35 results on '"Karem Shanab"'
Search Results
2. A One-Step Microwave-Assisted Synthetic Method for an O/S-Chemoselective Route to Derivatives of the First Adenosine A3 PET Radiotracer
- Author
-
Karem Shanab, Catharina Neudorfer, Wolfgang Holzer, Markus Mitterhauser, Wolfgang Wadsak, and Helmut Spreitzer
- Subjects
chemoselective ,alkylation ,microwave ,adenosine A3 ,PET ,radiotracer ,Organic chemistry ,QD241-441 - Abstract
The synthesis of reference standards and expected in vivo metabolites of the first adenosine A3 PET radiotracer [18F]FE@SUPPY ([18F]fluoroethyl 4,6-diethyl-5-[(ethyl-sulfanyl)carbonyl]-2-phenylpyridine-3-carboxylate) was achieved by using a straightforward microwave assisted alkylation method, which allowed O/S-chemoselective alkylation of the starting material 1 to give each target compound 2–8 in a single step.
- Published
- 2014
- Full Text
- View/download PDF
3. Syntheses of Precursors and Reference Compounds of the Melanin-Concentrating Hormone Receptor 1 (MCHR1) Tracers [11C]SNAP-7941 and [18F]FE@SNAP for Positron Emission Tomography
- Author
-
Cécile Philippe, Wolfgang Wadsak, Catharina Neudorfer, Markus Mitterhauser, Karem Shanab, Barbara Datterl, Eva Schirmer, and Helmut Spreitzer
- Subjects
MCH receptor 1 (MCHR1) ,SNAP-7941 ,racSNAP-7941 ,positron emission tomography ,adiposity ,Organic chemistry ,QD241-441 - Abstract
The MCH receptor has been revealed as a target of great interest in positron emission tomography imaging. The receptor′s eponymous substrate melanin-concentrating hormone (MCH) is a cyclic peptide hormone, which is located predominantly in the hypothalamus with a major influence on energy and weight regulation as well as water balance and memory. Therefore, it is thought to play an important role in the pathophysiology of adiposity, which is nowadays a big issue worldwide. Based on the selective and high-affinity MCH receptor 1 antagonist SNAP-7941, a series of novel SNAP derivatives has been developed to provide different precursors and reference compounds for the radiosyntheses of the novel PET radiotracers [11C]SNAP-7941 and [18F]FE@SNAP. Positron emission tomography promotes a better understanding of physiologic parameters on a molecular level, thus giving a deeper insight into MCHR1 related processes as adiposity.
- Published
- 2013
- Full Text
- View/download PDF
4. 1-(3-Amino-1-phenylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one
- Author
-
Catharina Neudorfer, Nadine Eberherr, Karem Shanab, Wolfgang Holzer, Christina Rami-Mark, Markus Mitterhauser, Wolfgang Wadsak, and Helmut Spreitzer
- Subjects
NET, PET, FAPPI ,Inorganic chemistry ,QD146-197 - Abstract
Starting from 1-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one (1) and (1-bromo-3-chloropropyl)benzene (2), the target compound 3, which represents a precursor for future radiolabeling, is prepared in a three-step synthesis.
- Published
- 2015
- Full Text
- View/download PDF
5. 2-Fluoro-N-methyl-N-{[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methyl}ethanamine
- Author
-
Catharina Neudorfer, Karem Shanab, Wolfgang Holzer, Christina Rami-Mark, Markus Mitterhauser, Wolfgang Wadsak, and Helmut Spreitzer
- Subjects
NET ,PET ,PHOXI ,Inorganic chemistry ,QD146-197 - Abstract
Starting from N-methyl-1-[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methanamine (1) target compound 2 is prepared in a mild, direct alkylation approach with 2-fluoroethyl trifluoromethanesulfonate.
- Published
- 2015
- Full Text
- View/download PDF
6. 2-Fluoro-N-methyl-N-({(3S,4S)-4-[2-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isochromen-3-yl}methyl)ethanamine
- Author
-
Catharina Neudorfer, Karem Shanab, Wolfgang Holzer, Christina Rami-Mark, Markus Mitterhauser, Wolfgang Wadsak, and Helmut Spreitzer
- Subjects
NET ,PET ,PHOXI ,Inorganic chemistry ,QD146-197 - Abstract
Starting from N-methyl-1-{(3S,4S)-4-[2-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isochromen-3-yl}methanamine (1) target compound 2 is prepared using a mild, direct alkylation approach with 2-fluoroethyl trifluoromethanesulfonate.
