex vivo autoradiography. At the present time, 75% of [ 18 F]FAMV in the plasma was shown to be metabolized to various hydrophilic compounds, as detected by high-performance liquid chromatography. The degradation of [ 18 F]FAMV was also detected in brain extracts as early as 15 min post injection (p.i.) and increased to 50% at 1 h postinjection. In conclusion, although the chemical properties of [ 18 F]FAMV and the selectivity of binding to VAChT appear to be promising indicators of a useful PET tracer for imaging VAChT, a low brain extraction, in combination with only moderate specific accumulation in cholinergic brain regions and an insufficient in vivo stability prevents the application of this compound for neuroimaging in humans.

The involvement of gamma amino butyric acid (GABA) receptors in a variety of neurological and psychiatric diseases has promoted the development and use of radiolabelled benzodiazepines (BZ) for brain imaging by PET. However, these radioligands are unable to distinguish between the various subtypes of GABAA receptors. Novel non-BZ such as the pyrazolo-pyrimidine indiplon proved to be selective for the α1-subunit of the GABAA receptor. Here, we describe the syntheses of four novel 18F-labelled indiplon derivatives. Radiosyntheses were performed via n.c.a. 18F-nucleophilic substitution starting from the tosyl, bromo, and 4-nitrobenzoyl precursors to obtain fluorine substituted N-alkylamide side chain derivatives of indiplon, followed by multistep purification using semi-preparative high-performance liquid chromatography and solid phase extraction. Tosyl and bromo precursors were converted into 18F-labelled indiplon derivatives with good and reproducible radiochemical yield (RCY) (35–70%, decay corrected), high radiochemical purity (≥98.5%), and high specific activity ( > 150 GBq/µmol). By contrast, a low RCY (5–10%) and specific activity (10–15 GBq/µmol) were achieved for the 4-nitrobenzoyl precursor. Copyright © 2008 John Wiley & Sons, Ltd.

Radiopharmacological investigations of [(18)F]NS14490 have proven that this radiotracer could be a potential PET radiotracer for imaging of alpha7 nicotinic acetylcholine receptor particularly with regard to vulnerable plaques of diseased vessels. For further optimisation of the previously automated one-pot radiosynthesis of [(18)F]NS14490 using a tosylate precursor, precursors with other leaving groups (nosylate and mosylate) were synthesized and compared with the tosylate with respect to their reactivities towards [(18)F]fluoride. The use of these different precursors resulted in comparable labelling yields of [(18)F]NS14490. A novel mosylate precursor was synthesized and evaluated, which has revealed a higher stability during a storage period of five months compared to the corresponding tosylate and nosylate.

To evaluate the suitability of [18F]perchorylfluoride [18F]FClO3 as an electrophilic fluorination agent for the preparation of radiopharmaceuticals, the reactivity non-radioactive FClO3 towards 4-substituted trimethyltin aromatic compounds was studied. Contrary to the expectation, an electrophilic fluorination of the aromatic nucleus did not occur. The reaction of perchlorylfluoride with aromatic trimethylstannyl compounds resulted in the formation of trimethyltin fluoride and the respective destannylated aromatics in variable yields.

A set of 40 subfossil Scots pines (Pinus sylvestris L.) was sampled in small lakes beyond the modernpine limit in the northwest Kola Peninsula, Russia. Radiocarbon dating suggests that the pine expanded north of its present-day limit between 7000 and 3500yr BP. The most extensive occurrence of pine forests was reconstructed between 6250 and 5750 yr BP. Numerous samples collected from trunks and stubs in situ clearly indicate lower lake levels between 6200 and 4400 yr BP. Living and14C dated subfossil pine samples were analysed for the mean carbon, oxygen and hydrogen stable isotope composition of their wood cellulose. The mean δ13C, δ18O and δ2H values of the wood samples from the mid-Holocene time are C. 1.1%, 0.9% and lock, respectively - more positive than those of living trees in this region. These results suggest that the mid-Holocene climate in the region was warmer and drier than nowadays. The data agree with previous palynological, macrofossil and limnological studies from northernmost Fennoscandia. During the late-Holocene climatic deterioration after c. 3500 yr BP, the decline of the northern pine limit was synchronous with other parts of northern Eurasia. Comparison with dated pine series from the north-central Kola Peninsula and Finnish Lapland suggests that the decline of the northernmost pine limit in the eastern part of the area may have occurred somewhat earlier than in the western part.

