65 results on '"Simon M. Ametamey"'
Search Results
2. Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors
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Francesco Spinelli, Pal Pacher, Kenneth Atz, Dieter Muri, Linjing Mu, Hazem Ahmed, Adrienne Müller Herde, Christoph Ullmer, Martin Binder, Thomas Johannes Woltering, Hans Iding, Luca Gobbi, Julian Kretz, Ahmed Haider, Markus Weber, Markus Bürkler, Uwe Grether, Roger Schibli, Simon M. Ametamey, Michael Honer, Andreas Brink, Claudia Keller, Irene Knuesel, Christian Bartelmus, University of Zurich, and Ametamey, Simon M
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Male ,Fluorine Radioisotopes ,Biodistribution ,Cannabinoid receptor ,Pyridines ,medicine.medical_treatment ,610 Medicine & health ,Ligands ,Tritium ,01 natural sciences ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,03 medical and health sciences ,Drug Discovery ,Radioligand ,medicine ,Animals ,Humans ,Rats, Wistar ,Receptor ,030304 developmental biology ,0303 health sciences ,Molecular Structure ,medicine.diagnostic_test ,Chemistry ,3002 Drug Discovery ,Radiochemistry ,Brain ,10181 Clinic for Nuclear Medicine ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Spinal Cord ,Positron emission tomography ,Positron-Emission Tomography ,1313 Molecular Medicine ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,Radiopharmaceuticals ,Spleen ,Ex vivo - Abstract
Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (Ki for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]RoSMA-18-d6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]RoSMA-18-d6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]RoSMA-18-d6 is a promising CB2 PET radioligand for clinical translation.
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- 2020
3. [ 18 F]Flurpiridaz: Facile and Improved Precursor Synthesis for this Next‐Generation Cardiac Positron Emission Tomography Imaging Agent
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Ahmed Haider, Hazem Ahmed, Catherine Gebhard, Simon M. Ametamey, Roger Schibli, and Livio Gisler
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Pharmacology ,Materials science ,medicine.diagnostic_test ,Organic Chemistry ,Early detection ,Coronary flow reserve ,Biochemistry ,Imaging agent ,Myocardial perfusion imaging ,Nuclear magnetic resonance ,Positron emission tomography ,Yield (chemistry) ,Drug Discovery ,medicine ,High spatial resolution ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Cardiac positron emission tomography - Abstract
[$^{18}$ F]Flurpiridaz is a recently developed positron emission tomography tracer that is currently being investigated in phase III clinical trials to measure myocardial blood flow. The relatively long physical half-life of fluorine-18 alongside the high spatial resolution and outstanding myocardium-to-background ratio fuels its potential to be the next gold standard for the early detection of coronary artery disease. Notwithstanding the expected widespread use of [$^{18}$ F]flurpiridaz, the reported multistep synthesis of its precursor for radiofluorination involves a hazardous alkylation step using carcinogenic ethylene oxide, and a low overall chemical yield of 7 %. In this work, we have improved the overall yield more than fivefold and concurrently replaced the hazardous step. Specificity of binding of [$^{18}$ F]flurpiridaz to mitochondrial complex 1 was demonstrated by in vitro autoradiography on mouse heart tissue sections. These results thus pave the way for assessing myocardial blood flow and coronary flow reserve in mouse models of cardiovascular disease.
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- 2020
4. Structure–Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors
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Christian Bartelmus, Markus Bürkler, Uwe Grether, Christoph Ullmer, Julian Kretz, Irene Knuesel, Ahmed Haider, Roger Schibli, Luca Gobbi, Hazem Ahmed, Linjing Mu, Markus Weber, Adrienne Müller Herde, Kenneth Atz, Michael Honer, Wolfgang Guba, Claudia Keller, Simon M. Ametamey, Jürgen Fingerle, and Andreas Brink
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Male ,Fluorine Radioisotopes ,Protein Conformation ,Pyridines ,Stereochemistry ,medicine.medical_treatment ,Neuroimaging ,Ligands ,Receptor, Cannabinoid, CB2 ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Pyridine ,Cyclic AMP ,medicine ,Animals ,Humans ,Structure–activity relationship ,Rats, Wistar ,Receptor ,Radiochemistry ,Molecular Structure ,medicine.diagnostic_test ,Brain ,Rats ,Mice, Inbred C57BL ,chemistry ,Positron emission tomography ,Positron-Emission Tomography ,Hepatocytes ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,Radiopharmaceuticals ,Derivative (chemistry) - Abstract
The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [
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- 2019
5. Structure–Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-<scp>d</scp>-aspartate Receptors
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Ahmed Haider, Linjing Mu, Jasmine Varisco, Bernhard Wünsch, Claudia Keller, Adrienne Müller Herde, Stefan Gruber, Irina Iten, Hazem Ahmed, Maja Stanković, Dirk Schepmann, Roger Schibli, Rahel Wallimann, Simon M. Ametamey, and Surya Häne
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0303 health sciences ,Biodistribution ,Stereochemistry ,Ligand binding assay ,01 natural sciences ,Imaging agent ,0104 chemical sciences ,3. Good health ,Benzazepine ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,Molecular Medicine ,Structure–activity relationship ,NMDA receptor ,Receptor ,030304 developmental biology - Abstract
Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [18F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [18F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [18F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.
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- 2019
6. Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and σ1 receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity
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Marta Pujol, Francisco R. Nieto, Eva Ayet, Bernhard Wünsch, Simone Thum, Simon M. Ametamey, and Dirk Schepmann
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Pharmacology ,0303 health sciences ,Benzazepines ,010405 organic chemistry ,Stereochemistry ,Ligand ,Organic Chemistry ,Ether ,General Medicine ,01 natural sciences ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Side chain ,Moiety ,NMDA receptor ,Receptor ,Selectivity ,030304 developmental biology - Abstract
The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in β- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in β-position. This effect was attributed to the reduced basicity of β-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.
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- 2019
7. Pharmacokinetic properties of enantiomerically pure GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold
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Bernhard Wünsch, Simon M. Ametamey, Kirstin Lehmkuhl, Frederik Börgel, Fabian Galla, and Dirk Schepmann
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Stereochemistry ,Metabolite ,Clinical Biochemistry ,Glucuronidation ,Pharmaceutical Science ,Ether ,Receptors, N-Methyl-D-Aspartate ,01 natural sciences ,Analytical Chemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Glucuronides ,Piperidines ,Drug Discovery ,medicine ,Ifenprodil ,Animals ,Humans ,Rats, Wistar ,Biotransformation ,Spectroscopy ,Phenol ,010405 organic chemistry ,010401 analytical chemistry ,Stereoisomerism ,Benzazepines ,Human serum albumin ,Rats ,0104 chemical sciences ,Mice, Inbred C57BL ,chemistry ,Lipophilicity ,Microsomes, Liver ,Enantiomer ,Glucuronide ,Protein Binding ,medicine.drug - Abstract
Recently, the eutomers of highly potent GluN2B selective NMDA receptor antagonists with 3-benzazepine scaffold were identified. Herein, pharmacokinetic properties regarding lipophilicity, plasma protein binding (PPB) and metabolism are analyzed. The logD7.4 values of 1.68 for phenol 1 and 2.46 for methyl ether 2 are in a very good range for CNS agents. A very similar logD7.4 value was recorded for the prototypical GluN2B antagonist ifenprodil (logD7.4 = 1.49). The herein developed high performance affinity chromatography (HPAC) method using human serum albumin as stationary phase led to PPB of 3-benzazepines (R)-1-3 and (S)-1-3 of 76–98%. Upon incubation with mouse liver microsomes, (R)-1-3 and (S)-1-3 showed moderate to high metabolic stability. The (R)-configured eutomers turned out to be metabolically more stable than their (S)-configured distomers. During phase I metabolism of 3-benzazepines 1-3 hydroxylations at both aromatic rings, the aliphatic side chain and the seven-membered ring were observed. O-demethylation of methyl ether (S)-2 was faster than O-demethylation of its enantiomer (R)-2. In phase I biotransformation the phenol eutomer (R)-1 showed comparable stability as ifenprodil. In phase II biotransformation, glucuronidation of the phenolic (only 1) and benzylic hydroxy groups was observed. Both enantiomers formed the same type of metabolites, respectively, but in different amounts. Whereas, the benzylic hydroxy group of (R)-2 was glucuronidated preferably, predominant benzylic glucuronidation of (S)-3 was detected. Mouse liver microsomes produced the glucuronide of phenol 1 (main metabolite) in larger amounts than rat liver microsomes.
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- 2019
8. Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A-selective nuclear imaging probes
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Simon M. Ametamey, Linjing Mu, Roger Schibli, and Yingfang He
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Protein subunit ,Allosteric regulation ,Single-photon emission computed tomography ,Receptors, N-Methyl-D-Aspartate ,01 natural sciences ,Biochemistry ,030218 nuclear medicine & medical imaging ,Analytical Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Allosteric Regulation ,Drug Discovery ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Receptor ,Spectroscopy ,medicine.diagnostic_test ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Molecular Imaging ,0104 chemical sciences ,Protein Subunits ,Positron emission tomography ,Synaptic plasticity ,NMDA receptor ,Nuclear Medicine ,Molecular imaging ,Neuroscience - Abstract
N-methyl-D-aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit-selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes. In this review, recent progresses in understanding its pathophysiological role, the structure-activity relationship, and the postulated mechanisms of novel GluN2A ligands as well as status of molecular imaging probes for PET are summarized.
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- 2019
9. Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development
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Steven H. Liang, Michael A. Schafroth, Jian Rong, Ahmed Haider, Linjing Mu, Daisuke Ogasawara, Cassis Varlow, Hao Xu, Christopher J. Fowler, Neil Vasdev, Lu Hou, Jiefeng Gan, Lu Wang, Benjamin F. Cravatt, Ming-Rong Zhang, and Simon M. Ametamey
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Cannabinoid receptor ,01 natural sciences ,Article ,Amidohydrolases ,03 medical and health sciences ,Neuroimaging ,Fatty acid amide hydrolase ,Drug Discovery ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Receptors, Cannabinoid ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,Drug discovery ,Chemistry ,Brain ,Endocannabinoid system ,3. Good health ,0104 chemical sciences ,Biomarker (cell) ,Monoacylglycerol lipase ,010404 medicinal & biomolecular chemistry ,Positron emission tomography ,Positron-Emission Tomography ,Molecular Medicine ,Neuroscience ,Biomarkers ,Endocannabinoids - Abstract
The endocannabinoid system (ECS) is involved in a wide range of biological functions and is comprised of cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past two decades, significant advances towards developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.