- Published
- 2015
- Full Text
- View/download PDF
7. Green Solvents in Organic Synthesis: An Overview II
- Author
-
Karem Shanab, Catharina Neudorfer, and Helmut Spreitzer
- Subjects
Organic Chemistry - Published
- 2016
8. Hide and seek: a comparative autoradiographic in vitro investigation of the adenosine A3 receptor
- Author
-
Friedrich Girschele, R. Höftberger, Daniela Haeusler, Karem Shanab, I. Leisser, W. Gerdenitsch, L. Grassinger, F. Fuchshuber, W. J. Hörleinsberger, Wolfgang Wadsak, Helmut Spreitzer, Michele R. Hacker, and Markus Mitterhauser
- Subjects
Pathology ,medicine.medical_specialty ,Pyridines ,Periphery ,Adenosine A3 Receptor Antagonists ,Arthritis ,Inflammation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Adenosine A3 receptor ,Receptor ,030304 developmental biology ,0303 health sciences ,MRS1523 ,business.industry ,Receptor, Adenosine A3 ,Nicotinic Acids ,Brain ,Cancer ,General Medicine ,Human brain ,medicine.disease ,Rats ,3. Good health ,Radiography ,medicine.anatomical_structure ,Radiology Nuclear Medicine and imaging ,Autoradiography ,Immunohistochemistry ,Original Article ,CNS ,medicine.symptom ,business ,FE@SUPPY ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Purpose Since the adenosine A3 receptor (A3R) is considered to be of high clinical importance in the diagnosis and treatment of ischaemic conditions (heart and brain), glaucoma, asthma, arthritis, cancer and inflammation, a suitable and selective A3R PET tracer such as [18F]FE@SUPPY would be of high clinical value for clinicians as well as patients. A3R was discovered in the late 1990s, but there is still little known regarding its distribution in the CNS and periphery. Hence, in autoradiographic experiments the distribution of A3R in human brain and rat tissues was investigated and the specific binding of the A3R antagonist FE@SUPPY and MRS1523 compared. Immunohistochemical staining (IHC) experiments were also performed to validate the autoradiographic findings. Methods For autoradiographic competition experiments human post-mortem brain and rat tissues were incubated with [125I]AB-MECA and highly selective compounds to block the other adenosine receptor subtypes. Additionally, IHC was performed with an A3 antibody. Results Specific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0 % and 46.4 %), lung (44.5 % and 45.0 %), heart (39.9 % and 42.9 %) and testes (27.4 % and 29.5 %, respectively). Low amounts of A3R were found in rat brain tissues (5.9 % and 5.6 %, respectively) and human brain tissues (thalamus 8.0 % and 9.1 %, putamen 7.8 % and 8.2 %, cerebellum 6.0 % and 7.8 %, hippocampus 5.7 % and 5.6 %, caudate nucleus 4.9 % and 6.4 %, cortex 4.9 % and 6.3 %, respectively). The outcome of the A3 antibody staining experiments complemented the results of the autoradiographic experiments. Conclusion The presence of A3R protein was verified in central and peripheral tissues by autoradiography and IHC. The specificity and selectivity of FE@SUPPY was confirmed by direct comparison with MRS1523, providing further evidence that [18F]FE@SUPPY may be a suitable A3 PET tracer for use in humans.
- Published
- 2015
9. Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter
- Author
-
Amir Seddik, Gerhard F. Ecker, Wolfgang Holzer, Wolfgang Wadsak, Karem Shanab, Andreas Jurik, Christina Rami-Mark, Helmut Spreitzer, Catharina Neudorfer, and Markus Mitterhauser
- Subjects
Stereochemistry ,In silico ,Pharmaceutical Science ,Ligands ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Norepinephrine (medication) ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Humans ,ADHD ,Computer Simulation ,Physical and Theoretical Chemistry ,Norepinephrine Plasma Membrane Transport Proteins ,FAPPI ,biology ,Methylamine ,Organic Chemistry ,BAT ,Transporter ,Reference Standards ,Ligand (biochemistry) ,NET ,cocaine dependence ,PET ,Monoamine neurotransmitter ,Norepinephrine transporter ,Biochemistry ,chemistry ,Chemistry (miscellaneous) ,Positron-Emission Tomography ,biology.protein ,Molecular Medicine ,Radiopharmaceuticals ,Sequence Alignment ,medicine.drug - Abstract
Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET.
- Published
- 2015
10. Development of potential selective and reversible pyrazoline based MAO-B inhibitors as MAO-B PET tracer precursors and reference substances for the early detection of Alzheimer’s disease
- Author
-
Chrysoula Vraka, Markus Mitterhauser, Veronika Schreiber, Karem Shanab, Helmut Spreitzer, Wolfgang Holzer, Catharina Neudorfer, Eva Schirmer, Carolina Neudorfer, Wolfgang Wadsak, Andreas Jurik, and Gerhard F. Ecker
- Subjects
Monoamine Oxidase Inhibitors ,Clinical Biochemistry ,Pharmaceutical Science ,Early detection ,Pyrazoline ,Pyrazoline derivatives ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Alzheimer Disease ,Drug Discovery ,Humans ,Pet tracer ,Monoamine Oxidase ,Molecular Biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Reference Standards ,Early Diagnosis ,chemistry ,Positron-Emission Tomography ,Pyrazoles ,Molecular Medicine ,Monoamine oxidase B - Abstract
Since high MAO-B levels are present in early stages of AD, the MAO-B system can be designated as an appropriate and prospective tracer target of molecular imaging biomarkers for the detection of early AD. According to the preceding investigations of Mishra et al. the aim of this work was the development of a compound library of selective and reversible MAO-B inhibitors by performing bioisosteric modifications of the core structure of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazoles. In conclusion, 13 new pyrazoline based derivatives have been prepared, which will serve as precursor substances for future radiolabeling as well as reference compounds for the investigation of increased MAO-B levels in AD.
- Published
- 2014
11. Green Solvents in Organic Synthesis: An Overview
- Author
-
Helmut Spreitzer, Catharina Neudorfer, Eva Schirmer, and Karem Shanab
- Subjects
Solvent ,chemistry.chemical_compound ,Supercritical carbon dioxide ,chemistry ,Organic Chemistry ,Ionic liquid ,Organic chemistry ,Organic synthesis - Abstract
Research concerning green solvents is focused on reducing environmental damages due to the use of toxic solvents in organic chemistry. Hence, there have been developed a lot of solvent-free processes as well as more efficient recycling protocols in the last dec- ades. Unfortunately, these approaches have their limitations. Therefore, the authors review different environmentally benign solvent al- ternatives. This report highlights reactions using water, fluorous solvents, ionic liquids, organic carbonates, supercritical carbon dioxide, as well as biosolvents instead of conventional organic solvents.
