Publications by authors named "Steffen Fischer"

87 Publications

Development of F-Labeled Radiotracers for PET Imaging of the Adenosine A Receptor: Synthesis, Radiolabeling and Preliminary Biological Evaluation.

Int J Mol Sci 2021 Feb 25;22(5). Epub 2021 Feb 25.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research site Leipzig, 04318 Leipzig, Germany.

The adenosine A receptor (AR) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the AR-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound (). Among those, the highly affine 4-fluorobenzyl derivate (; (AR) = 5.3 nM) and the 2-fluorobenzyl derivate (; (AR) = 2.1 nM) were chosen for F-labeling via an alcohol-enhanced copper-mediated procedure starting from the corresponding boronic acid pinacol ester precursors. Investigations of the metabolic stability of [F] and [18F] in CD-1 mice by radio-HPLC analysis revealed parent fractions of more than 76% of total activity in the brain. Specific binding of [F] on mice brain slices was demonstrated by in vitro autoradiography. In vivo PET/magnetic resonance imaging (MRI) studies in CD-1 mice revealed a reasonable high initial brain uptake for both radiotracers, followed by a fast clearance.
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http://dx.doi.org/10.3390/ijms22052285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956753PMC
February 2021

Apparatus for simultaneous stress and weight measurement during film drying in an environmentally controlled chamber.

Rev Sci Instrum 2020 Dec;91(12):123904

KU Leuven, Soft Matter, Rheology and Technology, Department of Chemical Engineering, Celestijnenlaan 200f, 3001 Leuven, Belgium.

The drying behavior of coatings is essential for the development of formulations in order to obtain reliable and defect free finishes. There are two major measures of interest: the development of the stress responsible for cracking and the drying rate that gives insight into the morphological structure. The cantilever deflection method is the predominant way of determining stresses under defined drying conditions such as temperature and humidity. However, both measures of interest are currently obtained using two different coatings when dried in a chamber or a single coating with simultaneous measurements that can only be dried under ambient conditions. In this paper, we present an apparatus design based on the cantilever deflection method that allows simultaneous measurement of the stress and drying rate in an environmentally controlled chamber.
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http://dx.doi.org/10.1063/5.0030739DOI Listing
December 2020

Possibilities for Optimization of Industrial Alkaline Steeping of Wood-Based Cellulose Fibers.

Molecules 2020 Dec 10;25(24). Epub 2020 Dec 10.

Institut für Pflanzen- und Holzchemie, Fakultät Biologie, Technische Universität Dresden, 01737 Tharandt, Germany.

Steeping of cellulosic materials in aqueous solution of NaOH is a common pre-treatment in several industrial processes for production of cellulose-based products, including viscose fibers. This study investigated whether the span of commonly applied process settings has the potential for process optimization regarding purity, yield, and degree of transformation to alkali cellulose. A hardwood kraft dissolving pulp was extracted with 17-20 wt% aq. NaOH at 40-50 °C. The regenerated residue of the pulp was characterized regarding its chemical composition, molecular structure, and cellulose conformation. Yield was shown to be favored primarily by low temperature and secondly by high alkali concentration. Purity of xylan developed inversely. Both purity of xylan and yield varied over the applied span of settings to an extent which makes case-adapted process optimization meaningful. Decreasing the steeping temperature by 2 °C increased xylan content in the residue with 0.13%-units over the whole span of applied alkali concentrations, while yield increased by 0.15%-units when extracting with 17 wt% aq. NaOH, and by 0.20%-units when extracting with 20 wt%. Moreover, the yield-favoring conditions resulted in a narrower molecular weight distribution. The degree of transformation via alkali cellulose to cellulose II, as determined with Raman spectroscopy, was found to be high at all extraction settings applied.
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http://dx.doi.org/10.3390/molecules25245834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764164PMC
December 2020

Suitability and Modification of Different Renewable Materials as Feedstock for Sustainable Flame Retardants.

Molecules 2020 Nov 4;25(21). Epub 2020 Nov 4.

Institute of Plant and Wood Chemistry, Technische Universität Dresden, 01062 Dresden, Germany.

Due to their chemical structure, conventional flame retardants are often toxic, barely biodegradable and consequently neither healthy nor environmentally friendly. Their use is therefore increasingly limited by regulations. For this reason, research on innovative flame retardants based on sustainable materials is the main focus of this work. Wheat starch, wheat protein, xylan and tannin were modified with phosphate salts in molten urea. The functionalization leads to the incorporation of phosphates (up to 48 wt.%) and nitrogen (up to 22 wt.%). The derivatives were applied on wood fibers and tested as flame retardants. The results indicate that these modified biopolymers can provide the same flame-retardant performances as commercial compounds currently used in the wood fiber industry. Besides, the flame retardancy smoldering effects may also be reduced compared to unmodified wood fibers depending on the used biopolymer. These results show that different biopolymers modified in phosphate/urea systems are a serious alternative to conventional flame retardants.
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http://dx.doi.org/10.3390/molecules25215122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662329PMC
November 2020

Using an added liquid to suppress drying defects in hard particle coatings.