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- 2021
10. Evaluation of 5H‐Thiazolo[3,2‐α]pyrimidin‐5‐ones as Potential GluN2A PET Tracers
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Yves Auberson, Roger Schibli, Yingfang He, Emmanuelle Briard, Shin Numao, David M. Whitehead, Linjing Mu, and Simon M. Ametamey
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Male ,Fluorine Radioisotopes ,Receptor ,Imaging agent ,Radiochemistry ,NMDA ,Defluorination ,Stereochemistry ,Allosteric regulation ,Pyrimidinones ,Tritium ,01 natural sciences ,Biochemistry ,Receptors, N-Methyl-D-Aspartate ,Madin Darby Canine Kidney Cells ,chemistry.chemical_compound ,Mice ,Dogs ,Drug Discovery ,Radioligand ,Animals ,Hydroxymethyl ,General Pharmacology, Toxicology and Pharmaceutics ,Rats, Wistar ,Pharmacology ,010405 organic chemistry ,Organic Chemistry ,Brain ,3. Good health ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Thiazoles ,chemistry ,Positron-Emission Tomography ,Microsomes, Liver ,Molecular Medicine ,NMDA receptor ,Pharmacophore ,Radiopharmaceuticals ,Preclinical imaging - Abstract
We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([18F]7b) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([3H2]15b), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A-containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1-GluN2A ligand-binding domain. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. ISSN:1860-7179 ISSN:1860-7187
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- 2020
11. A Review of Molecular Imaging of Glutamate Receptors
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János Marton, Simon M. Ametamey, Jong-Hoon Kim, and Paul Cumming
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positron emission tomography ,Pharmaceutical Science ,Glutamic Acid ,Kainate receptor ,610 Medicine & health ,AMPA receptor ,Glutamate receptors ,Positron emission tomography ,Single photon emission computed tomography ,Radioligands ,Review ,Analytical Chemistry ,single photon emission computed tomography ,lcsh:QD241-441 ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Organic chemistry ,Neurotransmitter receptor ,radioligands ,Drug Discovery ,Animals ,Humans ,Physical and Theoretical Chemistry ,030304 developmental biology ,Tomography, Emission-Computed, Single-Photon ,0303 health sciences ,Epilepsy ,Chemistry ,Metabotropic glutamate receptor 5 ,Organic Chemistry ,Glutamate receptor ,Brain ,Neurodegenerative Diseases ,Molecular Imaging ,Stroke ,Receptors, Glutamate ,Chemistry (miscellaneous) ,Metabotropic glutamate receptor ,glutamate receptors ,Schizophrenia ,Molecular Medicine ,NMDA receptor ,Neuroscience ,030217 neurology & neurosurgery ,Ionotropic effect - Abstract
Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research., Molecules, 25 (20), ISSN:1420-3049
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- 2020
12. Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists
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Julian A. Schreiber, Thomas J. Schmidt, Louisa Temme, Marina Szermerski, Guiscard Seebohm, Simon M. Ametamey, Bernhard Wünsch, Dirk Schepmann, Nathalie Strutz-Seebohm, Kirstin Lehmkuhl, and Frederik Börgel
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0301 basic medicine ,Circular dichroism ,Eudysmic ratio ,Stereochemistry ,Drug Evaluation, Preclinical ,Receptors, N-Methyl-D-Aspartate ,01 natural sciences ,Biochemistry ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Hydrogenolysis ,Drug Discovery ,Animals ,Humans ,Phenols ,General Pharmacology, Toxicology and Pharmaceutics ,Electrodes ,Chromatography, High Pressure Liquid ,Pharmacology ,010405 organic chemistry ,Circular Dichroism ,Organic Chemistry ,Stereoisomerism ,Electrochemical Techniques ,Ligand (biochemistry) ,0104 chemical sciences ,Chiral column chromatography ,030104 developmental biology ,chemistry ,Molecular Medicine ,NMDA receptor ,Enantiomer ,Excitatory Amino Acid Antagonists - Abstract
To determine the eutomers of potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists with a 3-benzazepine scaffold, 7-benzyloxy-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ols (S)-2 and (R)-2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)-2 and (R)-2 provided the enantiomeric phenols (S)-3 and (R)-3 [3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol] and methyl ethers (S)-4 and (R)-4. All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R-configured enantiomers turned out to be the eutomers in receptor binding studies and two-electrode voltage clamp experiments. The most promising ligand of this compound series is the R-configured phenol (R)-3, displaying high GluN2B affinity (Ki =30 nm), high inhibition of ion flux (IC50 =61 nm), and high cytoprotective activity (IC50 =93 nm). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.
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- 2018
13. Fluorinated GluN2B Receptor Antagonists with a 3-Benzazepine Scaffold Designed for PET Studies
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Marina Szermerski, Ahmed Haider, Thomas Betzel, Dirk Schepmann, Frederik Börgel, Bernhard Wünsch, and Simon M. Ametamey
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0301 basic medicine ,Hydrocarbons, Fluorinated ,Stereochemistry ,Receptors, N-Methyl-D-Aspartate ,01 natural sciences ,Biochemistry ,Benzazepine ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Discovery ,Ifenprodil ,Nucleophilic substitution ,Animals ,Moiety ,General Pharmacology, Toxicology and Pharmaceutics ,Binding site ,Pharmacology ,Binding Sites ,Molecular Structure ,010405 organic chemistry ,Ligand ,Organic Chemistry ,Radiosynthesis ,0104 chemical sciences ,030104 developmental biology ,chemistry ,Positron-Emission Tomography ,Molecular Medicine ,Eliprodil - Abstract
To analyze the N-methyl-d-aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B-subunit-containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1,7-diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7-position), 17 (9-position), 18a-c (1-position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18 F]14 was performed by nucleophilic substitution of the phenol 2 with 2-[18 F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18 F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981, and the non-labeled 3-benzazepine 14 were able to abolish the specific binding of [18 F]14.
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- 2018
14. Automated cGMP-compliant radiosynthesis of [18 F]-(E )-PSS232 for brain PET imaging of metabotropic glutamate receptor subtype 5
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Jun Young Park, Jeongmin Son, Mijin Yun, Joong-Hyun Chun, and Simon M. Ametamey
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0301 basic medicine ,Stereochemistry ,Dimethyl sulfoxide ,Mesylate ,Organic Chemistry ,Radiosynthesis ,Oxime ,Biochemistry ,High-performance liquid chromatography ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,In vivo ,Metabotropic glutamate receptor ,Drug Discovery ,Nucleophilic substitution ,Radiology, Nuclear Medicine and imaging ,030217 neurology & neurosurgery ,Spectroscopy ,Nuclear chemistry - Abstract
(E)-3-(Pyridin-2-yl ethynyl)cyclohex-2-enone O-(3-(2-[18 F]-fluoroethoxy)propyl) oxime ([18 F]-(E)-PSS232, [18 F]2a) is a recently developed radiotracer that can be used to visualize metabotropic glutamate receptor subtype 5 (mGlu5 ) in vivo. The mGlu5 has become an attractive therapeutic and diagnostic target owing to its role in many neuropsychiatric disorders. Several carbon-11-labeled and fluorine-18-labeled radiotracers have been developed to measure mGlu5 receptor occupancy in the human brain. The radiotracer [18 F]2a, which is used as an analogue for [11 C]ABP688 ([11 C]1) and has a longer physical half-life, is a selective radiotracer that exhibits high binding affinity for mGlu5 . Herein, we report the fully automated radiosynthesis of [18 F]2a using a commercial GE TRACERlab™ FX-FN synthesizer for routine production and distribution to nearby satellite clinics. Nucleophilic substitution of the corresponding mesylate precursor with cyclotron-produced [18 F]fluoride ion at 100°C in dimethyl sulfoxide (DMSO), followed by high-performance liquid chromatography (HPLC) purification and formulation, readily provided [18 F]2a with a radiochemical yield of 40 ± 2% (decay corrected, n = 5) at the end of synthesis. Radiochemical purity for the [18 F]-(E)-conformer was greater than 95%. Molar activity was determined to be 63.6 ± 9.6 GBq/μmol (n = 5), and the overall synthesis time was 70 minutes.
- Published
- 2017
15. Imaging the glutamate receptor subtypes—Much achieved, and still much to do
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Simon M. Ametamey and Stefan Gruber
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business.industry ,Glutamate receptor ,Pet imaging ,Biology ,030218 nuclear medicine & medical imaging ,Functional imaging ,Protein Subunits ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Receptors, Glutamate ,Positron-Emission Tomography ,Drug Discovery ,Animals ,Humans ,Molecular Medicine ,Nuclear medicine ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Functional imaging of glutamate receptors using PET imaging modality can be used to study numerous CNS disorders and also to select appropriate doses of clinically relevant glutamate-receptor-targeting candidate drugs. Great strides have been made in developing PET imaging probes for the non-invasive detection of glutamate receptors in the brain. This review highlights recent progress made towards the development of glutamatergic PET imaging agents. Focus is placed on PET imaging probes that have been labelled with either carbon-11 or fluorine-18.
- Published
- 2017
16. Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography
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Aristeidis Chiotellis, Tim Gruene, Dominik Schmid, Marco F. Taddio, Roger Schibli, Claudia Adrianna Castro Jaramillo, Stefanie D. Krämer, Simon M. Ametamey, Lukas Muskalla, Linjing Mu, and Tanja Bollmann
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chemical and pharmacologic phenomena ,Plasma protein binding ,Mice, SCID ,01 natural sciences ,Small Molecule Libraries ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,In vivo ,Positron Emission Tomography Computed Tomography ,Drug Discovery ,medicine ,Animals ,Humans ,Binding site ,030304 developmental biology ,0303 health sciences ,Binding Sites ,medicine.diagnostic_test ,Molecular Structure ,Neoplasms, Experimental ,Small molecule ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Positron emission tomography ,Biophysics ,B7-1 Antigen ,Molecular Medicine ,Lead compound ,CD80 - Abstract
The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [11C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [11C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.