- Published
- 2013
12. Synthesis and biological evaluation of new cytotoxic indazolo[4,3-gh]isoquinolinone derivatives
- Author
-
Manochehr Shahabi, Theerachart Leepasert, Helmut Spreitzer, Wolfgang Holzer, Lars Blumenstein, Eva Schirmer, Babette Aicher, Peter Schmidt, Karem Shanab, Gilbert Müller, Jana Ruzicka, and Eckhard Günther
- Subjects
Indazoles ,Clinical Biochemistry ,Intercalation (chemistry) ,Pharmaceutical Science ,Antineoplastic Agents ,Quinolones ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Structure–activity relationship ,Cytotoxic T cell ,Lung cancer ,Molecular Biology ,Cell Proliferation ,Mitoxantrone ,Cell growth ,Chemistry ,Organic Chemistry ,DNA ,Cell cycle ,medicine.disease ,Cell culture ,S Phase Cell Cycle Checkpoints ,Molecular Medicine ,Drug Screening Assays, Antitumor ,HeLa Cells ,medicine.drug - Abstract
A series of indazolo[4,3-gh]isoquinolinones derivatives have been synthesized to decrease cardiotoxic side effects in comparison to Mitoxantrone. The antiproliferative effects of different side chains were investigated and tested on at least four different cell lines of cervix, ovarian, CNS, NSCLC (non-small-cell lung cancer) and colon carcinoma. In addition to antiproliferative activities, influence on cell cycle and intercalation behavior have been tested.
- Published
- 2013
13. ChemInform Abstract: Green Solvents in Organic Synthesis: An Overview II
- Author
-
Karem Shanab, Catharina Neudorfer, and Helmut Spreitzer
- Subjects
General Medicine - Published
- 2016
14. [18F]FE@SNAP—a specific PET tracer for melanin-concentrating hormone receptor 1 imaging?
- Author
-
Karem Shanab, Wolfgang Wadsak, Thomas Scherer, Markus Zeilinger, Clemens Fürnsinn, Helmut Spreitzer, Cécile Philippe, Daniela Haeusler, Marcus Hacker, and Markus Mitterhauser
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Biodistribution ,Pathology ,Lateral hypothalamus ,[18F]FE@SNAP ,Imaging ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Receptor ,Original Research ,MCHR1 ,business.industry ,Melanin-concentrating hormone receptor ,030104 developmental biology ,Endocrinology ,Hormone receptor ,Autoradiography ,business ,Preclinical imaging ,Ex vivo - Abstract
Background The melanin-concentrating hormone receptor 1 (MCHR1), which is highly expressed in the lateral hypothalamus, plays a key role in energy homeostasis, obesity and other endocrine diseases. Hence, there is a major interest in in vivo imaging of this receptor. A PET tracer would allow non-invasive in vivo visualization and quantification of the MCHR1. The aim of the study was the ex vivo evaluation of the MCHR1 ligand [18F]FE@SNAP as a potential PET tracer for the MCHR1. Methods [18F]FE@SNAP was injected directly into the jugular vein of awake naïve rats for ex vivo brain autoradiography, biodistribution and additional blood metabolite analysis. Blocking experiments were conducted using the unlabeled MCHR1 ligand SNAP-7941. Results A high uptake of [18F]FE@SNAP was observed in the lateral hypothalamus and the ventricular system. Both regions were significantly blocked by SNAP-7941. Biodistribution evinced the highest uptake in the kidneys, adrenals, lung and duodenum. Specific blocking with SNAP-7941 led to a significant tracer reduction in the heart and adrenals. In plasma samples, 47.73 ± 6.1 % of a hydrophilic radioactive metabolite was found 45 min after tracer injection. Conclusions Since [18F]FE@SNAP uptake was significantly blocked in the lateral hypothalamus, there is strong evidence that [18F]FE@SNAP is a highly suitable agent for specific MCHR1 imaging in the central nervous system. Additionally, this finding is supported by the specific blocking in the ventricular system, where the MCHR1 is expressed in the ependymal cells. These findings suggest that [18F]FE@SNAP could serve as a useful imaging and therapy monitoring tool for MCHR1-related pathologies.
- Published
- 2016
15. [18F]FE@SNAP—A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): Microfluidic and vessel-based approaches
- Author
-
Lukas Nics, Eva Schirmer, Karem Shanab, Markus Mitterhauser, Georgios Karanikas, Helmut Viernstein, Wolfgang Wadsak, Cécile Philippe, Rupert Lanzenberger, Milica Zdravkovic, Helmut Spreitzer, Markus Zeilinger, and Johanna Ungersboeck
- Subjects
Clinical Biochemistry ,Microfluidics ,Radioligand ,Pharmaceutical Science ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,SNAP-7941 ,Drug Discovery ,Receptor ,Molecular Biology ,030304 developmental biology ,Medicine(all) ,0303 health sciences ,MCHR1 ,Chemistry ,Organic Chemistry ,Radiosynthesis ,Snap ,Combinatorial chemistry ,Fluorine-18 ,3. Good health ,Melanin-concentrating hormone receptor ,PET ,Microfluidic ,Molecular Medicine ,Microreactor ,030217 neurology & neurosurgery - Abstract
Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [11C]SNAP-7941—the first PET-Tracer for the MCHR1, we aimed to synthesize its [18F]fluoroethylated analogue: [18F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [18F]fluoroethylation was conducted via various [18F]fluoroalkylated synthons and direct [18F]fluorination. Only the direct [18F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [18F]FE@SNAP in 44.3±2.6%.