J Colloid Interface Sci 2021 Jan 17;582(Pt B):1231-1242. Epub 2020 Aug 17.

KU Leuven, Soft Matter, Rheology and Technology, Department of Chemical Engineering, Celestijnenlaan 200f, 3001 Leuven, Belgium. Electronic address:

Hypothesis: Lateral accumulation and film defects during drying of hard particle coatings is a common problem, typically solved using polymeric additives and surface active ingredients, which require further processing of the dried film. Capillary suspensions with their tunable physical properties, devoid of polymers, offer new pathways in producing uniform and defect free particulate coatings.

Experiments: We investigated the effect of small amounts of secondary liquid on the coating's drying behavior. Stress build-up and weight loss in a temperature and humidity controlled drying chamber were simultaneously measured. Changes in the coating's reflectance and height profile over time were related with the weight loss and stress curve.

Findings: Capillary suspensions dry uniformly without defects. Lateral drying is inhibited by the high yield stress, causing the coating to shrink to an even height. The bridges between particles prevent air invasion and extend the constant drying period. The liquid in the lower layers is transported to the interface via corner flow within surface pores, leading to a partially dry layer near the substrate while the pores above are still saturated. Using capillary suspensions for hard particle coatings results in more uniform, defect free films with better printing characteristics, rendering high additive content obsolete.
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http://dx.doi.org/10.1016/j.jcis.2020.08.055DOI Listing
January 2021

(+)-[F]Flubatine as a novel α4β2 nicotinic acetylcholine receptor PET ligand-results of the first-in-human brain imaging application in patients with β-amyloid PET-confirmed Alzheimer's disease and healthy controls.

Eur J Nucl Med Mol Imaging 2021 Mar 16;48(3):731-746. Epub 2020 Sep 16.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purposes: We present the first in-human brain PET imaging data of the new α4β2 nicotinic acetylcholine receptor (nAChR)-targeting radioligand (+)-[F]Flubatine. Aims were to develop a kinetic modeling-based approach to quantify (+)-[F]Flubatine and compare the data of healthy controls (HCs) and patients with Alzheimer's disease (AD); to investigate the partial volume effect (PVE) on regional (+)-[F]Flubatine binding; and whether (+)-[F]Flubatine binding and cognitive test data respective β-amyloid radiotracer accumulation were correlated.

Methods: We examined 11 HCs and 9 mild AD patients. All subjects underwent neuropsychological testing and [C]PiB PET/MRI examination. (+)-[F]Flubatine PET data were evaluated using full kinetic modeling and regional as well as voxel-based analyses.

Results: With 270-min p.i., the unchanged parent compound amounted to 97 ± 2%. Adequate fits of the time-activity curves were obtained with the 1 tissue compartment model (1TCM). (+)-[F]Flubatine distribution volume (binding) was significantly reduced in bilateral mesial temporal cortex in AD patients compared with HCs (right 10.6 ± 1.1 vs 11.6 ± 1.4, p = 0.049; left 11.0 ± 1.1 vs 12.2 ± 1.8, p = 0.046; one-sided t tests each). PVE correction increased not only (+)-[F]Flubatine binding of approximately 15% but also standard deviation of 0.4-70%. Cognitive test data and (+)-[F]Flubatine binding were significantly correlated in the left anterior cingulate, right posterior cingulate, and right parietal cortex (r > 0.5, p < 0.05 each). In AD patients, (+)-[F]Flubatine binding and [C]PiB standardized uptake value ratios were negatively correlated in several regions; whereas in HCs, a positive correlation between cortical (+)-[F]Flubatine binding and [C]PiB accumulation in the white matter was found. No adverse event related to (+)-[F]Flubatine occurred.

Conclusion: (+)-[F]Flubatine is a safe and stable PET ligand. Full kinetic modeling can be realized by 1TCM without metabolite correction. (+)-[F]Flubatine binding affinity was high enough to detect group differences. Of interest, correlation between white matter β-amyloid PET uptake and (+)-[F]Flubatine binding indicated an association between white matter integrity and availability of α4β2 nAChRs. Overall, (+)-[F]Flubatine showed favorable characteristics and has therefore the potential to serve as α4β2 nAChR-targeting PET ligand in further clinical trials.
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http://dx.doi.org/10.1007/s00259-020-05029-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036219PMC
March 2021

Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots.

