16 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. 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 [
- Published
- 2019
4. 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
- Author
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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.
- Published
- 2019
5. Reduced 18F-Folate Conjugates as a New Class of PET Tracers for Folate Receptor Imaging
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Roger Schibli, Silvan D. Boss, Raffaella M. Schmid, Cristina Müller, Josephine I. Büchel, Klaudia Siwowska, Viola Groehn, and Simon M. Ametamey
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0301 basic medicine ,Pharmacology ,Sodium ,Organic Chemistry ,Radiochemistry ,Biomedical Engineering ,Pharmaceutical Science ,chemistry.chemical_element ,Kidney metabolism ,Bioengineering ,Stereoisomerism ,Biological activity ,Conjugated system ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Folate receptor ,030220 oncology & carcinogenesis ,Pet tracer ,Biotechnology ,Conjugate - Abstract
5-Methyltetrahydrofolate (5-MTHF), a reduced folate form, is the biologically active folate involved in many different metabolic processes. To date, there are no studies available in the literature on 18F-labeled 6S- and 6R-5-MTHF radiotracers for imaging folate receptor (FR)-α-positive tissues. Therefore, the goal of this study was to synthesize four 18F-labeled 5-MTHF derivatives conjugated at either the α- or γ-carboxylic functionality of glutamate and to assess their suitability for FR-targeting. Organic syntheses of the precursors and the four reference compounds, namely, 6S-α, 6S-γ, 6R-α, and 6R-γ-click-fluoroethyl-5-MTHF, were carried out in low to moderate overall chemical yields. The radiosyntheses of the α- and γ-conjugated 18F-labeled folate derivatives were accomplished in approximately 100 min, low radiochemical yields (1–7% d.c.) and high molar activities (139–245 GBq/μmol). Radiochemically pure tracers were obtained after the addition of a mixture of antioxidants consisting of sodium ascorb...
- Published
- 2018
6. 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
7. Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor
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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
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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
8. Studies toward the Development of New Silicon-Containing Building Blocks for the Direct 18F-Labeling of Peptides
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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
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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.
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- 2013
9. Design, Synthesis, and Initial Evaluation of a High Affinity Positron Emission Tomography Probe for Imaging Matrix Metalloproteinases 2 and 9
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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
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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
10. 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
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Roger Schibli, Linjing Mu, W. Bernd Schweizer, Simon M. Ametamey, Stefanie-Dorothea Krämer, Selena Milicevic Sephton, University of Zurich, and Ametamey, Simon M
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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.
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- 2012
11. 4-[18F]Fluoroglutamic Acid (BAY 85-8050), a New Amino Acid Radiotracer for PET Imaging of Tumors: Synthesis and in Vitro Characterization
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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
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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
12. 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)
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Simon M. Ametamey, Cindy A Baumann, Pius A. Schubiger, Linjing Mu, Sinja Johannsen, and Michael Honer
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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
13. Direct One-Step18F-Labeling of Peptides via Nucleophilic Aromatic Substitution
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Dietmar Berndorff, Linjing Mu, Timo Stellfeld, Ludger Dinkelborg, Sandra Borkowski, Beate Koksch, Becaud Jessica, Mylène Karramkam, Ananth Srinivasan, P. A. Schubiger, René Smits, Lutz Lehmann, Simon M. Ametamey, and Keith Graham