- Published
- 2012
- Full Text
- View/download PDF
16. Radiosynthesis of [11C]SNAP-7941—the first PET-tracer for the melanin concentrating hormone receptor 1 (MCHR1)
- Author
-
Eva Schirmer, Helmut Spreitzer, Karem Shanab, Wolfgang Wadsak, Helmut Viernstein, Rupert Lanzenberger, Cécile Philippe, Georgios Karanikas, and Markus Mitterhauser
- Subjects
Quality Control ,Magnetic Resonance Spectroscopy ,Melanin-concentrating hormone ,Radioligand ,Carbon-11 ,Article ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,SNAP-7941 ,0302 clinical medicine ,Piperidines ,Humans ,Carbon Radioisotopes ,Receptors, Somatostatin ,Acetonitrile ,030304 developmental biology ,0303 health sciences ,MCHR1 ,Radiation ,integumentary system ,Chemistry ,Radiochemistry ,Radiosynthesis ,Antagonist ,Methylation ,3. Good health ,Melanin-concentrating hormone receptor ,PET ,Pyrimidines ,Biochemistry ,Positron-Emission Tomography ,030217 neurology & neurosurgery - Abstract
The melanin concentrating hormone (MCH) system is a new target to treat human disorders. Our aim was the preparation of the first PET-tracer for the MCHR1. [11C]SNAP-7941 is a carbon-11 labeled analog of the published MCHR1 antagonist SNAP-7941. The optimum reaction conditions were 2 min reaction time, ≤25 °C reaction temperature, and 2 mg/mL precursor (SNAP-acid) in acetonitrile, using [11C]CH3OTf as methylation agent. [11C]SNAP-7941 was prepared in a reliable and feasible manner with high radiochemical yields (2.9±1.6 GBq; 11.5±6.4% EOB, n=15)., Graphical Abstract Radiosynthesis of [11C]SNAP-7941. Highlights ► Synthesis of the first PET-tracer for the MCHR1 [11C]SNAP-7941. ► High radiochemical incorporation yields 2.9±1.6 GBq; 11.5±6.4% EOB. ► Preparation and characterization of a suitable labeling precursor; SNAP-acid.
- Published
- 2012
- Full Text
- View/download PDF
17. Microfluidic preparation of [18F]FE@SUPPY and [18F]FE@SUPPY:2 — comparison with conventional radiosyntheses
- Author
-
Daniela Haeusler, Robert Dudczak, Cécile Philippe, Markus Mitterhauser, Bernhard K. Keppler, Karem Shanab, L.K. Mien, Helmut Spreitzer, Wolfgang Wadsak, Rupert Lanzenberger, Kurt Kletter, and Johanna Ungersboeck
- Subjects
Reaction conditions ,Fluorine Radioisotopes ,Cancer Research ,Radiochemistry ,Microfluidics ,Nicotinic Acids ,Analytical chemistry ,Microfluidic Analytical Techniques ,A3 ADENOSINE RECEPTOR ,Volumetric flow rate ,chemistry.chemical_compound ,Adenosine a ,chemistry ,Nucleophilic substitution ,Molecular Medicine ,Radiology, Nuclear Medicine and imaging ,Chromatography, Thin Layer ,Fluoride ,Fluoroethyl - Abstract
Introduction Recently, first applications of microfluidic principles for radiosyntheses of positron emission tomography compounds were presented, but direct comparisons with conventional methods were still missing. Therefore, our aims were (1) the set-up of a microfluidic procedure for the preparation of the recently developed adenosine A 3 -receptor tracers [ 18 F]FE@SUPPY [5-(2-[ 18 F]fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and [ 18 F]FE@SUPPY:2 [5-ethyl-2,4-diethyl-3-((2-[ 18 F]fluoroethyl)sulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] and (2) the direct comparison of reaction conditions and radiochemical yields of the no-carrier-added nucleophilic substitution with [ 18 F]fluoride between microfluidic and conventional methods. Methods For the determination of optimal reaction conditions within an Advion NanoTek synthesizer, 5–50 μl of precursor and dried [ 18 F]fluoride solution were simultaneously pushed through the temperature-controlled reactor (26°C–180°C) with defined reactant bolus flow rates (10–50 μl/min). Radiochemical incorporation yields (RCIYs) and overall radiochemical yields for large-scale preparations were compared with data from conventional batch-mode syntheses. Results Optimal reaction parameters for the microfluidic set-up were determined as follows: 170°C, 30-μl/min pump rate per reactant (reaction overall flow rate of 60 μl/min) and 5-mg/ml precursor concentration in the reaction mixture. Applying these optimized conditions, we observed a significant increase in RCIY from 88.2% to 94.1% ( P n ≥11) for [ 18 F]FE@SUPPY and that from 42.5% to 95.5% ( P n ≥5) for [ 18 F]FE@SUPPY:2 using microfluidic instead of conventional heating. Precursor consumption was decreased from 7.5 and 10 mg to 1 mg per large-scale synthesis for both title compounds, respectively. Conclusion The direct comparison of radiosyntheses data applying a conventional method and a microfluidic approach revealed a significant increase of RCIY using the microfluidic approach.