14C dating on 8 samples of subfossil trunks ("black oaks") indicates the Holocene age of the upper parts of the valley bottom gravel of the Odra River in the Ostrava Basin. These strata west of the town of Bohumín were redeposited during hazard floods shortly after 760 ± 70 BP.

Anhand von 14 C-, 3 H- und δD-Untersuchungen wird ein Uberblick uber wesentliche Isotopenvariationen der Grundwasser insbesondere in den tieferen kanozoischen Grundwasserleitern im Bereich der Furstenwalde-Gubener Storungszone gegeben. Bei Betrachtung individueller Teufenabfolgen, wie auch unter Einteilung der Proben in hydrochemische Typgruppen, wurde trotz regional variierender chemischer Verhaltnisse im Mittel eine qualitativ gute Korrelation zwischen den isotopenanalytischen ( 14 C) und chemischen Parametern gefunden. Bei Deuterium ergab sich (auch im 14 C-D-Diagnramm) eine breite Wertestreuung, aus der sich typgebunden lediglich eine Gruppe mit niedrigen Werten (kaltzeitlich beeinflust) und eine Gruppe mit hoheren Werten (hohere Mineralisation und moglicherweise durch marine Reliktlosungen beeinflust) abheben lassen. Da im Gebiet Braunkohlenfloze verbreitet vorkommen, wird anhand von Beispieluntersuchungen im Raum Leipzig/Grimma auf die Notwendigkeit der Diskussion von Moglichkeiten zur Beeinflussung des DIC in derartigen Untersuchungsgebieten durch Kohleabbau hingewiesen.

In the opencast mine area of Zwenkau, Germany, many prehistoric wells and pits have recently been excavated. In this region there is generally no bone preservation and charred seeds are rare, seldom encountered in a reliable archaeological context, whereas charcoal is frequently found. From an archaeological point of view, however, charcoal from wood is not as reliable for radiocarbon dating as short-lived materials. Fortunately, many deep features were found where wood has been preserved. Over a dozen structures turned out to be prehistoric wells, some of them typologically dated by ceramics to between Early Bronze Age and Early Middle Ages. For other features without archaeological finds, 14C dating was the only way to get an age. Analysis showed that different types of wells were constructed by the same culture. On the other hand, the same constructions are not characteristic for a defined cultural period and were applied over a time span of three millennia.

A fully automatized radiosynthesis of (+)- and (−)-[ 18 F]Flubatine ((+)- and (−)NCFHEB) by means of a commercially available synthesis module (TRACERlab FX FN) under GMP conditions is reported. Radiochemical yields of 30% within an overall synthesis time of 40 min were achieved in more than 70 individual syntheses. Specific activities were approximately 3000 GBq/μmol and radiochemical purity was determined to be at least 97%.

Radiocarbon laboratories using liquid scintillation counting depend on the availability of a catalyst for benzene synthesis. One of the two commonly used is a commercially available chromium-activated silica-alumina catalyst, PKN/D1. As this catalyst will no longer be produced, we have tested similar catalysts as possible replacements. We measured benzene purity by gas chromatography and mass spectrometry, and found that chromium endowment was crucial for a proper catalyst function. The surface area of the catalyst also significantly affected benzene yield and purity. We also studied the effects of different reaction conditions of acetylene absorption and benzene desorption on benzene purity. A catalyst with half of the Cr endowment and doubled specific surface area created yield and purity comparable to PKN/D1.

Radiocarbon dating is an important tool for reconstructing Late Quaternary paleoenvironmental history of the Antarctic continent. Because of the scarcity of datable material, new suitable substances are welcomed. We present here novel paleoenvironmental records—subfossil stomach oil deposits (mumiyo). This waxy organic material is found in petrel breeding colonies, especially in those of snow petrels, Pagodroma nivea. The substance is formed by accumulation and solidification of stomach oil regurgitated for the purpose of defense. We demonstrate and outline the usefulness and limitations of 14C dating mumiyo for determining dates of local ice retreat, moraines and petrel occupation history.