Int J Mol Sci 2020 Jun 27;21(13). Epub 2020 Jun 27.

CENTOGENE AG, Am Strande 7, 18055 Rostock, Germany.

Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay's longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the "under treatment" versus "not under treatment" conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients.
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http://dx.doi.org/10.3390/ijms21134577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369829PMC
June 2020

Development of Novel Analogs of the Monocarboxylate Transporter Ligand FACH and Biological Validation of One Potential Radiotracer for Positron Emission Tomography (PET) Imaging.

Molecules 2020 May 14;25(10). Epub 2020 May 14.

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany.

Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs and were synthesized and their MCT1 inhibition was estimated by [C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds and showed lower MCT1 inhibitory potencies than FACH (IC = 11 nM) by factors of 11 and 25, respectively, (IC = 118 nM) could still be a suitable PET candidate. Therefore, was selected for radiosynthesis of [F] and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D result for [F] agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [F] compared to [F]FACH, the in vivo brain uptake of [F] was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.
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http://dx.doi.org/10.3390/molecules25102309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288138PMC
May 2020

Sigma-1 Receptor Positron Emission Tomography: A New Molecular Imaging Approach Using ()-(-)-[F]Fluspidine in Glioblastoma.

Molecules 2020 May 6;25(9). Epub 2020 May 6.

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Research site Leipzig, 04318 Leipzig, Germany.

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand ()-(-)-[F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical K values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology.
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http://dx.doi.org/10.3390/molecules25092170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248975PMC
May 2020

Flame Retardancy of Wood Fiber Materials Using Phosphorus-Modified Wheat Starch.

Molecules 2020 Jan 14;25(2). Epub 2020 Jan 14.

Technische Universität Dresden, Institute of Plant and Wood Chemistry, 01062 Dresden, Germany.

Biopolymer-based flame retardants (FR) are a promising approach to ensure adequate protection against fire while minimizing health and environmental risks. Only a few, however, are suitable for industrial purposes because of their poor flame retardancy, complex synthesis pathway, expensive cleaning procedures, and inappropriate application properties. In the present work, wheat starch was modified using a common phosphate/urea reaction system and tested as flame retardant additive for wood fibers. The results indicate that starch derivatives from phosphate/urea systems can reach fire protection efficiencies similar to those of commercial flame retardants currently used in the wood fiber industry. The functionalization leads to the incorporation of fire protective phosphates (up to 38 wt.%) and nitrogen groups (up to 8.3 wt.%). The lowest levels of burning in fire tests were measured with soluble additives at a phosphate content of 3.5 wt.%. Smoldering effects could be significantly reduced compared to unmodified wood fibers. The industrial processing of a starch-based flame retardant on wood insulating materials exhibits the fundamental applicability of flame retardants. These results demonstrate that starch modified from phosphate/urea-systems is a serious alternative to traditional flame retardants.
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http://dx.doi.org/10.3390/molecules25020335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024314PMC
January 2020

Effect of Sulfation Route and Subsequent Oxidation on Derivatization Degree and Biocompatibility of Cellulose Sulfates.

Macromol Biosci 2020 02 29;20(2):e1900403. Epub 2019 Dec 29.

Interdisciplinary Center of Materials Science, Martin Luther University Halle-Wittenberg, 06099, Halle (Saale), Germany.

Sulfated cellulose (CS) represents an interesting biopolymer due to bioactivity comparable to heparin. However, use of CS for making surface coatings or hydrogels requires the presence of reactive groups for covalent reactions. Here, an approach is presented to oxidize cellulose sulfates for subsequent cross-linking reactions with amino groups to form imine bonds. Cellulose is sulfated by direct sulfation or acetosulfation, followed by a Malaprade oxidation. The CS obtained is characterized by elemental analysis and C-NMR spectroscopy. The resulting oxidized cellulose sulfates (oxCS) have different degrees of sulfation ranging from 0.79 to 1.13 and oxidation degrees from 0.18 to 0.34, but also different mass average molecular mass (M ). Toxicity studies are carried out with mouse 3T3 fibroblasts exposed to aqueous solutions of oxCS. The results show that all oxCS are non-toxic at lower concentrations (0.5 mg mL ), but with both increasing degree of oxidation and concentrations, toxic effects are observed particularly for acetosulfated and lesser for direct sulfated oxCS, which is related to a decrease in the M of the products. It is concluded that oxCS obtained by direct sulfation with M above 70 kDa may represent a biocompatible material for the applications suggested above.
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http://dx.doi.org/10.1002/mabi.201900403DOI Listing
February 2020

Structure Selectivity of Alkaline Periodate Oxidation on Lignocellulose for Facile Isolation of Cellulose Nanocrystals.