- Published
- 2011
18. Gelation Behavior of 2H-Chromene N-Acylamino Acid Conjugates
- Author
-
Rajeev Sakhuja, Karem Shanab, Levan Khelashvili, and Alan R. Katritzky
- Subjects
chemistry.chemical_classification ,Ketone ,Aqueous solution ,Dipeptide ,Organic Chemistry ,Peptide ,Chemical synthesis ,Medicinal chemistry ,Amino acid ,Chain length ,chemistry.chemical_compound ,chemistry ,Organic chemistry ,Conjugate - Abstract
2H-Chromene-based conjugates of N-acyl-1,omega-amino acids (5, 9a-f, 14a-f) of natural amino acids (10a,b) and of dipeptide (10c) are prepared (60-97%) by N-acylbenzotriazole methodology in aqueous media at 20 degrees C. Gelation properties of the corresponding sodium salts in DMF and DMSO are generalized with respect to an increase or decrease in the chain length of the spacer.
- Published
- 2009
19. Preparation and first evaluation of [18F]FE@SUPPY: a new PET tracer for the adenosine A3 receptor
- Author
-
Robert Dudczak, Bernhard K. Keppler, Helmut Spreitzer, Leonhard-Key Mien, Wolfgang Wadsak, Rupert Lanzenberger, Karoline Sindelar, Daniela Haeusler, Helmut Viernstein, Kurt Kletter, Dagmar E. Ettlinger, Markus Mitterhauser, and Karem Shanab
- Subjects
Male ,Agonist ,Fluorine Radioisotopes ,Cancer Research ,Biodistribution ,medicine.medical_specialty ,medicine.drug_class ,Pharmacology ,Rats, Sprague-Dawley ,Internal medicine ,medicine ,Radioligand ,Animals ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Rats, Wistar ,Receptor ,Chemistry ,Receptor, Adenosine A3 ,Radiosynthesis ,Nicotinic Acids ,Adenosine A3 receptor ,Ligand (biochemistry) ,Adenosine ,Rats ,Endocrinology ,Positron-Emission Tomography ,Autoradiography ,Molecular Medicine ,Radiopharmaceuticals ,medicine.drug - Abstract
Introduction Changes of the adenosine A 3 receptor subtype (A3AR) expression have been shown in a variety of pathologies, especially neurological and affective disorders, cardiac diseases and oncological and inflammation processes. Recently, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY) was presented as a high-affinity ligand for the A3AR with good selectivity. Our aims were the development of a suitable labeling precursor, the establishment of a reliable radiosynthesis for the fluorine-18-labeled analogue [ 18 F]FE@SUPPY and a first evaluation of [ 18 F]FE@SUPPY in rats. Methods [ 18 F]FE@SUPPY was prepared in a feasible and reliable manner by radiofluorination of the corresponding tosylated precursor. Biodistribution was carried out in rats, and organs were removed and counted. Autoradiography was performed on rat brain slices in the presence or absence of 2-Cl-IB-MECA. Results Overall yields and radiochemical purity were sufficient for further preclinical and clinical applications. The uptake pattern of [ 18 F]FE@SUPPY found in rats mainly followed the described mRNA distribution pattern of the A3AR. Specific uptake in brain was demonstrated by blocking with a selective A3AR agonist. Conclusion We conclude that [ 18 F]FE@SUPPY has the potential to serve as the first positron emission tomography tracer for the A3AR.
- Published
- 2008
20. 2-Fluoro-N-methyl-N-({(3S,4S)-4-[2-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isochromen-3-yl}methyl)ethanamine
- Author
-
Wolfgang Wadsak, Christina Rami-Mark, Helmut Spreitzer, Wolfgang Holzer, Karem Shanab, Markus Mitterhauser, and Catharina Neudorfer
- Subjects
Trifluoromethyl ,Organic Chemistry ,PHOXI ,Alkylation ,Biochemistry ,lcsh:QD146-197 ,NET ,chemistry.chemical_compound ,PET ,chemistry ,lcsh:Inorganic chemistry ,Organic chemistry ,Physical and Theoretical Chemistry ,Trifluoromethanesulfonate - Abstract
Starting from N-methyl-1-{(3S,4S)-4-[2-(trifluoromethyl)phenoxy]-3,4-dihydro-1H-isochromen-3-yl}methanamine (1) target compound 2 is prepared using a mild, direct alkylation approach with 2-fluoroethyl trifluoromethanesulfonate.
- Published
- 2015
21. 1-(3-Amino-1-phenylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one
- Author
-
Wolfgang Holzer, Wolfgang Wadsak, Karem Shanab, Nadine Eberherr, Catharina Neudorfer, Markus Mitterhauser, Christina Rami-Mark, and Helmut Spreitzer
- Subjects
NET ,chemistry.chemical_compound ,PET ,FAPPI ,chemistry ,Organic Chemistry ,lcsh:Inorganic chemistry ,Physical and Theoretical Chemistry ,Benzene ,Biochemistry ,Combinatorial chemistry ,NET, PET, FAPPI ,lcsh:QD146-197 - Abstract
Starting from 1-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one (1) and (1-bromo-3-chloropropyl)benzene (2), the target compound 3, which represents a precursor for future radiolabeling, is prepared in a three-step synthesis.
- Published
- 2015
22. Synthesis and antiproliferative activity of new cytotoxic tri- and tetraazabenzo[3,2-a]fluorene-5,6-dione derivatives
- Author
-
Eva Schirmer, Theerachart Leepasert, Eckhard Günther, Wolfgang Holzer, Karem Shanab, Helmut Spreitzer, Manochehr Shahabi, Gilbert Müller, and Babette Aicher
- Subjects
Aza Compounds ,Fluorenes ,Molecular Structure ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Fluorene ,Oxime ,Biochemistry ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,chemistry ,Cell Line, Tumor ,Drug Discovery ,Benzene Derivatives ,Humans ,Molecular Medicine ,Cytotoxic T cell ,Molecular Biology ,Cell Proliferation - Abstract
A new series of substituted tri-/tetraazabenzo[3,2-a]fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least three different cell lines.