Solidified stomach oil deposits in snow petrel colonies in the Antarctic proved to be suitable for 14C dating and provide important palaeobiogeographical and palaeoenvironmental information. Following earlier studies in the Untersee oasis (Central Dronning Maud Land) we present here 14C measurements on comparable deposits from the Bunger Hills (66°10′S, 101°E). The conventional 14C age of the basal layer reflects the occupation age of any particular nesting site and therefore a minimum age for the time when this area became ice-free. According to the 14C results the occupation of the southern part of the Bunger Hills by petrels started about 10000yr ago. The breeding colonies expanded continuously following local ice retreat. The most intensive phases of colonization seem to have been from 8–6 kyr BP and during the past 2 kyr.

In this study, we synthesized and evaluated a new spirocyclic piperidine derivative 3, containing a 4-fluorobutyl side chain, as a PET radioligand for neuroimaging of σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K(i) =1.2 nM) as well as high selectivity. [¹⁸F]3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45-51 %), purity (98 %), and specific activity (201 GBq μmol⁻¹). Metabolic stability of [¹⁸F]3 in the brain of CD-1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [¹⁸F]3 in the brain corresponded to regions with high σ₁ receptor density. The highest region-specific total-to-nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [¹⁸F]3 (2.2 % ID per gram at 5 min p.i.). Pre-administration of haloperidol significantly inhibited [¹⁸F]3 uptake into the brain and σ₁ receptor-expressing organs, further confirming in vivo target specificity.

Radiolabeled vesamicol analogs are promising candidates as ligands for the vesicular acetylcholine transporter (VAChT) to enable in vivo imaging of early cholinergic degenerations in brain. The 4-fluorobenzoyl-substituted azaspirovesamicol derivative FBASV is one out of six novel vesamicol analogs and demonstrated most appropriate in vitro binding data. 18F-radiolabeling was performed by microwave-assisted nucleophilic aromatic substitution of the corresponding nitro precursor and two methods were developed for the purification of [18F]FBASV. Utilizing method A, the remaining nitro precursor was reduced to its corresponding amine, which was separated via semi-preparative HPLC on a conventional RP column. In method B a phenyl column was used for the direct separation of [18F]FBASV and its nitro precursor, resulting in a change of the elution order and better separation parameters. Thus, [18F]FBASV was synthesized with a RCY of 16–18%, a specific activity >300 GBq/µmol, and a radiochemical purity of >99.5% suitable for future in vivo studies. Copyright © 2011 John Wiley & Sons, Ltd.

To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [(18)F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs).Dynamic PET recordings were made in isoflurane-anaesthetized juvenile pigs during 120 min after administration of [(18)F]NS10743 under baseline conditions (n = 3) and after blocking of the α7 nAChR with NS6740 (3 mg·kg(-1) bolus + 1 mg·kg(-1)·h(-1) continuous infusion; n = 3). Arterial plasma samples were collected for determining the input function of the unmetabolized tracer. Kinetic analysis of regional brain time-radioactivity curves was performed, and parametric maps were calculated relative to arterial input.Plasma [(18)F]NS10743 passed readily into the brain, with peak uptake occurring in α7 nAChR-expressing brain regions such as the colliculi, thalamus, temporal lobe and hippocampus. The highest SUV(max) was approximately 2.3, whereas the lowest uptake was in the olfactory bulb (SUV(max) 1.53 ± 0.32). Administration of NS6740 significantly decreased [(18)F]NS10743 binding late in the emission recording throughout the brain, except in the olfactory bulb, which was therefore chosen as reference region for calculation of BP(ND). The baseline BP(ND) ranged from 0.39 ± 0.08 in the cerebellum to 0.76 ± 0.07 in the temporal lobe. Pretreatment and constant infusion with NS6740 significantly reduced the BP(ND) in regions with high [(18)F]NS10743 binding (temporal lobe -29%, p = 0.01; midbrain: -35%, p = 0.02), without significantly altering the BP(ND) in low binding regions (cerebellum: -16%, p = 0.2).This study confirms the potential of [(18)F]NS10743 as a target-specific radiotracer for the molecular imaging of central α7 nAChRs by PET.