Angew Chem Int Ed Engl 2020 02 4;59(8):3218-3225. Epub 2019 Dec 4.

Wood Technology and Wood Chemistry, Georg-August-University of Göttingen, 37077, Göttingen, Germany.

Reported here for the first time is the alkaline periodate oxidation of lignocelluloses for the selective isolation of cellulose nanocrystals (CNCs). With the high concentrations as a potassium salt at pH 10, periodate ions predominantly exist as dimeric orthoperiodate ions (H I O ). With reduced oxidizing activity in alkaline solutions, dimeric orthoperiodate ions preferentially oxidized non-ordered cellulose regions. The alkaline surroundings promoted the degradation of these oxidized cellulose chains by β-alkoxy fragmentation and generated CNCs. The obtained CNCs were uniform in size and generally contained carboxy groups. Furthermore, the reaction solution could be reused after regeneration of the periodate with ozone gas. This method allows direct production of CNCs from diverse sources, in particular lignocellulosic raw materials including sawdust (European beech and Scots pine), flax, and kenaf, in addition to microcrystalline cellulose and pulp.
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http://dx.doi.org/10.1002/anie.201912053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027850PMC
February 2020

and Human Metabolism of ()-[F]Fluspidine - A Radioligand for Imaging σ Receptors With Positron Emission Tomography (PET).

Front Pharmacol 2019 13;10:534. Epub 2019 Jun 13.

Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany.

()-[F]fluspidine (()-[F]) has recently been explored for positron emission tomography (PET) imaging of sigma-1 receptors in humans. In the current report, we have used plasma samples of healthy volunteers to investigate the radiometabolites of ()-[F] and elucidate their structures with LC-MS/MS. For the latter purpose additional studies were conducted by incubation of ()-[F] and ()- with human liver microsomes (HLM). metabolites were characterized by interpretation of MS/MS fragmentation patterns from collision-induced dissociation or by use of reference compounds. Thereby, structures of corresponding radio-HPLC-detected radiometabolites, both and (human), could be identified. By incubation with HLM, mainly debenzylation and hydroxylation occurred, beside further mono- and di-oxygenations. The product hydroxylated at the fluoroethyl side chain was glucuronidated. Plasma samples (10, 20, 30 min p.i., = 5-6), obtained from human subjects receiving 250-300 MBq ()-[F] showed 97.2, 95.4, and 91.0% of unchanged radioligand, respectively. In urine samples (90 min p.i.) the fraction of unchanged radioligand was only 2.6% and three major radiometabolites were detected. The one with the highest percentage, also found in plasma, matched the glucuronide formed . Only a small amount of debenzylated metabolite was detected. In conclusion, our metabolic study, in particular the high fractions of unchanged radioligand in plasma, confirms the suitability of ()-[F] as PET radioligand for sigma-1 receptor imaging.
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http://dx.doi.org/10.3389/fphar.2019.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585474PMC
June 2019

Development and radiosynthesis of the first F-labeled inhibitor of monocarboxylate transporters (MCTs).

J Labelled Comp Radiopharm 2019 06;62(8):411-424

Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Leipzig, Germany.

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT-mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [ F]FACH ((E)-2-cyano-3-{4-[(3-[ F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α-cyano-4-hydroxycinnamic acid (FACH) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L-[ C]lactate uptake assay. Radiolabeling was performed by a two-step protocol comprising the radiosynthesis of the intermediate (E)/(Z)-[ F]tert-Bu-FACH (tert-butyl (E)/(Z)-2-cyano-3-{4-[(3-[ F]fluoropropyl)(propyl)amino]-2-methoxyphenyl}acrylate) followed by deprotection of the tert-butyl group. The radiofluorination was successfully implemented using either K[ F]F-K -carbonate or [ F]TBAF. The final deprotected product [ F]FACH was only obtained when [ F]tert-Bu-FACH was formed by the latter procedure. After optimization of the deprotection reaction, [ F]FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).
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http://dx.doi.org/10.1002/jlcr.3739DOI Listing
June 2019

Acetyl Groups in : Fate of Acetates during Organosolv and Ionosolv Pulping.

Polymers (Basel) 2018 Jun 5;10(6). Epub 2018 Jun 5.

Chair of Forest Biomaterials, University of Freiburg, Werthmannstr. 6, 79085 Freiburg im Breisgau, Germany.