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Pharmacology ,chemistry.chemical_classification ,Fluorine Radioisotopes ,Molecular Structure ,Stereochemistry ,Biomolecule ,Organic Chemistry ,Biomedical Engineering ,Leaving group ,Pharmaceutical Science ,Stereoisomerism ,Bioengineering ,Ring (chemistry) ,Trimethyl Ammonium Compounds ,chemistry ,Nucleophile ,Nucleophilic aromatic substitution ,Benzene Derivatives ,Molecule ,Peptides ,Biotechnology - Abstract
Methods for the radiolabeling molecules of interest with [18F]-fluoride need to be rapid, convenient, and efficient. Numerous [18F]-labeled prosthetic groups, e.g., N-succinimidyl 4 [18F]-fluorobenzoate ([18F]-SFB), 4-azidophenacyl-[18F]-fluoride ([18F]-APF), and 1-(3-(2-[18F]fluoropyridin-3-yloxy)propyl)pyrrole-2,5-dione ([18F]-FpyMe), for conjugating to biomolecules have been developed. As the synthesis of these prosthetic groups usually requires multistep procedures, there is still a need for direct methods for the nucleophilic [18F]-fluorination of biomolecules. We report here on the development of a procedure based on the trimethylammonium (TMA) leaving group attached to an aromatic ring and activated with different electron-withdrawing groups (EWGs). A series of model compounds containing different electron-withdrawing substituents, a trimethylammonium leaving group, and carboxylic functionality for subsequent coupling to peptides were designed and synthesized. The optimal model compound, 2-cyano-4-(methoxycarbonyl)-N,N,N-trimethylbenzenaminium trifluoromethanesulfonate, was converted to carboxylic acid and coupled to peptides. The results of the one-step [18F]-fluorination of tetrapeptides and bombesin peptides show that the direct 18F-labeling of peptides is feasible under mild conditions and in good radiochemical yields.
- Published
- 2009
14. Fluorine-18 Click Radiosynthesis and Preclinical Evaluation of a New 18F-Labeled Folic Acid Derivative
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P. August Schubiger, Roger Schibli, Michael Honer, Thomas L. Mindt, Tobias L. Ross, Simon M. Ametamey, Phoebe Y.H. Lam, and Viola Groehn
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Male ,Fluorine Radioisotopes ,Biodistribution ,Drug Evaluation, Preclinical ,Biomedical Engineering ,Pharmaceutical Science ,Folic Acid Derivative ,Receptors, Cell Surface ,Bioengineering ,KB Cells ,Substrate Specificity ,Mice ,Folic Acid ,In vivo ,medicine ,Animals ,Humans ,Tissue Distribution ,Pharmacology ,Radiochemistry ,Staining and Labeling ,medicine.diagnostic_test ,Chemistry ,Folate Receptors, GPI-Anchored ,Organic Chemistry ,Radiosynthesis ,Stereoisomerism ,Molecular biology ,In vitro ,Biochemistry ,Positron emission tomography ,Folate receptor ,Positron-Emission Tomography ,Microsomes, Liver ,Radiopharmaceuticals ,Carrier Proteins ,Ex vivo ,Biotechnology - Abstract
The folate receptor (FR) is highly expressed on most epithelial cancer cells, while normal cells show only restricted expression of FR. As a result, the FR is an ideal target for receptor-based molecular imaging and therapy of cancer and has become a promising target in oncology. To date, several folate-based chemotherapeutics and imaging probes such as radiopharmaceuticals for single photon emission computed tomography (SPECT) have been developed. However, an (18)F-labeled folic acid derivative suitable for positron emission tomography (PET) imaging that can be routinely applied is still lacking. In this study, a new fluorinated and radiofluorinated folic acid derivative, (18/19)F-click folate, was synthesized using click chemistry. In a convenient and very efficient two-step radiosynthesis, the isolated (18)F-click folate was obtained in good radiochemical yields of 25-35% with a specific activity of 160+/-70 GBq/micromol after
- Published
- 2008
15. Molecular Imaging with PET
- Author
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Simon M. Ametamey, Michael Honer, and Pius A. Schubiger
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Central Nervous System ,Radioisotopes ,Chemistry ,Positron-Emission Tomography ,MEDLINE ,Animals ,Humans ,Molecular Probe Techniques ,General Chemistry ,Computational biology ,Molecular imaging ,Preclinical imaging - Published
- 2008
16. Molecular Imaging with PET
- Author
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Simon M. Ametamey
- Subjects
General Chemistry - Published
- 2008
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