Neuroimaging of σ(1) receptors in the human brain has been proposed for the investigation of the pathophysiology of neurodegenerative and psychiatric diseases. However, there is a lack of suitable (18)F-labelled PET radioligands for that purpose.The selective σ(1) receptor ligand [(18)F]fluspidine (1'-benzyl-3-(2-[(18)F]fluoroethyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]) was synthesized by nucleophilic (18)F(-) substitution of the tosyl precursor. In vitro receptor binding affinity and selectivity were assessed by radioligand competition in tissue homogenate and autoradiographic approaches. In female CD-1 mice, in vivo properties of [(18)F]fluspidine were evaluated by ex vivo brain section imaging and organ distribution of intravenously administered radiotracer. Target specificity was validated by organ distribution of [(18)F]fluspidine after treatment with 1 mg/kg i.p. of the σ receptor antagonist haloperidol or the emopamil binding protein (EBP) inhibitor tamoxifen. In vitro metabolic stability and in vivo metabolism were investigated by LC-MS(n) and radio-HPLC analysis.[(18)F]Fluspidine was obtained with a radiochemical yield of 35-45%, a radiochemical purity of ≥ 99.6% and a specific activity of 150-350 GBq/μmol (n = 6) within a total synthesis time of 90-120 min. In vitro, fluspidine bound specifically and with high affinity to σ(1) receptors (K (i) = 0.59 nM). In mice, [(18)F]fluspidine rapidly accumulated in brain with uptake values of 3.9 and 4.7%ID/g and brain to blood ratios of 7 and 13 at 5 and 30 min after intravenous application of the radiotracer, respectively. By ex vivo autoradiography of brain slices, resemblance between binding site occupancy of [(18)F]fluspidine and the expression of σ(1) receptors was shown. The radiotracer uptake in the brain as well as in peripheral σ(1) receptor expressing organs was significantly inhibited by haloperidol but not by tamoxifen. Incubation with rat liver microsomes led to a fast biotransformation of fluspidine. After an incubation period of 30 min only 13% of the parent compound was left. Seven metabolites were identified by HPLC-UV and LC-MS(n) techniques. However, [(18)F]fluspidine showed a higher metabolic stability in vivo. In plasma samples ∼ 94% of parent compound remained at 30 min and ∼ 67% at 60 min post-injection. Only one major radiometabolite was detected. None of the radiometabolites crossed the blood-brain barrier.[(18)F]Fluspidine demonstrated favourable target affinity and specificity as well as metabolic stability both in vitro and in animal experiments. The in vivo properties of [(18)F]fluspidine offer a high potential of this radiotracer for neuroimaging and quantitation of σ(1) receptors in vivo.

Phenylpiperidinyl-octahydro-benzo[1,4]oxazines represent a new class of conformationally restrained vesamicol analogues. Derived from this morpholine-fused vesamicol structure, a new fluorine-18-labeled 4-fluorobenzoyl derivative ([ 18 F]FBMV) was synthesized with an average specific activity of 75 GBq/μmol and a radiochemical purity of 99%. The radiolabeling method included an exchange reaction of a 4-nitro group of the precursor by fluorine-18, a reduction procedure to eliminate excess of the nitro compound, followed by a high-performance liquid chromatography purification. [ 18 F]FBMV demonstrates (i) a moderate lipophilic character with a logD pH7.0 1.8±0.10; (ii) a considerable binding affinity to the vesicular acetylcholine transporter (VAChT) ( K i =27.5 nM), as determined using PC12 cells transfected with a VAChT cDNA, and a low affinity to σ 1,2 receptors ( K i >3000 nM); (iii) a good uptake into the rat and pig brains; (iv) a typical accumulation in the VAChT-containing brain regions; and (v) an approximately 20% reduction in cortical tracer binding after a specific cholinergic lesion using 192IgG-saporin. [ 18 F]FBMV exhibits another PET marker within the group of vesamicol derivatives that demonstrates potentials in imaging brain cholinergic deficits, while its usefulness in clinical practice must await further investigation.

Aminocyclohexyl indoles bind with high affinity and specificity toward the serotonin transporter (SERT). Based on this structural lead, we designed fluoroalkoxydihydroisoquinoline-cyclohexyl indole carbonitriles for future application as 18F-labeled tracers for SERT imaging by PET. Six compounds, three pairs of cis- and trans-isomer derivatives, respectively, were synthesized and evaluated in vitro. The chemistry of the new compounds, their affinity and specificity data, the general route to the phenolic precursor for labeling, and the successful 18F-fluoroalkylation of one pair of compounds are described herein.