During biomass fractionation, any native acetylation of lignin and heteropolysaccharide may affect the process and the resulting lignin structure. In this study, (TC) and its lignin isolated by milling (MWL), ionosolv (ILL) and organosolv (EOL) methods were investigated for acetyl group content using FT-Raman, ¹H NMR, 2D-NMR, back-titration, and Zemplén transesterification analytical methods. The study revealed that TC is a highly acetylated grass; extractive free TC (TC) and TC MWL exhibited similar values of acetyl content: 6 wt % and 8 wt % by Zemplén transesterification, respectively, and 11 wt % by back-titration. In contrast, lignin extracted from organosolv and [EMIm][OAc] pulping lost 80% of the original acetyl groups. With a high acetyl content in the natural state, TC could be an interesting raw material in biorefinery in which acetic acid could become an important by-product.
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http://dx.doi.org/10.3390/polym10060619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404047PMC
June 2018

Low-molecular-weight sulfonated chitosan as template for anticoagulant nanoparticles.

Int J Nanomedicine 2018 30;13:4881-4894. Epub 2018 Aug 30.

Institute for Chemistry and Technology of Materials, Graz University of Technology, Graz, Austria,

Purpose: In this work, low-molecular-weight sulfoethyl chitosan (SECS) was used as a model template for the generation of silver core-shell nanoparticles with high potential as anticoagulants for medical applications.

Materials And Methods: SECS were synthesized by two reaction pathways, namely Michael addition and a nucleophilic substitution with sodium vinylsulfonate or sodium 2-bromoethanesulfonate (NaBES). Subsequently, these derivatives were used as reducing and capping agents for silver nanoparticles in a microwave-assisted reaction. The formed silver-chitosan core-shell particles were further surveyed in terms of their anticoagulant action by different coagulation assays focusing on the inhibition of either thrombin or cofactor Xa.

Results: In-depth characterization revealed a sulfoalkylation of chitosan mainly on its sterically favored 6-position. Moreover, comparably high average degrees of substitution with sulfoethyl groups (DS) of up to 1.05 were realized in reactions with NaBES. The harsh reaction conditions led to significant chain degradation and consequently, SECS exhibits masses of <50 kDa. Throughout the following microwave reaction, stable nanoparticles were obtained only from highly substituted products because they provide a sufficient charge density that prevented particles from aggregation. High-resolution transmission electron microscopy images reveal that the silver core (diameter ~8 nm) is surrounded by a 1-2 nm thick SECS layer. These core-shell particles and the SECS itself exhibit an inhibiting activity, especially on cofactor Xa.

Conclusion: This interesting model system enabled the investigation of structure-property correlations in the course of nanoparticle formation and anticoagulant activity of SECS and may lead to completely new anticoagulants on the basis of chitosan-capped nanoparticles.
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http://dx.doi.org/10.2147/IJN.S172230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122893PMC
October 2018

Diferrate [Fe (CO) (μ-CO){μ-P(aryl) }] as Self-Assembling Iron/Phosphor-Based Catalyst for the Hydrogen Evolution Reaction in Photocatalytic Proton Reduction-Spectroscopic Insights.

Chemistry 2018 Oct 19;24(60):16052-16065. Epub 2018 Oct 19.

Physical and Theoretical Chemistry Department, University of Rostock, Dr.-Lorenz-Weg 2, 18059, Rostock, Germany.

This work is focused on the identification and investigation of the catalytically relevant key iron species in a photocatalytic proton reduction system described by Beller and co-workers. The system is driven by visible light and consists of the low-cost [Fe (CO) ] as catalyst precursor, electron-poor phosphines P(R) as co-catalysts, and a standard iridium-based photosensitizer dissolved in a mixture of THF, water, and the sacrificial reagent triethylamine. The catalytic reaction system was investigated by operando continuous-flow FTIR spectroscopy coupled with H gas volumetry, as well as by X-ray absorption spectroscopy, NMR spectroscopy, DFT calculations, and cyclic voltammetry. Several iron carbonyl species were identified, all of which emerge throughout the catalytic process. Depending on the applied P(R) , the iron carbonyl species were finally converted into [Fe (CO) (μ-CO){μ-P(R) }] . This involves a P-C cleavage reaction. The requirements of P(R) and the necessary reaction conditions are specified. [Fe (CO) (μ-CO){μ-P(R) }] represents a self-assembling, sulfur-free [FeFe]-hydrogenase active-site mimic and shows good catalytic activity if the substituent R is electron poor. Deactivation mechanisms have also been investigated, for example, the decomposition of the photosensitizer or processes observed in the case of excessive amounts of P(R) . [Fe (CO) (μ-CO){μ-P(R) }] has potential for future applications.
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http://dx.doi.org/10.1002/chem.201802694DOI Listing
October 2018

Cognitive correlates of α4β2 nicotinic acetylcholine receptors in mild Alzheimer's dementia.

