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Simon M Ametamey - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Medicinal Chemistry, 2012Co-Authors: Selena Milicevic Sephton, Bernd W Schweizer, Roger Schibli, Stefaniedorothea Kramer, Simon M AmetameyAbstract: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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human pet studies of metabotropic glutamate receptor subtype 5 with 11c abp688
The Journal of Nuclear Medicine, 2007Co-Authors: Simon M Ametamey, Valerie Treyer, Johannes Streffer, Matthias T Wyss, Mark Schmidt, Milen Blagoev, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Uta FischerAbstract:3-(6-Methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime (11C-ABP688), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: Six healthy male volunteers (mean age, 25 y; range, 21–33 y) were studied. Brain perfusion (15O-H2O) was measured immediately before each 11C-ABP688 PET scan. For anatomic coregistration, T1-weighted MRI was performed on each subject. Arterial blood samples for the determination of the arterial input curve were obtained at predefined time points, and 11C-ABP688 uptake was assessed quantitatively using a 2-tissue-compartment model. Results: An initial rapid uptake of radioactivity followed by a gradual clearance from all examined brain regions was observed. Relatively high radioactivity concentrations were observed in mGluR5-rich brain regions such as the anterior cingulate, medial temporal lobe, amygdala, caudate, and putamen, whereas radioactivity uptake in the cerebellum and white matter, regions known to contain low densities of mGluR5, was low. Specific distribution volume as an outcome measure of mGluR5 density in the various brain regions ranged from 5.45 ± 1.47 (anterior cingulate) to 1.91 ± 0.32 (cerebellum), and the rank order of the corresponding specific distribution volumes of 11C-ABP688 in cortical regions was temporal > frontal > occipital > parietal. The metabolism of 11C-ABP688 in plasma was rapid; at 60 min after injection, 25% ± 0.03% of radioactivity measured in the plasma of healthy volunteers was intact parent compound. Conclusion: The results of these studies indicate that 11C-ABP688 has suitable characteristics and is a promising PET ligand for imaging mGluR5 distribution in humans. Furthermore, it could be of great value for the selection of appropriate doses of clinically relevant candidate drugs that bind to mGluR5 and for PET studies of patients with psychiatric and neurologic disorders.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: ABP688 was radiolabeled with 11C by reacting 11C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of 11C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with 11C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. Results: The overall synthesis time was 45−50 min from the end of radionuclide production. 11C-ABP688 was obtained in good radiochemical yield (35% ± 8%, n = 17, decay corrected), and the specific radioactivity was 150 ± 50 GBq/μmol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 ± 0.2 nmol/L and a maximum number of binding sites of 231 ± 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11C-ABP688 binding to mGluR5. Conclusion:11C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:UNLABELLED: (11)C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. METHODS: ABP688 was radiolabeled with (11)C by reacting (11)C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of (11)C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with (11)C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. RESULTS: The overall synthesis time was 45-50 min from the end of radionuclide production. (11)C-ABP688 was obtained in good radiochemical yield (35% +/- 8%, n = 17, decay corrected), and the specific radioactivity was 150 +/- 50 GBq/mumol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 +/- 0.2 nmol/L and a maximum number of binding sites of 231 +/- 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of (11)C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of (11)C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of (11)C-ABP688 binding to mGluR5. CONCLUSION: (11)C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
Ramin V Parsey - One of the best experts on this subject based on the ideXlab platform.
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in vivo variation in metabotropic glutamate receptor subtype 5 binding using positron emission tomography and 11c abp688
Journal of Cerebral Blood Flow and Metabolism, 2011Co-Authors: Christine Delorenzo, J Dileep S Kumar, John J Mann, Ramin V ParseyAbstract:The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders. Recently, a positron emission tomography (PET) tracer exhibiting high selectivity and specificity for mGluR5, 3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime ([11C]ABP688), was developed. In this work, eight healthy adult male humans were imaged twice to assess within-subject [11C]ABP688 binding variability using PET. In seven of the eight subjects, significantly higher binding was observed during the second (retest) scan. This binding increase could not be definitively explained by differences in ligand injected mass or dose, or changes in metabolism between scans. In addition, this type of systematic binding increase was not observed in a [11C]ABP688 test–retest study performed by our group on anaesthetized baboons. It is therefore possible that the increased binding was because of physiological changes occurring between scans, such as changes in endogenous glutamate levels. If PET imaging with [11C]ABP688 could detect such differences, as preliminary evidence suggests, it could be used to help uncover the role of glutamate in the pathophysiology of brain disorders. However, regardless of its ability to detect endogenous glutamate differences, [11C]ABP688 binding variability could make accurate assessments of drug occupancy or group differences using this ligand difficult.
