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The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes’ orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M1, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their physicochemical property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood–brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM1–hM5 were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM1 in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds’ structure–activity relationship and will guide the development towards highly selective mAChRs ligands.

Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability in Dulbecco&rsquo, s phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. Ki values toward M1 were determined as 99 &plusmn, 19 nM, 800 &plusmn, 200 nM, and 380 &plusmn, 90 nM for the (R,R)-, (S,S)-, and racemic (R,S)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (R,R)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest Ki value.

Supported by their involvement in many neurodegenerative disorders, muscarinic acetylcholine receptors (mAChRs) are an interesting target for PET imaging. Nevertheless, no radiotracer is established in clinical routine. Within this work we aim to develop novel PET tracers based on the structure of arecoline. Fifteen novel arecoline derivatives were synthesized, characterized and tested for their affinity to the mAChRs M1-M5 and the conceivable off-target acetylcholinesterase. Five arecoline derivatives and arecoline were labeled with carbon-11 in good yields. Arecaidine diphenylmethyl ester (3b), arecaidine bis(4-fluorophenyl)methyl ester (3c) and arecaidine (4-bromophenyl)(4-fluorophenyl)methyl ester (3e) showed a tremendous gain in mAChR affinity compared to arecoline and a pronounced subtype selectivity for M1. Metabolic stability and serum protein binding of [11C]3b and [11C]3c were in line with properties of established brain tracers. Nonspecific binding of [11C]3c was prevalent in kinetic and endpoint experiment on living cells as well as in autoradiography on native mouse brain sections, which motivates us to decrease the lipophilicity of this substance class prior to in vivo experiments.

Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.

Since high MAO-B levels are present in early stages of AD, the MAO-B system can be designated as an appropriate and prospective tracer target of molecular imaging biomarkers for the detection of early AD. According to the preceding investigations of Mishra et al. the aim of this work was the development of a compound library of selective and reversible MAO-B inhibitors by performing bioisosteric modifications of the core structure of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazoles. In conclusion, 13 new pyrazoline based derivatives have been prepared, which will serve as precursor substances for future radiolabeling as well as reference compounds for the investigation of increased MAO-B levels in AD.

Introduction Present data indicate that merging beneficial structural elements from previously published DAT-ligands highest DAT affinity, selectivity and a suitable metabolic profile should be achieved. This combination led to the development of IPCIT and FE@IPCIT. Methods Precursor synthesis was done starting from cocaine in a six step reaction. O -[ 11 C] - methylation was established using [ 11 C]methyl iodide, optimized and subsequently automated. Small scale 18 F-fluroroethylation as well as optimization of reaction parameters and automation were performed. Affinity and selectivity of the candidate substances were tested in standard binding experiments on human membranes. Metabolic stability and blood–brain-barrier (BBB) penetration were determined. Results Precursor compound, IPCITacid, and reference compounds, IPCIT and FE@IPCIT, were obtained in 4.9%, 12.7% and 4.1% yield, respectively. Automated radiosynthesis of [ 11 C]IPCIT yielded 1.9 ± 0.7 GBq (12.5 ± 4%, corrected for decay). Optimum parameters for 18 F-fluoroethylation were 110 °C for 15 min under TBAH catalysis, yielding 67 ± 16% radiochemical incorporation. Affinity was determined as 1.7 ± 0.6 nM for IPCIT, 1.3 ± 0.2 nM for FE@IPCIT and 37 ± 13 nM for the precursor molecule, IPCIT-acid. Results from in vitro and in silico evaluations revealed high stability but also high lipophilicity. Conclusion Present data indicate high affinity and stability of both IPCIT and FE@IPCIT. Radiolabelling, optimization of reaction parameters and automation succeeded. On the other hand, data concerning BBB-penetration are not promising.