- Published
- 2019
17. Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based GluN2B receptor antagonists
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Bernhard Wünsch, Marina Wagner, Dirk Schepmann, and Simon M. Ametamey
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Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,Receptors, N-Methyl-D-Aspartate ,Benzazepine ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Radioligand ,Ifenprodil ,Side chain ,Moiety ,Binding site ,Molecular Biology ,Binding Sites ,010405 organic chemistry ,Ligand ,Organic Chemistry ,Benzazepines ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Molecular Medicine - Abstract
Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11 , 12, 14 , and 15 were synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [ 3 H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol 15 ( K i = 193 nM) bearing a p -fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of 15 showing moderate σ 2 affinity ( K i = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ 1 and σ 2 receptors was rather low (K i > 100 nM).
- Published
- 2019
18. Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen-7-amines as GluN2B-selective NMDA receptor antagonists
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Raquel F. Reinoso, Simon M. Ametamey, Inés Alvarez, Bernhard Wünsch, Dirk Schepmann, and Simone Thum
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biology ,Halogenation ,Chemistry ,Stereochemistry ,Organic Chemistry ,hERG ,chemistry.chemical_element ,Chemistry Techniques, Synthetic ,Biochemistry ,Neuroprotection ,Receptors, N-Methyl-D-Aspartate ,Analytical Chemistry ,Substrate Specificity ,Norepinephrine transporter ,Drug Discovery ,biology.protein ,Fluorine ,NMDA receptor ,Radiology, Nuclear Medicine and imaging ,Amines ,Selectivity ,Receptor ,Spectroscopy ,Serotonin transporter - Abstract
Because of their neuroprotective potential, GluN2B-selective ligands are of great interest for the treatment of various neurological and neurodegenerative disorders. Fluorinated benzo[7]annulen-7-amines, capable for PET, were synthesized by combining fluorinated phenylalkylamines with differently substituted ketones. Relationships between substitution pattern and GluN2B affinity as well as selectivity towards σ1 and σ2 receptors were investigated. Two promising ligands (18a and 20c) were selected for further pharmacological evaluation. Besides a slight serotonin transporter (SERT), norepinephrine transporter (NET), and hERG affinity, they did not show interaction with other targets. Furthermore, the pKa value of a set fluorinated ligands, bearing the fluorine atom in different positions, was determined.
- Published
- 2019
19. Front Cover: Evaluation of 5 H ‐Thiazolo[3,2‐α]pyrimidin‐5‐ones as Potential GluN2A PET Tracers (ChemMedChem 24/2020)
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Simon M. Ametamey, Yingfang He, Shin Numao, David M. Whitehead, Emmanuelle Briard, Yves Auberson, Linjing Mu, and Roger Schibli
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Pharmacology ,Front cover ,Chemistry ,Organic Chemistry ,Drug Discovery ,Radiochemistry ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Pet tracer ,Biochemistry ,Imaging agent - Published
- 2020
20. Discovery of a fluorinated 4-oxo-quinoline derivative as a potential positron emission tomography radiotracer for imaging cannabinoid receptor type 2
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Markus Weber, Ahmed Haider, Simon M. Ametamey, Adrienne Müller Herde, Roger Schibli, Linjing Mu, Stefanie-Dorothea Krämer, and Roger Slavik
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Fluorine Radioisotopes ,Biodistribution ,Adamantane ,Neuroimaging ,CHO Cells ,Quinolones ,Biochemistry ,Substrate Specificity ,Receptor, Cannabinoid, CB2 ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cricetulus ,0302 clinical medicine ,Cricetinae ,Drug Discovery ,Radioligand ,Cannabinoid receptor type 2 ,Animals ,Humans ,Tissue Distribution ,Chemistry ,Radiosynthesis ,Ligand (biochemistry) ,Molecular biology ,Endocannabinoid system ,In vitro ,Rats ,030104 developmental biology ,Positron-Emission Tomography ,Quinolines ,Autoradiography ,lipids (amino acids, peptides, and proteins) ,Radiopharmaceuticals ,Spleen ,030217 neurology & neurosurgery ,Ex vivo ,Nuclear chemistry - Abstract
The cannabinoid receptor type 2 (CB2) is part of the endocannabinoid system and has gained growing attention in recent years because of its important role in neuroinflammatory/neurodegenerative diseases. Recently, we reported on a carbon-11 labeled 4-oxo-quinoline derivative, designated RS-016, as a promising radiotracer for imaging CB2 using PET. In this study, three novel fluorinated analogs of RS-016 were designed, synthesized, and pharmacologically evaluated. The results of our efforts led to the identification of N-(1-adamantyl)-1-(2-(2-fluoroethoxy)ethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-126) as the most potent candidate for evaluation as a CB2 PET ligand. [(18) F]RS-126 was obtained in ≥ 99% radiochemical purity with an average specific radioactivity of 98 GBq/μmol at the end of the radiosynthesis. [(18) F]RS-126 showed a logD7.4 value of 1.99 and is stable in vitro in rat and human plasma over 120 min, whereas 55% intact parent compound was found in vivo in rat blood plasma at 10 min post injection. In vitro autoradiographic studies with CB2-positive rat spleen tissue revealed high and blockable binding which was confirmed in in vivo displacement experiments with rats by dynamic PET imaging. Ex vivo biodistribution studies confirmed accumulation of [(18) F]RS-126 in rat spleen with a specificity of 79% under blocking conditions. The moderate elevated CB2 levels in LPS-treated mice brain did not permit the detection of CB2 by [(18) F]RS-126 using PET imaging. In summary, [(18) F]RS-126 demonstrated high specificity toward CB2 receptor in vitro and in vivo and is a promising radioligand for imaging CB2 receptor expression. Cannabinoid receptor type 2 (CB2) is an interesting target for PET imaging. Specific binding of [(18) F]RS-126 in CB2-positive spleen tissue (white arrow head) was confirmed in in vivo displacement experiments with rats. Time activity curve of [(18) F]RS-126 in the spleen after the addition of GW405833 (CB2 specific ligand, green) demonstrates faster radiotracer elimination (blue) compared to the tracer only (red).
- Published
- 2016
21. 64Cu- and 68Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA–Folate
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Cristina Müller, Simon M. Ametamey, Klaudia Siwowska, Roger Schibli, Renata Farkas, and Nicholas P. van der Meulen
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Nuclear imaging ,Mice, Nude ,Pharmaceutical Science ,Gallium Radioisotopes ,Acetates ,KB Cells ,030218 nuclear medicine & medical imaging ,Heterocyclic Compounds, 1-Ring ,Mice ,03 medical and health sciences ,Folic Acid ,0302 clinical medicine ,Albumins ,Drug Discovery ,Animals ,Humans ,Chelating Agents ,Radiochemistry ,Chemistry ,Albumin ,Pet imaging ,Biochemistry ,Folate receptor ,Positron-Emission Tomography ,030220 oncology & carcinogenesis ,Molecular Medicine ,Circulation time ,Radiopharmaceuticals ,Half-Life ,Conjugate - Abstract
A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with (64)Cu and (68)Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with (64)Cu and (68)Ga was carried out at room temperature within 10 min resulting in (64)Cu-rf42 and (68)Ga-rf42 with95% radiochemical purity. (64)Cu-rf42 and (68)Ga-rf42 were stable (95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of (64)Cu-rf42 and (68)Ga-rf42 was determined to be96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of (64)Cu-rf42 and (68)Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43-0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of (64)Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of (64)Cu-rf42 and (68)Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with (64)Cu-rf42 and a (64)Cu-labeled DOTA-folate conjugate (cm10) clearly proved the superiority of NODAGA for stable coordination of (64)Cu. (64)Cu-cm10 showed high liver uptake, most probably as a consequence of released (64)Cu(2+). The data reported in this study clearly proved the promising features of (64)Cu-rf42, particularly in terms of favorable tumor-to-kidney ratios. The relatively long half-life of (64)Cu (T1/2 = 12.7 h) matches well with the enhanced circulation time of the albumin-binding NODAGA-folate, allowing PET imaging at longer time points after injection than is possible when using (68)Ga (T1/2 = 68 min).
- Published
- 2016
22. Ketamine and Ceftriaxone-Induced Alterations in Glutamate Levels Do Not Impact the Specific Binding of Metabotropic Glutamate Receptor Subtype 5 Radioligand [18F]PSS232 in the Rat Brain
- Author
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Simon M. Ametamey, Adrienne Müller Herde, Yingfang He, Silvan D. Boss, Linjing Mu, and Roger Schibli
- Subjects
0301 basic medicine ,Allosteric modulator ,positron emission tomography ,ketamine ,metabotropic glutamate receptor subtype 5 ,Allosteric regulation ,lcsh:Medicine ,lcsh:RS1-441 ,Pharmaceutical Science ,glutamate ,Pharmacology ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,0302 clinical medicine ,[18F]PSS232 ,In vivo ,Drug Discovery ,medicine ,Radioligand ,Ketamine ,ABP688 ,Metabotropic glutamate receptor 5 ,Chemistry ,MMPEP ,allosteric modulators ,Positron emission tomography ,ceftriaxone ,lcsh:R ,Glutamate receptor ,allosteric modulator ,030104 developmental biology ,Metabotropic glutamate receptor ,Molecular Medicine ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Several studies showed that [11C]ABP688 binding is altered following drug-induced perturbation of glutamate levels in brains of humans, non-human primates and rats. We evaluated whether the fluorinated derivative [18F]PSS232 can be used to assess metabotropic glutamate receptor 5 (mGluR5) availability in rats after pharmacological challenge with ketamine, known to increase glutamate, or ceftriaxone, known to decrease glutamate. In vitro autoradiography was performed on rat brain slices with [18F]PSS232 to prove direct competition of the drugs for mGluR5. One group of rats were challenged with a bolus injection of either vehicle, racemic ketamine, S-ketamine or ceftriaxone followed by positron emission tomography PET imaging with [18F]PSS232. The other group received an infusion of the drugs during the PET scan. Distribution volume ratios (DVRs) were calculated using a reference tissue model. In vitro autoradiography showed no direct competition of the drugs with [18F]PSS232 for the allosteric binding site of mGluR5. DVRs of [18F]PSS232 binding in vivo did not change in any brain region neither after bolus injection nor after infusion. We conclude that [18F]PSS232 has utility for measuring mGluR5 density or occupancy of the allosteric site in vivo, but it cannot be used to measure in vivo fluctuations of glutamate levels in the rat brain., Pharmaceuticals, 11 (3), ISSN:1424-8247
- Published
- 2018
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23. Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands
- Author
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Bernhard Wünsch, Dirk Schepmann, Simon M. Ametamey, Dmitrii V. Kalinin, and Simone Thum
- Subjects
Models, Molecular ,Alkylation ,Halogenation ,Stereochemistry ,Xenopus ,chemistry.chemical_element ,Ligands ,01 natural sciences ,Biochemistry ,Receptors, N-Methyl-D-Aspartate ,chemistry.chemical_compound ,Structure-Activity Relationship ,Piperidines ,Drug Discovery ,Benzyl Compounds ,Side chain ,Moiety ,Animals ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Amines ,Butyraldehyde ,Pharmacology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Annulene ,Benzazepines ,Butylamines ,0104 chemical sciences ,Rats ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Docking (molecular) ,Positron-Emission Tomography ,Fluorine ,Molecular Medicine ,Lead compound ,Protein Binding - Abstract
The 4-benzylpiperidine moiety is a central structural element of potent N-methyl-d-aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated ω-phenylalkylamino groups. For this purpose three primary propyl- and butylamines 7 a-c and one butyraldehyde 7 d bearing a fluorine atom and an ω-phenyl moiety were prepared in 3- to 7-step syntheses. Compounds 7 a-d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4-benzylpiperidine moiety. Although benzoxazol-2-ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3-(fluoroalkyl)-substituted tetrahydro-1H-3-benzazepine (Ki =239 nm). However, high GluN2B affinity was obtained for the tetrahydro-5H-benzo[7]annulen-7-amines 12 a-c (Ki =17-30 nm). Docking studies resulted in the same binding pose for 12 a as for the lead compound Ro 25-6981. It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4-benzylpiperidine moiety with flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro-3-benzazepines and -benzo[7]annulenes retain interaction with NMDA receptors containing the GluN2B subunit.