- Published
- 2013
23. A One-Step Microwave-Assisted Synthetic Method for an O/S-Chemoselective Route to Derivatives of the First Adenosine A3 PET Radiotracer
- Author
-
Markus Mitterhauser, Karem Shanab, Helmut Spreitzer, Wolfgang Holzer, Wolfgang Wadsak, and Catharina Neudorfer
- Subjects
Fluorine Radioisotopes ,microwave ,Pharmaceutical Science ,Single step ,One-Step ,Alkylation ,01 natural sciences ,Microwave assisted ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,Structure-Activity Relationship ,0302 clinical medicine ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Organic chemistry ,Humans ,adenosine A3 ,Physical and Theoretical Chemistry ,Microwaves ,Reference standards ,alkylation ,Fluoroethyl ,010405 organic chemistry ,Chemistry ,Communication ,Organic Chemistry ,Receptor, Adenosine A3 ,Nicotinic Acids ,Reference Standards ,Combinatorial chemistry ,Adenosine ,radiotracer ,0104 chemical sciences ,PET ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Molecular Medicine ,chemoselective ,medicine.drug - Abstract
The synthesis of reference standards and expected in vivo metabolites of the first adenosine A3 PET radiotracer [18F]FE@SUPPY ([18F]fluoroethyl 4,6-diethyl-5-[(ethyl-sulfanyl)carbonyl]-2-phenylpyridine-3-carboxylate) was achieved by using a straightforward microwave assisted alkylation method, which allowed O/S-chemoselective alkylation of the starting material 1 to give each target compound 2–8 in a single step.
- Published
- 2014
24. Synthesis and biological evaluation of new cytotoxic azanaphthoquinone pyrrolo-annelated derivatives
- Author
-
Gilbert Müller, Eva Wulz, Helmut Spreitzer, Karem Shanab, Eckhard Günther, Babette Aicher, Peter Schmidt, Heike Knafl, Wolfgang Holzer, and Eva Schirmer
- Subjects
Stereochemistry ,Clinical Biochemistry ,Intercalation (chemistry) ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Side chain ,Humans ,Pyrroles ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Cell Cycle ,Organic Chemistry ,Stereoisomerism ,Cell cycle ,In vitro ,Quinone ,Cell culture ,Molecular Medicine ,Drug Screening Assays, Antitumor ,HeLa Cells ,Naphthoquinones - Abstract
A series of azanaphthoquinone pyrrolo-annelated derivatives attached to basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines. The effects on cell cycle and intercalation were investigated.
- Published
- 2010
25. ChemInform Abstract: Green Solvents in Organic Synthesis: An Overview
- Author
-
Catharina Neudorfer, Eva Schirmer, Helmut Spreitzer, and Karem Shanab
- Subjects
Green chemistry ,Solvent ,chemistry.chemical_compound ,Supercritical carbon dioxide ,chemistry ,Ionic liquid ,Organic chemistry ,Organic synthesis ,General Medicine - Abstract
Research concerning green solvents is focused on reducing environmental damages due to the use of toxic solvents in organic chemistry. Hence, there have been developed a lot of solvent-free processes as well as more efficient recycling protocols in the last dec- ades. Unfortunately, these approaches have their limitations. Therefore, the authors review different environmentally benign solvent al- ternatives. This report highlights reactions using water, fluorous solvents, ionic liquids, organic carbonates, supercritical carbon dioxide, as well as biosolvents instead of conventional organic solvents.
- Published
- 2013
26. Preclinical in vitroin vivo evaluation of [(11)C]SNAP-7941 - the first PET tracer for the melanin concentrating hormone receptor 1
- Author
-
Helmut Spreitzer, Markus Zeilinger, Thomas Wanek, Wolfgang Wadsak, Lukas Nics, Karem Shanab, Helmut Viernstein, Cécile Philippe, Markus Mitterhauser, Claudia Kuntner, and Severin Mairinger
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Biodistribution ,Biology ,Pharmacology ,Rats, Sprague-Dawley ,Carboxylesterase ,Drug Stability ,Piperidines ,In vivo ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,SNAP-7941 ,Carbon Radioisotopes ,Receptors, Somatostatin ,integumentary system ,Radiosynthesis ,medicine.disease ,In vitro ,Melanin-concentrating hormone receptor ,Rats ,Endocrinology ,Pyrimidines ,Positron-Emission Tomography ,Microsomes, Liver ,Molecular Medicine ,Female ,Carboxylic Ester Hydrolases ,Hydrophobic and Hydrophilic Interactions - Abstract
Introduction Due to its involvement in a variety of pathologies (obesity, diabetes, gut inflammation and depression), the melanin concentrating hormone receptor 1 (MCHR1) is a new target for the treatment of these lifestyle diseases. We previously presented the radiosynthesis of [ 11 C]SNAP-7941, the first potential PET tracer for the MCHR1. Methods We herein present its in vitro and in vivo evaluation, including binding affinity, plasma stability, stability against liver mircrosomes and carboxylesterase, lipohilicity, biodistribution, in vivo metabolism and small-animal PET. Results [ 11 C]SNAP-7941 evinced high stability against liver microsomes, carboxylesterase and in human plasma. The first small-animal PET experiments revealed a 5 fold increased brain uptake after Pgp/BCRP inhibition. Therefore, it can be assumed that [ 11 C]SNAP-7941 is a Pgp/BCRP substrate. No metabolites were found in brain. Conclusion On the basis of these experiments with healthy rats, the suitability of [ 11 C]SNAP-7941 for the visualisation of central and peripheral MCHR1 remains speculative.