P A Schubiger - One of the best experts on this subject based on the ideXlab platform.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: ABP688 was radiolabeled with 11C by reacting 11C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of 11C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with 11C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. Results: The overall synthesis time was 45−50 min from the end of radionuclide production. 11C-ABP688 was obtained in good radiochemical yield (35% ± 8%, n = 17, decay corrected), and the specific radioactivity was 150 ± 50 GBq/μmol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 ± 0.2 nmol/L and a maximum number of binding sites of 231 ± 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11C-ABP688 binding to mGluR5. Conclusion:11C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:UNLABELLED: (11)C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. METHODS: ABP688 was radiolabeled with (11)C by reacting (11)C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of (11)C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with (11)C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. RESULTS: The overall synthesis time was 45-50 min from the end of radionuclide production. (11)C-ABP688 was obtained in good radiochemical yield (35% +/- 8%, n = 17, decay corrected), and the specific radioactivity was 150 +/- 50 GBq/mumol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 +/- 0.2 nmol/L and a maximum number of binding sites of 231 +/- 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of (11)C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of (11)C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of (11)C-ABP688 binding to mGluR5. CONCLUSION: (11)C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
Samuel Hintermann - One of the best experts on this subject based on the ideXlab platform.
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human pet studies of metabotropic glutamate receptor subtype 5 with 11c abp688
The Journal of Nuclear Medicine, 2007Co-Authors: Simon M Ametamey, Valerie Treyer, Johannes Streffer, Matthias T Wyss, Mark Schmidt, Milen Blagoev, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Uta FischerAbstract:3-(6-Methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime (11C-ABP688), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: Six healthy male volunteers (mean age, 25 y; range, 21–33 y) were studied. Brain perfusion (15O-H2O) was measured immediately before each 11C-ABP688 PET scan. For anatomic coregistration, T1-weighted MRI was performed on each subject. Arterial blood samples for the determination of the arterial input curve were obtained at predefined time points, and 11C-ABP688 uptake was assessed quantitatively using a 2-tissue-compartment model. Results: An initial rapid uptake of radioactivity followed by a gradual clearance from all examined brain regions was observed. Relatively high radioactivity concentrations were observed in mGluR5-rich brain regions such as the anterior cingulate, medial temporal lobe, amygdala, caudate, and putamen, whereas radioactivity uptake in the cerebellum and white matter, regions known to contain low densities of mGluR5, was low. Specific distribution volume as an outcome measure of mGluR5 density in the various brain regions ranged from 5.45 ± 1.47 (anterior cingulate) to 1.91 ± 0.32 (cerebellum), and the rank order of the corresponding specific distribution volumes of 11C-ABP688 in cortical regions was temporal > frontal > occipital > parietal. The metabolism of 11C-ABP688 in plasma was rapid; at 60 min after injection, 25% ± 0.03% of radioactivity measured in the plasma of healthy volunteers was intact parent compound. Conclusion: The results of these studies indicate that 11C-ABP688 has suitable characteristics and is a promising PET ligand for imaging mGluR5 distribution in humans. Furthermore, it could be of great value for the selection of appropriate doses of clinically relevant candidate drugs that bind to mGluR5 and for PET studies of patients with psychiatric and neurologic disorders.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: ABP688 was radiolabeled with 11C by reacting 11C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of 11C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with 11C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. Results: The overall synthesis time was 45−50 min from the end of radionuclide production. 11C-ABP688 was obtained in good radiochemical yield (35% ± 8%, n = 17, decay corrected), and the specific radioactivity was 150 ± 50 GBq/μmol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 ± 0.2 nmol/L and a maximum number of binding sites of 231 ± 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11C-ABP688 binding to mGluR5. Conclusion:11C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:UNLABELLED: (11)C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. METHODS: ABP688 was radiolabeled with (11)C by reacting (11)C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of (11)C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with (11)C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. RESULTS: The overall synthesis time was 45-50 min from the end of radionuclide production. (11)C-ABP688 was obtained in good radiochemical yield (35% +/- 8%, n = 17, decay corrected), and the specific radioactivity was 150 +/- 50 GBq/mumol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 +/- 0.2 nmol/L and a maximum number of binding sites of 231 +/- 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of (11)C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of (11)C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of (11)C-ABP688 binding to mGluR5. CONCLUSION: (11)C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
Matthias T Wyss - One of the best experts on this subject based on the ideXlab platform.