- Published
- 2018
24. Evaluation of 4-oxo-quinoline-based CB2 PET radioligands in R6/2 chorea huntington mouse model and human ALS spinal cord tissue
- Author
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Simon M. Ametamey, Markus Margelisch, Ahmed Haider, Claudia Keller, Adrienne Müller Herde, Roger Schibli, Markus Weber, Linjing Mu, Francesco Spinelli, Boshuai Mu, University of Zurich, and Ametamey, Simon M
- Subjects
0301 basic medicine ,Fluorine Radioisotopes ,Cerebellum ,Cannabinoid receptor ,Mice, Transgenic ,610 Medicine & health ,Striatum ,Pharmacology ,Receptor, Cannabinoid, CB2 ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Dopamine receptor D2 ,Drug Discovery ,Radioligand ,Cannabinoid receptor type 2 ,medicine ,Animals ,Humans ,Rats, Wistar ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,3002 Drug Discovery ,Amyotrophic Lateral Sclerosis ,Organic Chemistry ,10181 Clinic for Nuclear Medicine ,General Medicine ,Spinal cord ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,medicine.anatomical_structure ,3004 Pharmacology ,Spinal Cord ,Positron-Emission Tomography ,Quinolines ,lipids (amino acids, peptides, and proteins) ,Radiopharmaceuticals ,030217 neurology & neurosurgery ,1605 Organic Chemistry - Abstract
The cannabinoid receptor 2 (CB2) has been implicated in a series of neurodegenerative disorders and has emerged as an interesting biological target for therapeutic as well as diagnostic purposes. In the present work, we describe an improved radiosynthetic approach to obtain the previously reported CB2-specific PET radioligand [18F]RS-126 in higher radiochemical yields and molar activities. Additionally, the study revealed that prolongation of the [18F]RS-126 fluoroalkyl side chain ultimately leads to an improved stability towards mouse liver enzymes but is accompanied by a reduction in selectivity over the cannabinoid receptor 1 (CB1). Huntington-related phenotypic changes as well as striatal D2R downregulation were confirmed for the transgenic R6/2 mouse model. CB2 upregulation in R6/2 Chorea Huntington mice was observed in hippocampus, cortex, striatum and cerebellum by qPCR, however, these results could not be confirmed at the protein level by PET imaging. Furthermore, we evaluated the utility of the newly developed [11C]RS-028, a potent [18F]RS-126 derivative with increased polarity and high selectivity over CB1 in post-mortem human ALS spinal cord and control tissue. Applying in vitro autoradiography, the translational relevance of CB2 imaging was demonstrated by the specific binding of [11C]RS-028 to post-mortem human ALS spinal cord tissue.
- Published
- 2018
25. Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor
- Author
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Christoph Ullmer, Uwe Grether, Luca Gobbi, Roger Slavik, Simon M. Ametamey, Adrienne Müller Herde, Jürgen Fingerle, Stefanie-Dorothea Krämer, Linjing Mu, and Roger Schibli
- Subjects
Male ,Biodistribution ,Cannabinoid receptor ,Pyridines ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Contrast Media ,Mice, Inbred Strains ,CHO Cells ,Pharmacology ,Receptor, Cannabinoid, CB2 ,Cricetulus ,Drug Stability ,Receptor, Cannabinoid, CB1 ,In vivo ,Drug Discovery ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Tissue Distribution ,Rats, Wistar ,Picolinic Acids ,Receptor ,Chemistry ,Imaging agent ,In vitro ,Positron-Emission Tomography ,Azetidines ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid - Abstract
As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([(11)C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. It might serve as a tool for the investigation of CB2 receptor expression levels in healthy tissues and different neuroinflammatory disorders in humans.
- Published
- 2015
26. Synthesis, radiolabeling and evaluation of novel 4-oxo-quinoline derivatives as PET tracers for imaging cannabinoid type 2 receptor
- Author
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Markus Weber, Adrienne Müller Herde, Roger Schibli, Simon M. Ametamey, Linjing Mu, Roger Slavik, Daniel Bieri, and Stefanie-Dorothea Krämer
- Subjects
Male ,Biodistribution ,Pathology ,medicine.medical_specialty ,Cannabinoid receptor ,medicine.medical_treatment ,Adamantane ,Spleen ,Quinolones ,Receptor, Cannabinoid, CB2 ,Mice ,Drug Discovery ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Tissue Distribution ,Carbon Radioisotopes ,Rats, Wistar ,Receptor ,Neuroinflammation ,Inflammation ,Pharmacology ,Molecular Structure ,Chemistry ,Organic Chemistry ,General Medicine ,Molecular biology ,Molecular Imaging ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Positron-Emission Tomography ,Lipophilicity ,Autoradiography ,Cannabinoid ,Nervous System Diseases - Abstract
Our goal is to develop a highly specific and selective PET brain tracer for imaging CB2 expression in patients with neuroinflammatory diseases. Based on our previous findings on a carbon-11 labeled 4-oxo-quinoline structure, designated KD2, further structural optimizations were performed, which led to the discovery of N-(1-adamantyl)-1-(2-ethoxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxamide (RS-016). Compared to KD2, RS-016 exhibits a higher binding affinity towards CB2 (Ki = 0.7 nM) with a selectivity over CB1 of >10,000 and lower lipophilicity (logD7.4 = 2.78). [11C]RS-016 was obtained in ≥99% radiochemical purity and up to 850 GBq/μmol specific radioactivity at the end of synthesis. In vitro autoradiography on rodent spleen tissue showed high specific binding to CB2. [11C]RS-016 was stable in vitro in rodent and human plasma over 40 min, whereas 47% intact compound was found in vivo in rat blood plasma 20 min post injection (p.i.). High specific binding to CB2 was observed in murine spleen tissues and postmortem ALS patient spinal cord tissues in vitro autoradiography, ex vivo biodistribution data confirmed the high and specific uptake of [11C]RS-016 in spleen region in rats. In vivo specificity of [11C]RS-016 could also be shown in brain by PET imaging using a murine neuroinflammation model, which has higher CB2 receptor expression level in the brain induced by lipopolysaccharide (LPS) application.
- Published
- 2015
27. Evaluation of the Radiolabeled Boronic Acid-Based FAP Inhibitor MIP-1232 for Atherosclerotic Plaque Imaging
- Author
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Simon M. Ametamey, Stefanie D. Krämer, Aristeidis Chiotellis, Romana Meletta, Roger Schibli, Adrienne Müller Herde, Zoran Rancic, Nicole Borel, Malsor Isa, University of Zurich, and Krämer, Stefanie D
- Subjects
fibroblast activation protein ,Carotid Artery Diseases ,Male ,Pathology ,boronic acid ,medicine.medical_treatment ,3003 Pharmaceutical Science ,Drug Evaluation, Preclinical ,Melanoma, Experimental ,Pharmaceutical Science ,Gene Expression ,Analytical Chemistry ,Iodine Radioisotopes ,Mice ,Fibroblast activation protein, alpha ,Drug Discovery ,Gene expression ,carotid artery plaque ,1602 Analytical Chemistry ,Chemistry ,3002 Drug Discovery ,Melanoma ,Serine Endopeptidases ,Plaque, Atherosclerotic ,Real-time polymerase chain reaction ,Chemistry (miscellaneous) ,Gelatinases ,Benzamides ,based inhibitor ,Molecular Medicine ,Immunohistochemistry ,Female ,1606 Physical and Theoretical Chemistry ,Boron Compounds ,medicine.medical_specialty ,1601 Chemistry (miscellaneous) ,10184 Institute of Veterinary Pathology ,Article ,lcsh:QD241-441 ,lcsh:Organic chemistry ,Endopeptidases ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Radionuclide Imaging ,Aged ,Messenger RNA ,Protease ,Organic Chemistry ,Membrane Proteins ,boronic acid-based inhibitor ,medicine.disease ,In vitro ,Actins ,10020 Clinic for Cardiac Surgery ,1313 Molecular Medicine ,570 Life sciences ,biology ,atherosclerosis ,Radiopharmaceuticals ,Atherosclerosis ,Fibroblast activation protein ,Carotid artery plaque ,Boronic acid-based inhibitor ,Neoplasm Transplantation ,1605 Organic Chemistry - Abstract
Research towards the non-invasive imaging of atherosclerotic plaques is of high clinical priority as early recognition of vulnerable plaques may reduce the incidence of cardiovascular events. The fibroblast activation protein alpha (FAP) was recently proposed as inflammation-induced protease involved in the process of plaque vulnerability. In this study, FAP mRNA and protein levels were investigated by quantitative polymerase chain reaction and immunohistochemistry, respectively, in human endarterectomized carotid plaques. A published boronic-acid based FAP inhibitor, MIP-1232, was synthetized and radiolabeled with iodine-125. The potential of this radiotracer to image plaques was evaluated by in vitro autoradiography with human carotid plaques. Specificity was assessed with a xenograft with high and one with low FAP level, grown in mice. Target expression analyses revealed a moderately higher protein level in atherosclerotic plaques than normal arteries correlating with plaque vulnerability. No difference in expression was determined on mRNA level. The radiotracer was successfully produced and accumulated strongly in the FAP-positive SK-Mel-187 melanoma xenograft in vitro while accumulation was negligible in an NCI-H69 xenograft with low FAP levels. Binding of the tracer to endarterectomized tissue was similar in plaques and normal arteries, hampering its use for atherosclerosis imaging., Molecules, 20 (2), ISSN:1420-3049
- Published
- 2015
28. Radioligands for positron emission tomography imaging of cannabinoid type 2 receptor
- Author
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Francesco Spinelli, Simon M. Ametamey, and Linjing Mu
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Biochemistry ,Neuroprotection ,Analytical Chemistry ,Receptor, Cannabinoid, CB2 ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Drug Discovery ,Radioligand ,Cannabinoid receptor type 2 ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Receptor ,Spectroscopy ,Neuroinflammation ,medicine.diagnostic_test ,Chemistry ,Organic Chemistry ,030104 developmental biology ,Positron emission tomography ,Positron-Emission Tomography ,Cancer research ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,Radiopharmaceuticals ,030217 neurology & neurosurgery ,Protein Binding - Abstract
The cannabinoid type 2 (CB2) receptor is an immunomodulatory receptor mainly expressed in peripheral cells and organs of the immune system. The expression level of CB2 in the central nervous system under physiological conditions is negligible, however under neuroinflammatory conditions an upregulation of CB2 protein or mRNA mainly colocalized with activated microglial cells has been reported. Consequently, CB2 agonists have been confirmed to play a role in neuroprotective and anti-inflammatory processes. A suitable positron emission tomography radioligand for imaging CB2 would provide an invaluable research tool to explore the role of CB2 receptor expression in inflammatory disorders. In this review, we provide a summary of so far published CB2 radioligands as well as their in vitro and in vivo binding characteristics.