- Published
- 2013
27. [¹⁸F]FE@SNAP-A new PET tracer for the melanin concentrating hormone receptor 1 (MCHR1): microfluidic and vessel-based approaches
- Author
-
Cécile, Philippe, Johanna, Ungersboeck, Eva, Schirmer, Milica, Zdravkovic, Lukas, Nics, Markus, Zeilinger, Karem, Shanab, Rupert, Lanzenberger, Georgios, Karanikas, Helmut, Spreitzer, Helmut, Viernstein, Markus, Mitterhauser, and Wolfgang, Wadsak
- Subjects
Fluorine Radioisotopes ,MCHR1 ,Microfluidics ,Radioligand ,Article ,Fluorine-18 ,Pyrimidines ,PET ,SNAP-7941 ,Piperidines ,Microfluidic ,Positron-Emission Tomography ,Humans ,Receptors, Somatostatin - Abstract
Graphical abstract SNAP-7941 derivatives 1–4 (1: SNAP-7941; 2: [18F]FE@SNAP; 3: SNAP-acid; 4: Tos@SNAP)., Changes in the expression of the melanin concentrating hormone receptor 1 (MCHR1) are involved in a variety of pathologies, especially obesity and anxiety disorders. To monitor these pathologies in-vivo positron emission tomography (PET) is a suitable method. After the successful radiosynthesis of [11C]SNAP-7941—the first PET-Tracer for the MCHR1, we aimed to synthesize its [18F]fluoroethylated analogue: [18F]FE@SNAP. Therefore, microfluidic and vessel-based approaches were tested. [18F]fluoroethylation was conducted via various [18F]fluoroalkylated synthons and direct [18F]fluorination. Only the direct [18F]fluorination of a tosylated precursor using a flow-through microreactor was successful, affording [18F]FE@SNAP in 44.3 ± 2.6%.
- Published
- 2012
28. Synthesis and antiproliferative activity of new cytotoxic azanaphthoquinone pyrrolo-annelated derivatives: Part II
- Author
-
Rita Slanz, Wolfgang Holzer, Sigrid Lassnig, Karem Shanab, Babette Aicher, Eva Wulz, Gilbert Müller, Germana Fösleitner, Barbara Weissenbacher, Helmut Spreitzer, Eva Schirmer, Peter Schmidt, and Eckhard Günther
- Subjects
Tertiary amine ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,medicine ,Side chain ,Cytotoxic T cell ,Humans ,Pyrroles ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Mitoxantrone ,Molecular Structure ,Chemistry ,Organic Chemistry ,Quinone ,DNA Intercalation ,Molecular Medicine ,Drug Screening Assays, Antitumor ,medicine.drug ,Naphthoquinones - Abstract
A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behavior were investigated.
- Published
- 2011
29. [18F]FE@SUPPY and [18F]FE@SUPPY:2--metabolic considerations
- Author
-
Robert Dudczak, Karem Shanab, Leonhard-Key Mien, Helmut Spreitzer, Johanna Ungersboeck, Daniela Haeusler, Helmut Viernstein, Kurt Kletter, Wolfgang Wadsak, Markus Mitterhauser, Karoline Sindelar, Lukas Nics, Karl-Heinz Wagner, and Rupert Lanzenberger
- Subjects
Male ,Cancer Research ,Fluorine Radioisotopes ,Chromatography ,Radiochemistry ,Metabolite ,Analytical chemistry ,Nicotinic Acids ,Metabolism ,Adenosine A3 receptor ,High-performance liquid chromatography ,Carboxylesterase ,Rats ,chemistry.chemical_compound ,chemistry ,Drug Stability ,In vivo ,Enzymatic hydrolysis ,Positron-Emission Tomography ,Pi ,Molecular Medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Radioactive Tracers - Abstract
Introduction Recently, [ 18 F]FE@SUPPY and [ 18 F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A 3 receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A 3 receptor PET tracers. Methods In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points ( n =3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol. Results The rate of enzymatic hydrolysis by CES demonstrated Michaelis–Menten constants in a micromolar range (FE@SUPPY, 20.15 μM, and FE@SUPPY:2, 13.11 μM) and limiting velocities of 0.035 and 0.015 μM/min for FE@SUPPY and FE@SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [ 18 F]FE@SUPPY was intact compared to 33.1% of [ 18 F]FE@SUPPY:2; 30 min pi 30.3% intact [ 18 F]FE@SUPPY was found compared to 15.6% [ 18 F]FE@SUPPY:2. In brain, [ 18 F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [ 18 F]FE@SUPPY was not observed before 30 min pi Conclusion Knowing that metabolism in rats is several times faster than in human, we conclude that [ 18 F]FE@SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [ 18 F]FE@SUPPY.
- Published
- 2009
30. Dye labelling of nucleosides
- Author
-
Levan Khelashvili, Alan R. Katritzky, Judit Kovacs, and Karem Shanab
- Subjects
Pharmacology ,Magnetic Resonance Spectroscopy ,Staining and Labeling ,Organic Chemistry ,Threoninol ,Nucleosides ,Triazoles ,Biochemistry ,Amino Alcohols ,chemistry.chemical_compound ,Azobenzene ,chemistry ,Elemental analysis ,Labelling ,Drug Discovery ,Molecular Medicine ,Organic chemistry ,Butylene Glycols ,Coloring Agents ,Azo Compounds - Abstract
Dye-labelled nucleosides were obtained in 30-79% (average 45%) yields by treating N-(4-arylazobenzoyl)-1H-benzotriazoles 3a-b with appropriate nucleosides. Similarly, 3a-b afforded dye-labelled threoninol conjugates in 55-89% (average 67%) yields. All novel products were characterized by NMR and elemental analysis.