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human pet studies of metabotropic glutamate receptor subtype 5 with 11c abp688
The Journal of Nuclear Medicine, 2007Co-Authors: Simon M Ametamey, Valerie Treyer, Johannes Streffer, Matthias T Wyss, Mark Schmidt, Milen Blagoev, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Uta FischerAbstract:3-(6-Methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime (11C-ABP688), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: Six healthy male volunteers (mean age, 25 y; range, 21–33 y) were studied. Brain perfusion (15O-H2O) was measured immediately before each 11C-ABP688 PET scan. For anatomic coregistration, T1-weighted MRI was performed on each subject. Arterial blood samples for the determination of the arterial input curve were obtained at predefined time points, and 11C-ABP688 uptake was assessed quantitatively using a 2-tissue-compartment model. Results: An initial rapid uptake of radioactivity followed by a gradual clearance from all examined brain regions was observed. Relatively high radioactivity concentrations were observed in mGluR5-rich brain regions such as the anterior cingulate, medial temporal lobe, amygdala, caudate, and putamen, whereas radioactivity uptake in the cerebellum and white matter, regions known to contain low densities of mGluR5, was low. Specific distribution volume as an outcome measure of mGluR5 density in the various brain regions ranged from 5.45 ± 1.47 (anterior cingulate) to 1.91 ± 0.32 (cerebellum), and the rank order of the corresponding specific distribution volumes of 11C-ABP688 in cortical regions was temporal > frontal > occipital > parietal. The metabolism of 11C-ABP688 in plasma was rapid; at 60 min after injection, 25% ± 0.03% of radioactivity measured in the plasma of healthy volunteers was intact parent compound. Conclusion: The results of these studies indicate that 11C-ABP688 has suitable characteristics and is a promising PET ligand for imaging mGluR5 distribution in humans. Furthermore, it could be of great value for the selection of appropriate doses of clinically relevant candidate drugs that bind to mGluR5 and for PET studies of patients with psychiatric and neurologic disorders.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. Methods: ABP688 was radiolabeled with 11C by reacting 11C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of 11C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with 11C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. Results: The overall synthesis time was 45−50 min from the end of radionuclide production. 11C-ABP688 was obtained in good radiochemical yield (35% ± 8%, n = 17, decay corrected), and the specific radioactivity was 150 ± 50 GBq/μmol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 ± 0.2 nmol/L and a maximum number of binding sites of 231 ± 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of 11C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of 11C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of 11C-ABP688 binding to mGluR5. Conclusion:11C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
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radiosynthesis and preclinical evaluation of 11c abp688 as a probe for imaging the metabotropic glutamate receptor subtype 5
The Journal of Nuclear Medicine, 2006Co-Authors: Simon M Ametamey, Michael Honer, Matthias T Wyss, Samuel Hintermann, Yves Auberson, Fabrizio Gasparini, Lea J Kessler, Alfred Buck, P A SchubigerAbstract:UNLABELLED: (11)C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone-O-(11)C-methyl-oxime), a noncompetitive and highly selective antagonist for the metabotropic glutamate receptor subtype 5 (mGluR5), was evaluated for its potential as a PET agent. METHODS: ABP688 was radiolabeled with (11)C by reacting (11)C-methyl iodide with the sodium salt of desmethyl-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-Cyclohex-2-Enone oxime). The affinity of (11)C-ABP688 for mGluR5 was determined by Scatchard analysis using rat whole-brain membranes (without cerebellum). Ex vivo autoradiography, biodistribution, and PET studies with (11)C-ABP688 were performed on rats, wild-type mice, and mGluR5-knock-out mice. RESULTS: The overall synthesis time was 45-50 min from the end of radionuclide production. (11)C-ABP688 was obtained in good radiochemical yield (35% +/- 8%, n = 17, decay corrected), and the specific radioactivity was 150 +/- 50 GBq/mumol (n = 17) at the end of the synthesis. Scatchard analysis revealed a single high-affinity binding site with a dissociation constant of 1.7 +/- 0.2 nmol/L and a maximum number of binding sites of 231 +/- 18 fmol/mg of protein. Ex vivo autoradiography in wild-type mice and rats showed a heterogeneous distribution pattern consistent with the known distribution of mGluR5 in the brain, with the highest uptake in hippocampus, striatum, and cortex. Blocking studies by coinjection of (11)C-ABP688 and unlabeled 2-methyl-6-(3-methoxyphenyl)ethynyl-pyridine (1 mg/kg), an antagonist for mGluR5, revealed up to 80% specific binding in rat brain. In mGluR5-knock-out mouse brain, a homogeneous and markedly reduced accumulation of (11)C-ABP688 was observed. PET studies on rats and mice using a small-animal PET scanner also demonstrated radioactivity uptake in the brain regions known to be rich in mGluR5. In contrast, radioactivity uptake in mGluR5-knock-out mice was fairly uniform, substantiating the specificity of (11)C-ABP688 binding to mGluR5. CONCLUSION: (11)C-ABP688 is a selective tracer for imaging mGluR5 in vivo in rodents and may offer a future tool for imaging mGluR5 in humans using PET.