- Published
- 2017
29. Synthesis and Preliminary Evaluation of a 2-Oxoquinoline Carboxylic Acid Derivative for PET Imaging the Cannabinoid Type 2 Receptor
- Author
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Linjing Mu, Roger Slavik, Roger Schibli, Markus Weber, Kasim Popaj, Stjepko Cermak, Stefanie-Dorothea Krämer, Adrienne Müller, Simon M. Ametamey, University of Zurich, and Mu, Linjing
- Subjects
radiolabeling ,Cannabinoid receptor ,medicine.medical_treatment ,3003 Pharmaceutical Science ,Pharmaceutical Science ,lcsh:Medicine ,lcsh:RS1-441 ,610 Medicine & health ,Pharmacology ,autoradiography ,Article ,small-animal PET ,lcsh:Pharmacy and materia medica ,In vivo ,Drug Discovery ,Cannabinoid receptor type 2 ,Medicine ,Receptor ,cannabinoid receptor type 2 ligand ,CB2 receptor ,neurodegeneration ,business.industry ,Cannabinoid receptor type 2 ligand ,Radiolabeling ,Small-animal PET ,Neurodegeneration ,lcsh:R ,10181 Clinic for Nuclear Medicine ,Ligand (biochemistry) ,medicine.disease ,In vitro ,1313 Molecular Medicine ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,business - Abstract
Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a very promising target for therapeutic approaches as well as for imaging. A promising 2-oxoquinoline derivative designated KP23 was synthesized and radiolabeled and its potential as a ligand for PET imaging the CB2 receptor was evaluated. [11C]KP23 was obtained in 10%–25% radiochemical yield (decay corrected) and 99% radiochemical purity. It showed high stability in phosphate buffer, rat and mouse plasma. In vitro autoradiography of rat and mouse spleen slices, as spleen expresses a high physiological expression of CB2 receptors, demonstrated that [11C]KP23 exhibits specific binding towards CB2. High spleen uptake of [11C]KP23 was observed in dynamic in vivo PET studies with Wistar rats. In conclusion, [11C]KP23 showed promising in vitro and in vivo characteristics. Further evaluation with diseased animal model which has higher CB2 expression levels in the brain is warranted., Pharmaceuticals, 7 (3), ISSN:1424-8247
- Published
- 2014
30. Synthesis and biological evaluation of 18F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging
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Simon M. Ametamey, Aristeidis Chiotellis, Claudia Keller, Roger Schibli, Svetlana V. Selivanova, Adrienne Müller, Stefanie-Dorothea Krämer, and Linjing Mu
- Subjects
Pharmacology ,chemistry.chemical_classification ,Tyrosine analog ,Tetrabutylammonium hydroxide ,Stereochemistry ,Organic Chemistry ,Radiosynthesis ,Tryptophan ,General Medicine ,In vitro ,Amino acid ,chemistry.chemical_compound ,Biotransformation ,chemistry ,In vivo ,Drug Discovery - Abstract
In the search for an efficient, fluorine-18 labeled amino acid based radiotracer for tumor imaging with positron emission tomography (PET), two new tryptophan analogs were synthesized and characterized in vitro and in vivo. Both are tryptophan alkyl-derivatives, namely 2-(3-[(18)F]fluoropropyl)-DL-tryptophan ([(18)F]2-FPTRP) and 5-(3-[(18)F]fluoro-propyl)-DL-tryptophan ([(18)F]5-FPTRP). Standard reference compounds and precursors were prepared by multi step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [(18)F]fluorination in 29-34% decay corrected yields with radiochemical purity over 99%. In vitro cell uptake assays showed that both compounds are substrates for amino acid transport and enter small cell lung cancer cells (NCI-H69) most probably almost exclusively via large neutral amino acids transporter(s) (LAT). Small animal PET imaging with xenograft bearing mice revealed high tumor/background ratios for [(18)F]2-FPTRP comparable to the well established tyrosine analog O-(2-[(18)F]fluroethyl)-L-tyrosine ([(18)F]FET). Radiometabolite studies showed no evidence of involvement of a biotransformation step in tumor accumulation.
- Published
- 2013
31. Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of σ2 receptors
- Author
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Svetlana V. Selivanova, Carmen Abate, Francesco Berardi, Roger Schibli, Roberto Perrone, Adrienne Müller, Stefanie-Dorothea Krämer, Simon M. Ametamey, Roberta Marottoli, and Mauro Niso
- Subjects
Pharmacology ,Pathology ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,Chemistry ,Organic Chemistry ,Radiosynthesis ,General Medicine ,Blood–brain barrier ,In vitro ,medicine.anatomical_structure ,Positron emission tomography ,In vivo ,Drug Discovery ,Lipophilicity ,medicine ,biology.protein ,Cancer research ,Receptor ,P-glycoprotein - Abstract
σ₂ Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ₂ receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal σ₂ pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ₂ profile, was developed and σ₂ specific binding for the corresponding [(18)F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [(18)F]-26 could not successfully image σ₂ receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [(18)F]-26 may still be worthy of further investigation for the imaging of σ₂ receptors in peripheral tumors devoid of P-gp overexpression.
- Published
- 2013
32. Studies toward the Development of New Silicon-Containing Building Blocks for the Direct 18F-Labeling of Peptides
- Author
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Ludger Dinkelborg, Roger Schibli, Markus Reiher, Timo Stellfeld, Carmen J. Müller, Stefanie D. Krämer, Svetlana V. Selivanova, Simon M. Ametamey, Keith Graham, Lukas O. Dialer, and Adrienne Müller
- Subjects
Male ,Fluorine Radioisotopes ,Biodistribution ,Silicon ,Mice, Nude ,chemistry.chemical_element ,Conjugated system ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Stability ,In vivo ,Drug Discovery ,Animals ,Humans ,Tissue Distribution ,chemistry.chemical_classification ,Hydrolysis ,Biomolecule ,Bombesin ,Neoplasms, Experimental ,Silanes ,Combinatorial chemistry ,Receptors, Bombesin ,chemistry ,Isotope Labeling ,Positron-Emission Tomography ,Heterografts ,Quantum Theory ,Molecular Medicine ,Radiopharmaceuticals ,Peptides ,Hydrophobic and Hydrophilic Interactions ,Linker ,Conjugate - Abstract
Silicon-containing prosthetic groups have been conjugated to peptides to allow for a single-step labeling with (18)F radioisotope. The fairly lipophilic di-tert-butylphenylsilane building block contributes unfavorably to the pharmacokinetic profile of bombesin conjugates. In this article, theoretical and experimental studies toward the development of more hydrophilic silicon-based building blocks are presented. Density functional theory calculations were used to predict the hydrolytic stability of di-tert-butylfluorosilanes 2-23 with the aim to improve the in vivo properties of (18)F-labeled silicon-containing biomolecules. As a further step toward improving the pharmacokinetic profile, hydrophilic linkers were introduced between the lipophilic di-tert-butylphenylsilane building block and the bombesin congeners. Increased tumor uptake was shown with two of these peptides in xenograft-bearing mice using positron emission tomography and biodistribution studies. The introduction of a hydrophilic linker is thus a viable approach to improve the tumor uptake of (18)F-labeled silicon-bombesin conjugates.