The MCH receptor has been revealed as a target of great interest in positron emission tomography imaging. The receptor's eponymous substrate melanin-concentrating hormone (MCH) is a cyclic peptide hormone, which is located predominantly in the hypothalamus with a major influence on energy and weight regulation as well as water balance and memory. Therefore, it is thought to play an important role in the pathophysiology of adiposity, which is nowadays a big issue worldwide. Based on the selective and high-affinity MCH receptor 1 antagonist SNAP-7941, a series of novel SNAP derivatives has been developed to provide different precursors and reference compounds for the radiosyntheses of the novel PET radiotracers [(11)C]SNAP-7941 and [(18)F]FE@SNAP. Positron emission tomography promotes a better understanding of physiologic parameters on a molecular level, thus giving a deeper insight into MCHR1 related processes as adiposity.

A series of indazolo[4,3-gh]isoquinolinones derivatives have been synthesized to decrease cardiotoxic side effects in comparison to Mitoxantrone. The antiproliferative effects of different side chains were investigated and tested on at least four different cell lines of cervix, ovarian, CNS, NSCLC (non-small-cell lung cancer) and colon carcinoma. In addition to antiproliferative activities, influence on cell cycle and intercalation behavior have been tested.

Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [11C]SNAP-7941—the first PET-Tracer for the MCHR1, we aimed to synthesize its [18F]fluoroethylated analogue: [18F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [18F]fluoroethylation was conducted via various [18F]fluoroalkylated synthons and direct [18F]fluorination. Only the direct [18F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [18F]FE@SNAP in 44.3±2.6%.

A new series of substituted tri-/tetraazabenzo[3,2-a]fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least three different cell lines.

A series of azanaphthoquinone pyrrolo-annelated derivatives attached to basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines. The effects on cell cycle and intercalation were investigated.

Several stereoisomeric, monocyclic analogs of (−)-β-vetivone (1), one of the main constituents of vetiver oil, were studied to examine if the olfactory properties of (−)-β-vetivone (1) could be reproduced from these structurally simpler, synthetically accessible compounds. The effects of diastereomeric and enantiomeric structural differences on the odor of the partial vetivone structure were studied. A chiral phenyl sulfoximine was used for separation of the racemic mixtures. Detailed nuclear magnetic resonance (NMR)-spectroscopic studies (1H, 13C) were used to determine relative configurations whereas absolute configurations were determined by circular dichroism (CD) methods. Chirality 11:133–138, 1999. © 1999 Wiley-Liss, Inc.

(−)-β-Vetivone ((−)-3a), one of the main constituents of vetiver oil, was submitted to a structure/odor relationship study. The influence of the Me groups at the cyclohexenone ring and of the configuration on the odor was examined. Detailed 1H- and 13C-NMR-spectroscopic data were collected, and the absolute configurations were determined by CD methods.

Khusimone (1), one of the main odor-donating compounds of vetiver oil, is subject of the following study on structure/odor relationship. The omittance of the methano bridge of the tricyclic khusimone should lead to the bicyclic partial structure (−)-2. Unexpectedly, (−)-2 could not be obtained since epimerization favored (−)-16. The stereochemical key step of the synthesis of the hydrazulene nucleus is based on a highly diastereoselective conjugate addition to a chiral oxocyclopent-1-ene-1-carboxylate.

The synthesis of reference standards and expected in vivo metabolites of the first adenosine A3 PET radiotracer [18F]FE@SUPPY ([18F]fluoroethyl 4,6-diethyl-5-[(ethyl-sulfanyl)carbonyl]-2-phenylpyridine-3-carboxylate) was achieved by using a straightforward microwave assisted alkylation method, which allowed O/S-chemoselective alkylation of the starting material 1 to give each target compound 2–8 in a single step.

Khusimone (1), one of the main odor-donating compounds of vetiver oil, is subject of the following study on structure/odor relationship. Ring opening of the carbonyl-functionalized bridge of the tricyclic khusimone leads to the bicyclic structures 2a/b. The enantioselective approach to these degraded structures is described, and the olfactory consequences are studied. Starting point of the synthesis is an enantiomerically pure enone ester which is easily obtainable from camphorsulfonic acid.

A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behavior were investigated.

In continuation of studying structure/activity relationships of odorous compounds, the influence of the bridgehead-bonded Me group of (+)-norpatchoulenol (1) and (−)-patchoulol (2) and the olfactory properties of the corresponding unsaturated and saturated derivatives (±)−3, (±)−4 and (±)−5, (±)−6, respectively, are studied. The key odour descriptors-wood, earth, and camphor-are used for classification.