Brain 2018 06;141(6):1840-1854

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Leipzig, Germany.

In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (-)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (-)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (-)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (-)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (-)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.
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http://dx.doi.org/10.1093/brain/awy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972585PMC
June 2018

N-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling.

J Med Chem 2018 05 10;61(10):4528-4560. Epub 2018 May 10.

Institut für Radiopharmazeutische Krebsforschung , Helmholtz-Zentrum Dresden-Rossendorf , Bautzner Landstraße 400 , 01328 Dresden , Germany.

Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10 000 M s, which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00286DOI Listing
May 2018

Bridging from Brain to Tumor Imaging: (S)-(-)- and (R)-(+)-[F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice.

Molecules 2018 Mar 20;23(3). Epub 2018 Mar 20.

Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany.

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers ()-(-)- and ()-(+)-[F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB).
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http://dx.doi.org/10.3390/molecules23030702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017399PMC
March 2018

Exploring the Metabolism of (+)-[F]Flubatine in Vitro and in Vivo: LC-MS/MS Aided Identification of Radiometabolites in a Clinical PET Study.

Molecules 2018 Feb 20;23(2). Epub 2018 Feb 20.

Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany.

Both (+)-[F]flubatine and its enantiomer (-)-[F]flubatine are radioligands for the neuroimaging of α4β2 nicotinic acetylcholine receptors (nAChRs) by positron emission tomography (PET). In a clinical study in patients with early Alzheimer's disease, (+)-[F]flubatine ((+)-[F]) was examined regarding its metabolic fate, in particular by identification of degradation products detected in plasma and urine. The investigations included an in vivo study of (+)-flubatine ((+)-) in pigs and structural elucidation of formed metabolites by LC-MS/MS. Incubations of (+)- and (+)-[F] with human liver microsomes were performed to generate in vitro metabolites, as well as radiometabolites, which enabled an assignment of their structures by comparison of LC-MS/MS and radio-HPLC data. Plasma and urine samples taken after administration of (+)-[F] in humans were examined by radio-HPLC and, on the basis of results obtained in vitro and in vivo, formed radiometabolites were identified.
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http://dx.doi.org/10.3390/molecules23020464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017759PMC
February 2018

Radiosynthesis of (S)-[F]T1: The first PET radioligand for molecular imaging of α3β4 nicotinic acetylcholine receptors.

Appl Radiat Isot 2017 Jun 18;124:106-113. Epub 2017 Mar 18.

Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318 Leipzig, Germany. Electronic address:

Recent pharmacologic data revealed the implication of α3β4 nicotinic acetylcholine receptors (nAChRs) in nicotine and drug addiction. To image α3β4 nAChRs in vivo, we aimed to establish the synthesis of a [F]-labelled analog of the highly affine and selective α3β4 ligand (S)-3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)quinuclidine ((S)-T1). (S)-[F]T1 was synthesized from ethynyl-4-[F]fluorobenzene ([F]5) and (S)-azidoquinuclidine by click reaction. After a synthesis time of 130min (S)-[F]T1 was obtained with a radiochemical yield (non-decay corrected) of 4.3±1.3%, a radiochemical purity of >99% and a molar activity of >158 GBq/μmol. The brain uptake and the brain-to-blood ratio of (S)-[F]T1 in mice at 30min post injection were 2.02 (SUV) and 6.1, respectively. According to an ex-vivo analysis, the tracer remained intact (>99%) in brain. Only one major radiometabolite was detected in plasma and urine samples. In-vitro autoradiography on pig brain slices revealed binding of (S)-[F]T1 to brain regions associated with the expression of α3β4 nAChRs, which could be reduced by the α3β4 nAChR selective drug AT-1001. These findings make (S)-[F]T1 a potential tool for the non-invasive imaging of α3β4 nAChRs in the brain by PET.
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http://dx.doi.org/10.1016/j.apradiso.2017.03.015DOI Listing
June 2017

Suppressing Crack Formation in Particulate Systems by Utilizing Capillary Forces.

ACS Appl Mater Interfaces 2017 Mar 14;9(12):11095-11105. Epub 2017 Mar 14.

Institute for Mechanical Process Engineering and Mechanics, Karlsruhe Institute of Technology , Gotthard-Franz-Straße 3, 76131 Karlsruhe, Germany.