- Published
- 2013
33. Design, Synthesis, and Initial Evaluation of a High Affinity Positron Emission Tomography Probe for Imaging Matrix Metalloproteinases 2 and 9
- Author
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Tobias Heinrich, Roger Schibli, Bernhard Vos, P. August Schubiger, Marcus Bauser, Joachim Dr. Hütter, Adrienne Müller, Stefanie-Dorothea Krämer, Ludger Dinkelborg, Timo Stellfeld, Svetlana V. Selivanova, Jörg Meding, and Simon M. Ametamey
- Subjects
Fluorine Radioisotopes ,Gelatinases ,Stereochemistry ,Chemistry Techniques, Synthetic ,Matrix Metalloproteinase Inhibitors ,Matrix metalloproteinase ,Multimodal Imaging ,Mice ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Humans ,Gelatinase ,IC50 ,Radiochemistry ,In vitro ,Mice, Inbred C57BL ,Propanoic acid ,Matrix Metalloproteinase 9 ,chemistry ,Drug Design ,Positron-Emission Tomography ,Yield (chemistry) ,Matrix Metalloproteinase 2 ,Molecular Medicine ,Tomography, X-Ray Computed - Abstract
The activity of matrix metalloproteinases (MMPs) is elevated locally under many pathological conditions. Gelatinases MMP2 and MMP9 are of particular interest because of their implication in angiogenesis, cancer cell proliferation and metastasis, and atherosclerotic plaque rupture. The aim of this study was to identify and develop a selective gelatinase inhibitor for imaging active MMP2/MMP9 in vivo. We synthesized a series of N-sulfonylamino acid derivatives with low to high nanomolar inhibitory potencies. (R)-2-(4-(4-Fluorobenzamido)phenylsulfonamido)-3-(1H-indol-3-yl)propanoic acid (7) exhibited the best in vitro binding properties: MMP2 IC50 = 1.8 nM, MMP9 IC50 = 7.2 nM. Radiolabeling of 7 with no carrier added (18)F-radioisotope was accomplished starting from iodonium salts as precursors. The radiochemical yield strongly depended on the iodonium counteranion (ClO4(-) > Br(-) > TFA(-) > tosylate). (18)F-7 was obtained in up to 20% radiochemical yield (decay corrected), high radiochemical purity, and >90 GBq/μmol specific radioactivity. The radiolabeled compound showed excellent stability in vitro and in mice in vivo.
- Published
- 2013
34. Synthesis and biological evaluation of a new acyclic pyrimidine derivative as a probe for imaging herpes simplex virus type 1 thymidine kinase gene expression
- Author
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Andrijana Meščić, Simon M. Ametamey, Adrienne Müller, Roger Slavik, Thomas Betzel, Silvana Raić-Malić, and Stjepko Cermak
- Subjects
Gene Expression Regulation, Viral ,Pyrimidine ,Stereochemistry ,Pharmaceutical Science ,acyclic pyrimidine nucleoside analogues ,Herpesvirus 1, Human ,medicine.disease_cause ,Thymidine Kinase ,Article ,030218 nuclear medicine & medical imaging ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,HSV1-TK ,lcsh:Organic chemistry ,Nucleophile ,In vivo ,Drug Discovery ,medicine ,Humans ,PCV-like side chain ,fluorination ,radiosynthesis ,positron emission tomography (PET) ,Hydroxymethyl ,Physical and Theoretical Chemistry ,030304 developmental biology ,0303 health sciences ,Organic Chemistry ,Radiosynthesis ,3. Good health ,Herpes simplex virus ,Pyrimidines ,chemistry ,Biochemistry ,Chemistry (miscellaneous) ,Thymidine kinase ,Positron-Emission Tomography ,Molecular Medicine ,Derivative (chemistry) ,Acyclic pyrimidine nucleoside analogues ,Fluorination ,Positron emission tomography (PET) - Abstract
With the idea of finding a more selective radiotracer for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression by means of positron emission tomography (PET), a novel [18F]fluorine radiolabeled pyrimidine with 4-hydroxy-3-(hydroxymethyl)butyl side chain at N-1 (HHB-5-[18F]FEP) was prepared and evaluated as a potential PET probe. Unlabeled reference compound, HHB-5-FEP, was synthesized via a five-step reaction sequence starting from 5-(2-acetoxyethyl)-4-methoxypyrimidin-2-one. The radiosynthesis of HHB-[18F]-FEP was accomplished by nucleophilic radiofluorination of a tosylate precursor using [18F]fluoride-cryptate complex in 45% ± 4 (n = 4) radiochemical yields and high purity (>, 99%). The biological evaluation indicated the feasibility of using HHB-5-[18F]FEP as a PET radiotracer for monitoring HSV1-tk expression in vivo.
- Published
- 2013
35. Synthesis, Radiolabeling, and Biological Evaluation of 5-Hydroxy-2-[(18)F]fluoroalkyl-tryptophan Analogues as Potential PET Radiotracers for Tumor Imaging
- Author
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Adrienne Müller Herde, Claudia Keller, Roger Schibli, Simon L. Rössler, Stefanie-Dorothea Krämer, Ante Brekalo, Erika Gedeonova, Simon M. Ametamey, Linjing Mu, and Aristeidis Chiotellis
- Subjects
0301 basic medicine ,Decarboxylation ,Mice, Nude ,03 medical and health sciences ,Mice ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Tyrosine ,Radioactive Tracers ,Fluoroethyl ,chemistry.chemical_classification ,Aromatic L-amino acid decarboxylase ,Molecular Structure ,Chemistry ,Radiochemistry ,Radiosynthesis ,Tryptophan ,Neoplasms, Experimental ,Amino acid ,030104 developmental biology ,Biochemistry ,Positron-Emission Tomography ,Molecular Medicine ,Female - Abstract
Aiming at developing mechanism-based amino acid (18)F-PET tracers for tumor imaging, we synthesized two (18)F-labeled analogues of 5-hydroxy-l-[β-(11)C]tryptophan ([(11)C]5HTP) whose excellent in vivo performance in neuroendocrine tumors is mainly attributed to its decarboxylation by aromatic amino acid decarboxylase (AADC), an enzyme overexpressed in these malignancies. Reference compounds and precursors were synthesized following multistep synthetic approaches. Radiosynthesis of tracers was accomplished in good radiochemical yields (15-39%), high specific activities (45-95 GBq/μmol), and excellent radiochemical purities. In vitro cell uptake was sodium-independent and was inhibited ≥95% by 2-amino-2-norbornanecarboxylic acid (BCH) and ∼30% by arginine. PET imaging in mice revealed distinctly high tumor/background ratios for both tracers, outperforming the well-established O-(2-[(18)F]fluoroethyl)tyrosine ([(18)F]FET) tracer in a head-to-head comparison. Biological evaluation revealed that the in vivo performance is most probably independent of any interaction with AADC. Nevertheless, the excellent tumor visualization qualifies the new tracers as interesting probes for tumor imaging worthy for further investigation.
- Published
- 2016
36. Synthesis and Evaluation of Novel α-Fluorinated (E)-3-((6-Methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyl Oxime (ABP688) Derivatives as Metabotropic Glutamate Receptor Subtype 5 PET Radiotracers
- Author
-
Roger Schibli, Linjing Mu, W. Bernd Schweizer, Simon M. Ametamey, Stefanie-Dorothea Krämer, Selena Milicevic Sephton, University of Zurich, and Ametamey, Simon M
- Subjects
Fluorine Radioisotopes ,Pyridines ,Stereochemistry ,Receptor, Metabotropic Glutamate 5 ,610 Medicine & health ,Stereoisomerism ,In Vitro Techniques ,Crystallography, X-Ray ,Receptors, Metabotropic Glutamate ,Binding, Competitive ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Oximes ,Drug Discovery ,Animals ,Structure–activity relationship ,Rats, Wistar ,Metabotropic glutamate receptor 5 ,3002 Drug Discovery ,Radiosynthesis ,Brain ,10181 Clinic for Nuclear Medicine ,Keto–enol tautomerism ,Oxime ,Rats ,chemistry ,Metabotropic glutamate receptor ,1313 Molecular Medicine ,Positron-Emission Tomography ,Autoradiography ,Molecular Medicine ,Radiopharmaceuticals ,Enone - Abstract
In the search for an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5), we have prepared a series of five α-fluorinated derivatives based on the ABP688 structural manifold by application of a two-step enolization/NFSI α-fluorination method. Their binding affinities were evaluated in vitro, and the most promising candidate (Z)-16 exhibited a K(i) of 5.7 nM and a clogP value of 2.3. The synthesis of the precursor tosylate (E)-22 revealed a preference for the (E)-configurational isomer (K(i) = 31.2 nM), and successful radiosynthesis afforded (E)-[(18)F]-16 which was used as a model PET tracer to establish plasma and PBS stability. (E)-[(18)F]-16 (K(d) = 70 nM) exhibited excellent specificity for mGluR5 in autoradiographic studies on horizontal rat brain slices in vitro.
- Published
- 2012
37. Radiofluorinated histamine H3 receptor antagonist as a potential probe for in vivo PET imaging: Radiosynthesis and pharmacological evaluation
- Author
-
Michael Honer, Kathleen Isensee, Holger Stark, Svetlana V. Selivanova, Stefanie D. Krämer, Simon M. Ametamey, P. August Schubiger, and Francine Combe
- Subjects
Mesylate ,Organic Chemistry ,Clinical Biochemistry ,Radiosynthesis ,Antagonist ,Pharmaceutical Science ,Striatum ,Pharmacology ,Biochemistry ,In vitro ,chemistry.chemical_compound ,chemistry ,In vivo ,Drug Discovery ,Lipophilicity ,Molecular Medicine ,Histamine H3 receptor ,Molecular Biology - Abstract
The histamine H3 receptor (H3R) plays a role in cognition and memory processes and is implicated in different neurological disorders, including Alzheimer’s disease, schizophrenia, and narcolepsy. In vivo studies of the H3R occupancy using a radiolabeled PET tracer would be very useful for CNS drug discovery and development. We report here the radiosynthesis, in vitro and in vivo evaluation of a novel 18F-labeled high-affinity H3R antagonist 18F-ST889. The radiosynthesis was accomplished via nucleophilic substitution of the mesylate leaving group with a radiochemical yield of 8–20%, radiochemical purity >99%, and specific radioactivity >65 GBq/μmol. 18F-ST889 exhibited high in vivo stability and rather low lipophilicity (log D7.4 = 0.35 ± 0.09). In vitro autoradiography showed specific binding in H3R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with 18F-ST889 was not successful. Possible reasons are discussed.