- Published
- 2009
31. ChemInform Abstract: Synthesis of in vivo Metabolites of the New Adenosine A3Receptor PET-Radiotracer [18F]FE@SUPPY
- Author
-
Leonhard-Key Mien, Karem Shanab, Wolfgang Holzer, Wolfgang Wadsak, Markus Mitterhauser, Victoria Polster, Helmut Viernstein, and Helmut Spreitzer
- Subjects
In vivo ,Stereochemistry ,Chemistry ,General Medicine ,Adenosine A3 receptor - Published
- 2008
32. Radiosynthesis of the adenosine A3 receptor ligand 5-(2-[18F]fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)- 6-phenylpyridine-5-carboxylate ([18F]FE@SUPPY)
- Author
-
K. Weber, Robert Dudczak, Helmut Spreitzer, Bernhard K. Keppler, Leonhard-Key Mien, Dagmar E. Ettlinger, Helmut Viernstein, Kurt Kletter, Daniela Haeusler, Karem Shanab, Markus Mitterhauser, Wolfgang Wadsak, B. Schmidt, and Karoline Sindelar
- Subjects
Stereochemistry ,Chemistry ,Radiosynthesis ,Adenosine A3 receptor ,Ligand (biochemistry) ,Adenosine ,chemistry.chemical_compound ,Radioligand ,medicine ,Carboxylate ,Physical and Theoretical Chemistry ,Receptor ,Fluoroethyl ,medicine.drug - Published
- 2008
33. Synthesis and biological evaluation of novel cytotoxic azanaphthoquinone annelated pyrrolo oximes
- Author
-
Karem Shanab, Peter Schmidt, Gilbert Müller, Eva Wulz, Babette Aicher, Eckhard Günther, Wolfgang Holzer, Helmut Spreitzer, and Nipawan Pongprom
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Oximes ,Cytotoxic T cell ,Humans ,Pyrroles ,Cytotoxicity ,Molecular Biology ,Caspase ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Cell Cycle ,Biological activity ,Cell cycle ,Oxime ,Cell culture ,Caspases ,biology.protein ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Mitoxantrone ,HeLa Cells ,Naphthoquinones - Abstract
Two series of azanaphthoquinone annelated pyrrolo oximes have been synthesized. The antiproliferative activities of 10 compounds were evaluated on at least four different cell lines. One series of pyrrolo derivatives showed high cytotoxic activity. The effects on cell cycle and caspase activity were investigated. Compounds 9a and 9b showed an accumulation of cells in G2/M phase. Substantial and dose-dependent caspase activity was found after treatment of cells with 9a and 9b. This indicates an apoptosis inducing property of these compounds.
- Published
- 2007
34. Synthesis of in vivo Metabolites of the New Adenosine A3 Receptor PET-Radiotracer [18F]FE@SUPPY
- Author
-
Leonhard-Key Mien, Wolfgang Wadsak, Markus Mitterhauser, Victoria Polster, Karem Shanab, Helmut Spreitzer, Wolfgang Holzer, and Helmut Viernstein
- Subjects
Pharmacology ,chemistry.chemical_compound ,Biochemistry ,In vivo ,Chemistry ,Organic Chemistry ,Pyridine ,Nuclear magnetic resonance spectroscopy ,Adenosine A3 receptor ,Analytical Chemistry - Published
- 2008
35. [18F]FE@SUPPY: a suitable PET tracer for the adenosine A3 receptor? An in vivo study in rodents
- Author
-
Helmut Spreitzer, Claudia Kuntner, Lukas Nics, Karem Shanab, Oliver Langer, Thomas Wanek, Markus Mitterhauser, Markus Zeilinger, Panagiotis Karagiannis, Wolfgang Wadsak, Markus Savli, Marcus Hacker, Rupert Lanzenberger, and Daniela Haeusler
- Subjects
Male ,Pathology ,medicine.medical_specialty ,CHO Cells ,Pharmacology ,Rats sprague dawley ,030218 nuclear medicine & medical imaging ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cricetulus ,In vivo ,Cricetinae ,Tumour marker ,Medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Tissue Distribution ,Tissue distribution ,Pet tracer ,Adenosine A3 receptor ,Efflux transporter ,Small-animal PET ,medicine.diagnostic_test ,business.industry ,Xenograft ,Receptor, Adenosine A3 ,Antagonist ,Nicotinic Acids ,General Medicine ,Neoplasms, Experimental ,3. Good health ,Rats ,Positron emission tomography ,Radiology Nuclear Medicine and imaging ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Therapy monitoring ,Original Article ,Radiopharmaceuticals ,business ,[18F]FE@SUPPY ,Protein Binding - Abstract
Purpose The adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [18F]FE@SUPPY. Methods Rats were injected with [18F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [18F]FE@SUPPY and [18F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [18F]FE@SUPPY in human and rat plasma was also evaluated. Results [18F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [18F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [18F]FE@SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [18F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [18F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [18F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [18F]FE@SUPPY was stable in human plasma. Conclusion Selective and significant tracer uptake of [18F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [18F]FE@SUPPY in “humanized animal models”. In conclusion, preclinical evaluation points to the suitability of [18F]FE@SUPPY as an A3R PET tracer in humans.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.