Cracks, formed during the drying of particulate films, can reduce the effectiveness or even render products useless. We present a novel, generic approach to suppress crack formation in thin films made from hard particle suspensions, which are otherwise highly susceptible to cracking, using the capillary force between particles present when a trace amount of an immiscible liquid is added to a suspension. This secondary liquid preserves the particle cohesion, modifying the structure and increasing the drying rate. Crack-free films can be produced at thicknesses much greater than the critical cracking thickness for a suspension without capillary interactions, and even persists after sintering. This capillary suspension strategy is applicable to a broad range of materials, including suspensions of metals, semiconductive and ceramic oxides, or glassy polymeric particles, and can be easily implemented in many industrial processes since it is based on well-established unit operations. Promising fields of application include ceramic foils and printed electronic devices.
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http://dx.doi.org/10.1021/acsami.6b13624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375100PMC
March 2017

PET Imaging Evaluation of Four σ Radiotracers in Nonhuman Primates.

J Nucl Med 2017 06 23;58(6):982-988. Epub 2017 Feb 23.

PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut

The σ receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-labeled spirocyclic piperidine-based PET radiotracers (F- to F-). Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of F- and F- Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for F- and F-, and much slower for F- and F-, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F- showed greater differential uptake across brain regions and 3-fold-higher binding potential than F- SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-) and 95% (F-) of radiotracer binding. Tracers F- and F- displayed high brain uptake and fast tissue kinetics, with F- having higher specific binding signals than F- in the same monkey. Taken together, these data indicate that both F- and F- possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.
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http://dx.doi.org/10.2967/jnumed.116.188052DOI Listing
June 2017

Impact of pre-treatments on properties of lignocelluloses and their accessibility for a subsequent carboxymethylation.

Carbohydr Polym 2017 Apr 29;161:82-89. Epub 2016 Dec 29.

Institute of Plant and Wood Chemistry, Technische Universität Dresden Pienner Straße 19, D-01737 Tharandt, Germany.

In this issue, different chemical (alkaline and sulfite pulping, ozonolysis) and mechanical (vibratory ball milling) pre-treatments were utilized for activating wheat straw and beech sawdust prior to carboxymethylation. Detailed analysis by a range of methods, including Klason-lignin, cellulose and hemicellulose quantification, Powder-X-ray diffraction (PXRD) and attenuated total reflection (ATR) IR spectroscopy, enabled the investigation of material alterations. Subsequently, carboxymethylation was carried out with both untreated and activated materials, allowing the evaluation of activation steps by determining degrees of substitution with carboxymethyl groups (DS). Moreover, carboxymethylation conditions were optimized, realizing high DS of up to 1.05. Results further revealed that ball milling enhanced the subsequent conversion; whereas chemical pre-treatments did not effectively increase material accessibilities. Further studies on chemically untreated materials emphasized that a highly reactive surface was already generated in the course of the carboxymethylation, inter alia through the concomitant dissolution of matrix components.
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http://dx.doi.org/10.1016/j.carbpol.2016.12.066DOI Listing
April 2017

Synthesis of thiolated polysaccharides for formation of polyelectrolyte multilayers with improved cellular adhesion.

Carbohydr Polym 2017 Feb 3;157:1205-1214. Epub 2016 Nov 3.

Biomedical Materials Group, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, D-06120 Halle (Saale), Germany; Interdisciplinary Center for Material Research & Institute of Physics, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany. Electronic address:

Intrinsic cross-linking is not only useful for increasing stability, but also for tailoring mechanical properties of polyelectrolyte multilayers (PEM) on implants and tissue engineering scaffolds. Here, a novel route for synthesizing thiolated chitosan (t-Chi) based on the application of 3,3'-dithiodipropionic acid was applied, while thiolated chondroitin sulfate (t-CS) was conjugated by 3,3'-dithiobis (propanoic hydrazide). Both products were subsequently reduced to obtain the free thiols. The thiol content, structural changes and degree of substitution were studied by UV-vis, FTIR, Raman and H NMR spectroscopy, respectively. Chi and CS can be used for PEM formation with the layer-by-layer method, due to the cationic nature of Chi at pH values below 5.0 and the anionic character of CS. Comparative studies on the formation of native Chi/CS versus t-Chi/t-CS PEM with surface plasmon resonance and ellipsometry revealed higher layer mass. We also found that the PEM composed of t-Chi/t-CS had superior cell adhesion properties for human keratinocytes in comparison to the native PEM.
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http://dx.doi.org/10.1016/j.carbpol.2016.10.088DOI Listing
February 2017

A Stable Manganese Pincer Catalyst for the Selective Dehydrogenation of Methanol.

Angew Chem Int Ed Engl 2017 01 2;56(2):559-562. Epub 2016 Dec 2.