- Published
- 2012
38. Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains
- Author
-
Tatjana Gazivoda Kraljević, Janez Plavec, Martina Petrovic, Tobias L. Ross, Damjan Makuc, Svjetlana Krištafor, Silvana Raić-Malić, and Simon M. Ametamey
- Subjects
Pyrimidine ,Nitrogen ,N-methoxymethyl protecting group ,Stereochemistry ,Pharmaceutical Science ,010402 general chemistry ,01 natural sciences ,Article ,C-6 isobutyl pyrimidine derivatives ,N-1 and N-3 regioisomers ,NOE experiments ,positron emission tomography (PET) ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Drug Discovery ,Side chain ,Molecule ,Moiety ,Hydroxymethyl ,Physical and Theoretical Chemistry ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Uracil ,Carbon ,0104 chemical sciences ,3. Good health ,Pyrimidines ,Chemistry (miscellaneous) ,Reagent ,Molecular Medicine ,Positron emission tomography (PET) ,Nucleoside - Abstract
Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH3-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET). ISSN:1420-3049
- Published
- 2011
39. 4-[18F]Fluoroglutamic Acid (BAY 85-8050), a New Amino Acid Radiotracer for PET Imaging of Tumors: Synthesis and in Vitro Characterization
- Author
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P. August Schubiger, Luiz Lehmann, Mathias Berndt, Keith Graham, Ludger Dinkelborg, O. F. Kuznetsova, V. I. Maleev, Andre Mueller, Simon M. Ametamey, Matthias Friebe, Yuri N. Belokon, Linjing Mu, Raisa Krasikova, Norman Koglin, and Olga S. Fedorova
- Subjects
chemistry.chemical_classification ,Fluorine Radioisotopes ,Anabolism ,Chemistry ,Radiosynthesis ,Glutamate receptor ,Stereoisomerism ,Pet imaging ,In vitro ,Amino acid ,Glutamine ,Glutamates ,Biochemistry ,Cell Line, Tumor ,Isotope Labeling ,Positron-Emission Tomography ,Drug Discovery ,Humans ,Molecular Medicine ,Radiopharmaceuticals ,Energy source - Abstract
There is a high demand for tumor specific PET tracers in oncology imaging. Besides glucose, certain amino acids also serve as energy sources and anabolic precursors for tumors. Therefore, (18)F-labeled amino acids are interesting probes for tumor specific PET imaging. As glutamine and glutamate play a key role in the adapted intermediary metabolism of tumors, the radiosynthesis of 4-[(18)F]fluoro l-glutamic acid (BAY 85-8050) as a new specific PET tracer was established. Cell-uptake studies revealed specific tumor cell accumulation.
- Published
- 2010
40. Radioligands for the PET Imaging of Metabotropic Glutamate Receptor Subtype 5 (mGluR5)
- Author
-
P. August Schubiger, Simon M. Ametamey, and Linjing Mu
- Subjects
Pathology ,medicine.medical_specialty ,Receptor, Metabotropic Glutamate 5 ,Biology ,Ligands ,Receptors, Metabotropic Glutamate ,mental disorders ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,G protein-coupled receptor ,Molecular Structure ,medicine.diagnostic_test ,Metabotropic glutamate receptor 5 ,Radiosynthesis ,Glutamate receptor ,Stereoisomerism ,General Medicine ,medicine.disease ,nervous system ,Schizophrenia ,Positron emission tomography ,Metabotropic glutamate receptor ,Positron-Emission Tomography ,Neuroscience - Abstract
Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCR), which activate intracellular secondary messenger systems when bound by the physiological ligand glutamate. Modulation of mGluR5s has potential for the treatment of variety of psychiatric and neurological diseases such as depression, anxiety, schizophrenia and Parkinson's disease. Positron emission tomography (PET) might offer the possibility to visualize the mGluR5 and present an interesting tool for studying this receptor-subtype under physiologic and pathologic conditions. In this review paper, emphasis is given to the radiosynthesis, in vitro and in vivo characterization of recently published mGluR5 PET tracers.
- Published
- 2010
41. Structure−Activity Relationships of Fluorinated (E)-3-((6-Methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyloxime (ABP688) Derivatives and the Discovery of a High Affinity Analogue as a Potential Candidate for Imaging Metabotropic Glutamate Recepors Subtype 5 (mGluR5) with Positron Emission Tomography (PET)
- Author
-
Simon M. Ametamey, Cindy A Baumann, Pius A. Schubiger, Linjing Mu, Sinja Johannsen, and Michael Honer
- Subjects
Male ,Models, Molecular ,Fluorine Radioisotopes ,Pyridines ,Stereochemistry ,Receptor, Metabotropic Glutamate 5 ,Stereoisomerism ,In Vitro Techniques ,Receptors, Metabotropic Glutamate ,Binding, Competitive ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Oximes ,Drug Discovery ,Animals ,Structure–activity relationship ,Chemistry ,Metabotropic glutamate receptor 5 ,Brain ,Oxime ,Rats ,Metabotropic receptor ,Biochemistry ,Metabotropic glutamate receptor ,Alkynes ,Positron-Emission Tomography ,Molecular Medicine ,Enone ,Protein Binding ,Methyl group - Abstract
The metabotropic glutamate receptor subtype 5 (mGluR5) is recognized to be involved in numerous brain disorders. In an effort to obtain a fluorine-18 labeled analogue of the mGluR5 PET tracer [(11)C]ABP688, 13 novel ligands based on the core structure of ABP688 were synthesized. Molecules in which the methyl group at the oxime functionality of ABP688 was replaced by fluorobenzonitriles, fluoropyridines, and fluorinated oxygen containing alkyl side chains were investigated. Substituents at the oxime functionality are well tolerated and resulted in five candidates with K(i) values below 10 nM. The most promising candidate, (E)-3-(pyridin-2-ylethynyl)cyclohex-2-enone-O-2-(2-fluoroethoxy)ethyloxime (38, K(i) = 3.8 nM), was radiolabeled with fluorine-18. Scatchard analysis of [(18)F]38 which modeled best for two sites pointed to high binding affinity (K(D1) = 0.61 +/- 0.19 nM and K(D2) = 13.73 +/- 4.69 nM) too. These data strongly suggest the further evaluation of [(18)F]38 as a candidate for imaging the mGluR5.
- Published
- 2010
42. Improved Syntheses of the mGlu5 Antagonists MMPEP and MTEP Using Sonogashira Cross-Coupling
- Author
-
Selena Milicevic Sephton, Linjing Mu, Boshuai Mu, Simon M. Ametamey, and Roger Schibli
- Subjects
Molecular model ,mGlu5 antagonist ,Aryl halide ,lcsh:Medicine ,lcsh:RS1-441 ,Pharmaceutical Science ,Alkyne ,Sonogashira coupling ,010402 general chemistry ,01 natural sciences ,Article ,Sonogashira cross-coupling ,MMPEP ,MTEP ,lcsh:Pharmacy and materia medica ,Drug Discovery ,chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,lcsh:R ,Combinatorial chemistry ,0104 chemical sciences ,Yield (chemistry) ,Molecular Medicine - Abstract
The Sonogashira cross-coupling, a key step in the syntheses of the mGlu5 antagonists MMPEP and MTEP, provided an improved three-step method for the preparation of MMPEP in 62% overall yield. Using Spartan molecular modeling kit an explanation for the failure to employ analogues method in the synthesis of MTEP was sought. The DFT calculations indicated that meaningful isolated yields were obtained when the HOMO energy of the aryl halide was lower than the HOMO energy of the respective alkyne., Pharmaceuticals, 11 (1), ISSN:1424-8247
- Published
- 2018
43. Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor
- Author
-
Selena Milicevic Sephton, Peter T. Vetterli, Aristeidis Chiotellis, Adrienne Müller Herde, Sylvia Roscales, Roger Schibli, Simon M. Ametamey, Yves Auberson, Valentina Pedani, and Stjepko Cermak
- Subjects
0301 basic medicine ,Protein subunit ,Organic Chemistry ,Biochemistry ,Catalysis ,Calcium in biology ,Imaging agent ,In vitro ,Inorganic Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Quinoxaline ,chemistry ,Drug Discovery ,NMDA receptor ,Acid hydrolysis ,Physical and Theoretical Chemistry ,Receptor ,030217 neurology & neurosurgery - Abstract
Due to the biological complexity of the N-methyl-d-aspartate receptor (NMDAR), the development of a positron emission tomography radiotracer for the imaging of NMDAR has met with limited success. Recent studies have established the presence of GluN2A subunit of the NMDAR in the heart and its role in the regulation of intracellular calcium levels. In our efforts to develop an imaging agent for the GluN2A subunit, we designed three new compounds based on a quinoxaline scaffold. The synthesis of the analogues was based on a two-step Kabachnik–Fields reaction in sequence with Suzuki cross-coupling and acid hydrolysis. They exhibited comparable high binding affinity values below 5 nm. A two-step radiolabeling procedure was successfully developed for the synthesis of [18F]1. [18F]1 was obtained in a modest overall radiochemical yield of 5.5 ± 4.2%, a good specific radioactivity of 254 ± 158 GBq/μmol, and a radiochemical purity > 99%. While compounds 2 and 3 showed comparable binding affinity towards NMDAR, sluggish radiolabeling, prevented their further evaluation. For [18F]1, in vitro autoradiography on rat heart slices demonstrated heterogeneous but unspecific accumulation, whereas for the brain a high in vitro specificity towards NMDAR, could be demonstrated.
- Published
- 2017
44. P08 - Miscellaneous
- Author
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M. Honer, S.R. Malic, A. Johayem, August P. Schubiger, I. Novak, Simon M. Ametamey, and Leonardo Scapozza
- Subjects
Chemistry ,Organic Chemistry ,Drug Discovery ,Gene expression ,Cancer research ,Radiology, Nuclear Medicine and imaging ,Pet imaging ,Biochemistry ,Nucleoside ,Spectroscopy ,Analytical Chemistry ,Hsv 1 tk - Published
- 2005
45. Synthesis and biological evaluation of (18)F-labeled Fluoroethoxy tryptophan analogues as potential PET tumor imaging agents
- Author
-
Roger Schibli, Simon M. Ametamey, Stefanie D. Krämer, Aristeidis Chiotellis, Claudia Keller, Linjing Mu, and Adrienne Müller
- Subjects
Fluorine Radioisotopes ,Lung Neoplasms ,Amino Acid Transport System y+ ,Stereochemistry ,Pharmaceutical Science ,Mice, Nude ,5-Hydroxytryptophan ,Mice ,Nucleophile ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Side chain ,Animals ,Humans ,Tyrosine ,Fluoroethyl ,Indole test ,Chemistry ,Radiosynthesis ,Tryptophan ,Amino Acid Transport System y+L ,Drug Design ,Positron-Emission Tomography ,Molecular Medicine ,Female ,Radiopharmaceuticals ,Neoplasm Transplantation - Abstract
As a continuation of our research efforts toward the development of tryptophan-based radiotracers for tumor imaging with positron emission tomography (PET), three new fluoroethoxy tryptophan analogues were synthesized and evaluated in vivo. These new tracers (namely, 4-(2-[(18)F]fluoroethoxy)-dl-tryptophan ([(18)F]4-FEHTP), 6-(2-[(18)F]fluoroethoxy)-dl-tryptophan ([(18)F]6-FEHTP), and 7-(2-[(18)F]fluoroethoxy)-dl-tryptophan ([(18)F]7-FEHTP) carry the fluoroethoxy side chain either at positions 4-, 6-, or 7- of the indole core. Reference compounds and precursors were synthesized by multistep approaches. Radiosynthesis was accomplished by no-carrier-added nucleophilic (18)F-fluorination following either an indirect approach (O-alkylation of the corresponding hydroxytryptophan with [(18)F]fluoroethyltosylate) or a direct approach (nucleophilic [(18)F] fluorination using a protected mesyl precursor). Radiochemical yields (decay corrected) for both methods were in the range of 10-18%. Small animal PET imaging with xenograft-bearing mice revealed the highest tumor/background ratio for [(18)F]6-FEHTP which, in a direct comparison, outperformed the other two tryptophan tracers and also the well-established tyrosine analogue O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]l-FET). Investigation of the transport mechanism of [(18)F]6-FEHTP in small cell lung cancer cells (NCI-H69) revealed that it is most probably taken up exclusively via the large neutral amino acid transporter(s) (LAT).