Neuroimaging of GABA(A) receptors offers the potential for a better diagnosis of diseases related to a dysfunction of the GABAergic neurotransmission. A series of potent fluorinated analogues of the pyrazolopyrimidine Indiplon has been synthesized and evaluated in vitro as potential agents for imaging the GABA(A) receptor by means of positron emission tomography (PET). The most promising compound N-(3-fluoropropyl)-N-[3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl]-acetamide (5b) showed an IC(50) value of 2.78+/-0.63 nM comparable to the lead compound Indiplon (IC(50) 3.29+/-0.37 nM), thus making it an interesting candidate for further investigations. In addition to the fluorinated reference compounds, suitable precursors for (18)F-radiolabelling studies have been synthesized.

An approach to synthesize the electrophilic fluorinating agent no-carrier-added (n.c.a.) [18F]perchloryl fluoride ([18F]FClO3) in superacidic media in the presence of KClO4 or anhydrous perchloric acid starting from [18F]fluoride was demonstrated in this study. However, the radiochemical yields were low (1–6%) and poorly reproducible. Fluorosulphonic acid proved to be an essential intermediate as revealed by non-radioactive experiments. A key problem in the preparation of [18F]FClO3 is the assumed kinetic inhibition due to the unfavourable stoichiometric ratio of the ClO4 moiety to [18F]HSO3F.

Introduction Gamma amino butyric acid type A (GABA A ) receptors are involved in a variety of neurological and psychiatric diseases, which have promoted the development and use of radiotracers for positron emission tomography imaging. Radiolabeled benzodiazepine antagonists such as flumazenil have most extensively been used for this purpose so far. Recently, the non-benzodiazepine pyrazolopyrimidine derivative indiplon with higher specificity for the α 1 subtype of the GABA A receptor has been introduced for treatment of insomnia. The aim of this study was the development and biological evaluation of an 18 F-labeled derivative of indiplon. Methods Both [ 18 F]fluoro-indiplon and its labeling precursor were synthesized by two-step procedures starting from indiplon. The radiosynthesis of [ 18 F]fluoro-indiplon was performed using the bromoacetyl precursor followed by multiple-stage purification using semipreparative HPLC and solid phase extraction. Stability, partition coefficients, binding affinities and regional brain binding were determined in vitro. Biodistribution and radiotracer metabolism were studied in vivo. Results [ 18 F]Fluoro-indiplon was readily accessible in good yields (38–43%), with high purity and high specific radioactivity (>150 GBq/μmol). It displays high in vitro stability and moderate lipophilicity. [ 18 F]Fluoro-indiplon has an affinity to GABA A receptors comparable to indiplon ( K i =8.0 nM vs. 3.4 nM). In vitro autoradiography indicates high [ 18 F]fluoro-indiplon binding in regions with high densities of GABA A receptors. However, ex vivo autoradiography and organ distribution studies show no evidence of specific binding of [ 18 F]fluoro-indiplon. Furthermore, the radiotracer is rapidly metabolized with high accumulation of labeled metabolites in the brain. Conclusions Although [ 18 F]fluoro-indiplon shows good in vitro features, it is not suitable for in vivo imaging studies because of its metabolism. Structural modifications are needed to develop derivatives with higher in vivo stability.

Two 4-substituted aromatic iodosyl compounds were investigated with regard to their solubility, stability and chromatographic behaviour. 1-Iodosyl-4-methoxy- and 1-iodosyl-4-nitro-benzene are soluble in methanol and provide acceptable 1H and 13C NMR spectra; however, gradual oxidation of the solvent was observed. LC-MS analyses suggest that unlike the parent substance, iodosylbenzene, which has a polymeric structure, both compounds rather exist in the monomeric form. Copyright © 2006 John Wiley & Sons, Ltd.

Aus Paläorinnensedimenten und fossilen Bodenhorizonten in der Weißen Elsteraue wurden konventionelle und AMS 14C-Altersbestimmungen der organischen Substanz durchgeführt. Die Ergebnisse liefern z.T. sehr große Altersdifferenzen der verschiedenen Komponenten einer Probe bis über 20.000 14C-Jahre, die der Beimischung von umgelagertem tertiären Material zuzuschreiben ist. Die Resultate belegen, dass bei der Interpretation von 14C-Altersbestimmungen an organischem Material aus fluviatilen Sedimenten große Vorsicht geboten ist, wenn nicht die Altershomogenität des Probenmaterials bewiesen werden kann oder weitere Absicherungen durch unabhängige absolute Datierungsmethoden vorliegen., research