Leibniz-Institut für Katalyse an der Universität Rostock, Albert-Einstein-Straße 29a, 18059, Rostock, Germany.

For the first time, structurally defined manganese pincer complexes catalyze the dehydrogenation of aqueous methanol to hydrogen and carbon dioxide, which is a transformation of interest with regard to the implementation of a hydrogen and methanol economy. Excellent long-term stability was demonstrated for the Mn-PNPiPr catalyst, as a turnover of more than 20 000 was reached. In addition to methanol, other important hydrogen carriers were also successfully dehydrogenated.
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http://dx.doi.org/10.1002/anie.201610182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586016PMC
January 2017

Radiosynthesis and biological evaluation of the new PDE10A radioligand [ F]AQ28A.

J Labelled Comp Radiopharm 2017 01 29;60(1):36-48. Epub 2016 Nov 29.

Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals, Leipzig, Germany.

Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[ F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([ F]AQ28A). [ F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[ F]F-K -carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [ F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol ) for further evaluation. Initially, we investigated the binding of [ F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [ F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [ F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.
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http://dx.doi.org/10.1002/jlcr.3471DOI Listing
January 2017

Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds.

ACS Med Chem Lett 2016 Oct 9;7(10):890-895. Epub 2016 Aug 9.

Center of Excellence for Innovation in Drug Design and Discovery, Faculty of Pharmacy, Mahidol University , 447 Sri-Ayutthaya Road, Bangkok 10400, Thailand.

The novel quinuclidine -1,2,3-triazole derivatives - were designed based on the structure of . The binding studies revealed that the stereochemistry at the C3 position of the quinuclidine scaffold plays an important role in the nAChR subtype selectivity. Whereas the ()-enantiomers are selective to α7 over α4β2 (by factors of 44-225) and to a smaller degree over α3β4 (3-33), their ()-counterparts prefer α3β4 over α4β2 (62-237) as well as over α7 (5-294). The ()-derivatives were highly selective to α7 over α3β4 subtypes compared to ()- and ()-. The ()-enantiomers are 5-10 times more selective to α4β2 than their () forms. The overall strongest affinity is observed for the ()-enantiomer binding to α3β4 (, 2.25-19.5 nM) followed by their ()-counterpart binding to α7 (, 22.5-117 nM), with a significantly weaker ()-enantiomer binding to α4β2 (, 414-1980 nM) still above the very weak respective ()-analogue affinity (, 5059-10436 nM).
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http://dx.doi.org/10.1021/acsmedchemlett.6b00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066149PMC
October 2016

Radiation dosimetry of the αβ nicotinic receptor ligand (+)-[F]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results.

EJNMMI Phys 2016 Dec 21;3(1):25. Epub 2016 Oct 21.

Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, 04318, Leipzig, Germany.

Background: Both enantiomers of [F]flubatine are new radioligands for neuroimaging of αβ nicotinic acetylcholine receptors with positron emission tomography (PET) exhibiting promising pharmacokinetics which makes them attractive for different clinical questions. In a previous preclinical study, the main advantage of (+)-[F]flubatine compared to (-)-[F]flubatine was its higher binding affinity suggesting that (+)-[F]flubatine might be able to detect also slight reductions of αβ nAChRs and could be more sensitive than (-)-[F]flubatine in early stages of Alzheimer's disease. To support the clinical translation, we investigated a fully image-based internal dosimetry approach for (+)-[F]flubatine, comparing mouse data collected on a preclinical PET/MRI system to piglet and first-in-human data acquired on a clinical PET/CT system. Time-activity curves (TACs) were obtained from the three species, the animal data extrapolated to human scale, exponentially fitted and the organ doses (OD), and effective dose (ED) calculated with OLINDA.

Results: The excreting organs (urinary bladder, kidneys, and liver) receive the highest organ doses in all species. Hence, a renal/hepatobiliary excretion pathway can be assumed. In addition, the ED conversion factors of 12.1 μSv/MBq (mice), 14.3 μSv/MBq (piglets), and 23.0 μSv/MBq (humans) were calculated which are well within the order of magnitude as known from other F-labeled radiotracers.

Conclusions: Although both enantiomers of [F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the tolerability of the radiation risk of (+)-[F]flubatine imaging which is well within the range as caused by other F-labeled tracers. However, as shown in previous studies, the ED in humans is underestimated by up to 50 % using preclinical imaging for internal dosimetry. This fact needs to be considered when applying for first-in-human studies based on preclinical biokinetic data scaled to human anatomy.
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http://dx.doi.org/10.1186/s40658-016-0160-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074934PMC
December 2016