- Published
- 2014
46. Synthesis, radiolabelling and biological characterization of ( d )-7-iodo- N -(1-phosphonoethyl)-5-aminomethylquinoxaline-2,3-dione, a glycine-binding site antagonist of NMDA receptors
- Author
-
Nathalie Carrey-Rémy, Peter Bläuenstein, Martine Willmann, Markus Schmutz, Yves Auberson, Marco Kokic, Serge Bischoff, Simon M. Ametamey, and Pius A. Schubiger
- Subjects
Stereochemistry ,Clinical Biochemistry ,Glycine ,Organophosphonates ,Pharmaceutical Science ,Kidney ,Receptors, N-Methyl-D-Aspartate ,Biochemistry ,Substrate Specificity ,Iodine Radioisotopes ,Inhibitory Concentration 50 ,Mice ,Radioligand Assay ,Glycine binding ,In vivo ,Quinoxalines ,Drug Discovery ,Animals ,Tissue Distribution ,Binding site ,Molecular Biology ,Glycine receptor ,Mice, Inbred BALB C ,Binding Sites ,Chemistry ,Organic Chemistry ,Antagonist ,Biological activity ,Molecular Medicine ,NMDA receptor ,Anticonvulsants ,Female ,Radiopharmaceuticals - Abstract
(D)-7-Iodo-N-(1-phosphonoethyl)-5-aminomethylquinoxaline-2,3 -dione (I-PAMQX), is a potent, in vivo active antagonist acting at the glycine binding site of the NMDA receptor complex. Radioiodinated [131I]I-PAMQX was prepared with good yields and high specific activity from its 7-bromo analogue. Biodistribution studies of [131I]I-PAMQX in mice showed a relatively slow clearance from the blood. The uptake of radioactivity was highest in the kidneys, moderate in the heart, lung, liver and bones, and low in the brain.
- Published
- 2000
47. Efficient synthesis of enantiomerically pure thioester precursors of [11C]McN-5652 from racemic McN-5652
- Author
-
Bernd Johannsen, Peter Brust, P. Gucker, Joerg Steinbach, J. Zessin, Simon M. Ametamey, Pius A. Schubiger, and Franz X. Vollenweider
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Diastereomer ,Thioester ,Biochemistry ,Chemical synthesis ,Analytical Chemistry ,Chiral column chromatography ,chemistry.chemical_compound ,chemistry ,Acetyl chloride ,Sodium amide ,Drug Discovery ,Radiology, Nuclear Medicine and imaging ,Enantiomer ,Racemization ,Spectroscopy - Abstract
An improved synthesis of the anantiomerically pure thioester precursors of [11C](+)-McN-5652 ([11C](+)−1]), and [11C](−)-McN5652 ([11C](−)−1]) starting from racemic McN-5652 ((±)−1) is described. The synthetic method includes the resolution of (±)−1 by repeated crystallization of the (+)- and (−)-di-p-toluoyltartrates yielding (+)-McN-5652 ((+)−1) and (−)-McN-5652 ((−)-1), each with >98% enantiomeric purity. S-Demethylation of (±)−1, (+)−1, and (−)-1, respectively was achieved by treatment with sodium amide at low temperatures (−78°C) followed by conversion of the intermediate thiols 2 with acetyl chloride to give the corresponding thioester precursors (±)−3, (+)−3 or (−)−3. This demethylation method almost completely suppressed the isomerization of the pharmacologically active trans diastereomer into the inactive cis form. Chiral HPLC analyses confirmed that the S-demethylation proceeded without any racemization. 11C-Labelling of (+)−3 or (−)−3, yields enantiomerically pure [11C](+)-McN-5652 or [11C](−)-McN5652, each in 22% radiochemical yield (decay-corrected, related to [11C]CO2) and a specific radioactivity of 74 GBq/μmol (2 Ci/μmol) at the end of synthesis (EOS) Copyright © 1999 John Wiley & Sons, Ltd.
- Published
- 1999
48. Synthesis and11C-radiolabelling of a tropane derivative lacking the 2β ester group: a potential PET-tracer for the dopamine transporter
- Author
-
Pius A. Schubiger, Simon M. Ametamey, and Roland D. Schönbächler
- Subjects
chemistry.chemical_classification ,biology ,Bicyclic molecule ,Stereochemistry ,Organic Chemistry ,Iodide ,chemistry.chemical_element ,Tropane ,Desmethyl ,Iodine ,Biochemistry ,Medicinal chemistry ,Chemical synthesis ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,biology.protein ,Radiology, Nuclear Medicine and imaging ,Spectroscopy ,Derivative (chemistry) ,Dopamine transporter - Abstract
The synthesis and 11 C-radiolabelling of a new tropane analogue. 3β-(4'-chlorophenyl)-2β-(3'-phenylisoxazol-5'-yl)tropane (β-CPPIT), an inhibitor of the dopamine transporter, is reported. The desmethyl compound, 3β-(4'-chlorophenyl)-2β-(3'-phenylisoxazol-5'-yl)nortropane (5) was prepared via a six-step reaction sequence starting from cocaine. [ 11 C]-β-CPPIT was labelled by N-methylation using [ 11 C]-methyl iodide obtained from the gas phase reaction of [ 11 C]-methane with iodine in 60 ± 10 % radiochemical yield (decay corrected from [ 11 C]-methyl iodide). The overall synthesis time was on average 60 minutes at EOB (end of bombardment). The final product had a specific activity of 2000 - 2700 Ci/mmol (74 - 100 TBq/mmol) at EOS (end of synthesis) and the radiochemical purity was greater than 99%. [ 11 C]-β-CPPIT showed a logP value of 2.1 indicating that a free diffusion through the blood-brain-barrier should be possible.
- Published
- 1999
49. 11C-radiolabeling of hallucinogenic psilocin, a potential radioligand for studying the role of serotonin receptors in psychotic symptom formation
- Author
-
Pius A. Schubiger, J. Patt, H.-F. Beer, Franz X. Vollenweider, Simon M. Ametamey, Daniel Bourquin, and Felix Hasler
- Subjects
Indole test ,Tertiary amine ,Chemistry ,Stereochemistry ,Organic Chemistry ,Radiosynthesis ,Desmethyl ,Biochemistry ,Chemical synthesis ,Analytical Chemistry ,Psilocin ,Drug Discovery ,Radioligand ,medicine ,Radiology, Nuclear Medicine and imaging ,Spectroscopy ,5-HT receptor ,medicine.drug - Abstract
The desmethyl compound, 4-hydroxy-N-methyltryptamine (4), was synthesized via a four-step reaction sequence starting from 4-benzyloxyindole (1). Psilocin (4-hydroxy-N,N-dimethyltryptamine), an indole hallucinogen, was labeled by N-monomethylation of the side chain using the classical methylating agent [ 11 C]CH 3 I in 20±5% (decay corrected from [ 11 C]CH 3 I) radiochemical yield. Specific activities obtained ranged from 900-2300Ci/mmol at EOS (end of synthesis). The radiosynthesis, semi-preparative HPLC and formulation were completed in an average time of 45 minutes.
- Published
- 1998
50. Synthesis and preliminary in vitro evaluation of a new memantine derivative 1-amino-3-[18F]fluoromethyl-5-methyl-adamantane: A potential ligand for mapping the N-methyl-D-aspartate receptor complex
- Author
-
Samuel Samnick, Markus R. Gold, Simon M. Ametamey, and Pius A. Schubiger
- Subjects
Receptor complex ,Aqueous solution ,Stereochemistry ,Adamantane ,Organic Chemistry ,Total synthesis ,Ligand (biochemistry) ,Biochemistry ,Chemical synthesis ,Analytical Chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Lipophilicity ,Radiology, Nuclear Medicine and imaging ,Spectroscopy ,Derivative (chemistry) - Abstract
The new memantine derivative 1-amino-3-[18F]fluoromethyl-5-methyl-adamantane (18F-MEM) was prepared in a two-step reaction sequence for evaluation as a PET tracer. This involves the no-carrier-added nucleophilic radiofluorination of 1-[N-(tert-butyloxy)-carbamoyl]-3-(toluenesulfonyloxy)methyl-5-methyl-adamantane (3) with K18F/Kryptofix 2.2.2 in DMSO and the subsequent deprotection of the resulting 18F-BOC-MEM by addition of aqueous HCl. 18F-MEM was obtained after purification by reversed phase HPLC in 22±7 % radiochemical yield (decay corrected to EOB) with a radiochemical purity > 99% and a total synthesis time of 100 min. 18F-MEM is stable up to 6 h in aqueous solution at room temperature and revealed appropriate lipophilicity for good diffusion through the blood-brain-barrier. In vitro studies with the non-radioactive analog, 1-amino-3-fluoromethyl-5-methyl-adamantane (19F-MEM) indicated that this compound binds selectively to the phencyclidine (PCP) binding site within the NMDA receptor complex. © 1997 John Wiley & Sons, Ltd.
- Published
- 1997
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