Ausgehend von den entspr: Aminen werden neue, potentiell fungizide Norbomylharnstoffe hergestellt. Es sind dies Derivate der Tricyclo[5.2.1.02,6]decan-, Isocamphenilan-, Camphenilan-, exo- und endo-Dimethylnorbornan- und der Bicyclo[2.2.2]octanreihe. Mit Ausnahme der erstgenannten Verbindungen tragen alle anderen neuen Substanzen die wegen ihres Schirmeffektes bedeutsame, geminale Dimethylgruppe am C-3 des Bicyclus. Einige Harnstoffe, vor allem 6 und das Acetamid 5 erwiesen sich gegenuber phytopathogenen Pilzen als wirksam. Syntheses in the Isocamphane Series, XXXIII: The Synthesis of Norbornane Derivatives with Fungicidal Activity Starting from the corresponding amines the syntheses of various norbornyl ureas with potential fungicidal activity are described. These new compounds possess a tricyclo[5.2.1.02,6]decane, or an isocamphenilane, a camphenilane, an exo- and endo- dimethylnorbornane or a bicyclo[2.2.2]octane carbon skeleton. With the exception of the first class all other derivatives bear a geminal dimethyl group - important because of its shielding effect - at C-3 of the bicyclus. Some ureas, especially 6 and the acetamide 5, are active against phytopathogenic fungi.

Two series of azanaphthoquinone annelated pyrrolo oximes have been synthesized. The antiproliferative activities of 10 compounds were evaluated on at least four different cell lines. One series of pyrrolo derivatives showed high cytotoxic activity. The effects on cell cycle and caspase activity were investigated. Compounds 9a and 9b showed an accumulation of cells in G2/M phase. Substantial and dose-dependent caspase activity was found after treatment of cells with 9a and 9b. This indicates an apoptosis inducing property of these compounds.

Im Zuge der Untersuchungen an Herzklappentransplantaten1) bestimmten wir die Glutaraldehyd-Freisetzung mit dem Hydrazin 1 als Reagens2).

Herzklappentransplantate aus Kalberperikard erleiden im Laufe der Zeit Schaden durch Mineralisation. Diese Schaden und mogliche toxische Nebenwirkungen konnen eventuell auf Glutaraldehydruckstande, die aus der notwendigen Vorbehandlung stammen, verursacht werden. Unterschiedliche Waschmethoden, die vor der Transplantation durchgefuhrt werden, wurden hinsichtlich ihrer Fahigkeit, Glutaraldehyd zu entfernen, untersucht. Glutaraldehyde Residues in Bioprosthetic Heart Valves Bioprosthetic heart valves prepared from glutaraldehyde-pretreated bovine pericardium are used to replace diseased human cardiac valves. Mineralisation in the course of time and toxic effects are possibly caused by glutaraldehyde residues. Different washing methods carried out before transplantation are compared with regard to the different ability of glutaraldehyde extraction.

A New Approach to Bicyclo[4.1.0]heptane Derivatives The reaction of the dienone 1 with ethyl α-bromoacetate does not furnish the expected glycidic acid ester 2 but leads to the bicyclo[4.1.0]heptenone derivative 3. The structure of this new compound has been proved by means of spectroscopic methods (1R, 1H-NMR, 13C-NMR, MS). The elucidation of the configuration at C(7) could be realized by measuring a NOE effect. Other α-alkylated α-bromoacetates react with 1 in the same manner.

The title compound 2 is easily available in good yields by selective reduction of oxime 1 with TiCl4/NaBH4 or Na0/n-C3H7OH. The selectivities of numerous reduction methods are compared.

Structure-Activity Relationships of Odorants with a Bicyclo[2.2.2]octane System The synthesis of the olfactory interesting homonojigikualcohol 2 and of its epimer 10 leads to the keto alcohols 6a, b and 7a, b as intermediates. The latter have OH and CO groups (an AH/B system) fixed at the rigid bicyclic nucleus at different distances (2.8 and 4.7 A) and confirm Ohloff's rule for odoriferous properties which is based on this distance.