Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor
Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Buiter, Hans JC [verfasserIn] Windhorst, Albert D [verfasserIn] Huisman, Marc C [verfasserIn] De Maeyer, Joris H [verfasserIn] Schuurkes, Jan AJ [verfasserIn] Lammertsma, Adriaan A [verfasserIn] Leysen, Josée E [verfasserIn] |
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E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2013 |
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| Übergeordnetes Werk: |
Enthalten in: EJNMMI Research - Berlin : Springer, 2011, 3(2013), 1 vom: 04. Apr. |
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| Übergeordnetes Werk: |
volume:3 ; year:2013 ; number:1 ; day:04 ; month:04 |
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| DOI / URN: |
10.1186/2191-219X-3-24 |
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| Katalog-ID: |
SPR031778372 |
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| 100 | 1 | |a Buiter, Hans JC |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor |
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| 520 | |a Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. | ||
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| 700 | 1 | |a Windhorst, Albert D |e verfasserin |4 aut | |
| 700 | 1 | |a Huisman, Marc C |e verfasserin |4 aut | |
| 700 | 1 | |a De Maeyer, Joris H |e verfasserin |4 aut | |
| 700 | 1 | |a Schuurkes, Jan AJ |e verfasserin |4 aut | |
| 700 | 1 | |a Lammertsma, Adriaan A |e verfasserin |4 aut | |
| 700 | 1 | |a Leysen, Josée E |e verfasserin |4 aut | |
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10.1186/2191-219X-3-24 doi (DE-627)SPR031778372 (SPR)2191-219X-3-24-e DE-627 ger DE-627 rakwb eng 610 ASE Buiter, Hans JC verfasserin aut Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. [ (dpeaa)DE-He213 C]Prucalopride (dpeaa)DE-He213 Radiosynthesis (dpeaa)DE-He213 5-HT (dpeaa)DE-He213 receptor (dpeaa)DE-He213 Agonist (dpeaa)DE-He213 G-protein coupled receptor (dpeaa)DE-He213 Rat (dpeaa)DE-He213 Biodistribution (dpeaa)DE-He213 PET imaging (dpeaa)DE-He213 Windhorst, Albert D verfasserin aut Huisman, Marc C verfasserin aut De Maeyer, Joris H verfasserin aut Schuurkes, Jan AJ verfasserin aut Lammertsma, Adriaan A verfasserin aut Leysen, Josée E verfasserin aut Enthalten in EJNMMI Research Berlin : Springer, 2011 3(2013), 1 vom: 04. Apr. (DE-627)664970265 (DE-600)2619892-7 2191-219X nnns volume:3 year:2013 number:1 day:04 month:04 https://dx.doi.org/10.1186/2191-219X-3-24 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2013 1 04 04 |
| spelling |
10.1186/2191-219X-3-24 doi (DE-627)SPR031778372 (SPR)2191-219X-3-24-e DE-627 ger DE-627 rakwb eng 610 ASE Buiter, Hans JC verfasserin aut Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. [ (dpeaa)DE-He213 C]Prucalopride (dpeaa)DE-He213 Radiosynthesis (dpeaa)DE-He213 5-HT (dpeaa)DE-He213 receptor (dpeaa)DE-He213 Agonist (dpeaa)DE-He213 G-protein coupled receptor (dpeaa)DE-He213 Rat (dpeaa)DE-He213 Biodistribution (dpeaa)DE-He213 PET imaging (dpeaa)DE-He213 Windhorst, Albert D verfasserin aut Huisman, Marc C verfasserin aut De Maeyer, Joris H verfasserin aut Schuurkes, Jan AJ verfasserin aut Lammertsma, Adriaan A verfasserin aut Leysen, Josée E verfasserin aut Enthalten in EJNMMI Research Berlin : Springer, 2011 3(2013), 1 vom: 04. Apr. (DE-627)664970265 (DE-600)2619892-7 2191-219X nnns volume:3 year:2013 number:1 day:04 month:04 https://dx.doi.org/10.1186/2191-219X-3-24 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2013 1 04 04 |
| allfields_unstemmed |
10.1186/2191-219X-3-24 doi (DE-627)SPR031778372 (SPR)2191-219X-3-24-e DE-627 ger DE-627 rakwb eng 610 ASE Buiter, Hans JC verfasserin aut Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. [ (dpeaa)DE-He213 C]Prucalopride (dpeaa)DE-He213 Radiosynthesis (dpeaa)DE-He213 5-HT (dpeaa)DE-He213 receptor (dpeaa)DE-He213 Agonist (dpeaa)DE-He213 G-protein coupled receptor (dpeaa)DE-He213 Rat (dpeaa)DE-He213 Biodistribution (dpeaa)DE-He213 PET imaging (dpeaa)DE-He213 Windhorst, Albert D verfasserin aut Huisman, Marc C verfasserin aut De Maeyer, Joris H verfasserin aut Schuurkes, Jan AJ verfasserin aut Lammertsma, Adriaan A verfasserin aut Leysen, Josée E verfasserin aut Enthalten in EJNMMI Research Berlin : Springer, 2011 3(2013), 1 vom: 04. Apr. (DE-627)664970265 (DE-600)2619892-7 2191-219X nnns volume:3 year:2013 number:1 day:04 month:04 https://dx.doi.org/10.1186/2191-219X-3-24 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2013 1 04 04 |
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10.1186/2191-219X-3-24 doi (DE-627)SPR031778372 (SPR)2191-219X-3-24-e DE-627 ger DE-627 rakwb eng 610 ASE Buiter, Hans JC verfasserin aut Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. [ (dpeaa)DE-He213 C]Prucalopride (dpeaa)DE-He213 Radiosynthesis (dpeaa)DE-He213 5-HT (dpeaa)DE-He213 receptor (dpeaa)DE-He213 Agonist (dpeaa)DE-He213 G-protein coupled receptor (dpeaa)DE-He213 Rat (dpeaa)DE-He213 Biodistribution (dpeaa)DE-He213 PET imaging (dpeaa)DE-He213 Windhorst, Albert D verfasserin aut Huisman, Marc C verfasserin aut De Maeyer, Joris H verfasserin aut Schuurkes, Jan AJ verfasserin aut Lammertsma, Adriaan A verfasserin aut Leysen, Josée E verfasserin aut Enthalten in EJNMMI Research Berlin : Springer, 2011 3(2013), 1 vom: 04. Apr. (DE-627)664970265 (DE-600)2619892-7 2191-219X nnns volume:3 year:2013 number:1 day:04 month:04 https://dx.doi.org/10.1186/2191-219X-3-24 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2013 1 04 04 |
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10.1186/2191-219X-3-24 doi (DE-627)SPR031778372 (SPR)2191-219X-3-24-e DE-627 ger DE-627 rakwb eng 610 ASE Buiter, Hans JC verfasserin aut Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. [ (dpeaa)DE-He213 C]Prucalopride (dpeaa)DE-He213 Radiosynthesis (dpeaa)DE-He213 5-HT (dpeaa)DE-He213 receptor (dpeaa)DE-He213 Agonist (dpeaa)DE-He213 G-protein coupled receptor (dpeaa)DE-He213 Rat (dpeaa)DE-He213 Biodistribution (dpeaa)DE-He213 PET imaging (dpeaa)DE-He213 Windhorst, Albert D verfasserin aut Huisman, Marc C verfasserin aut De Maeyer, Joris H verfasserin aut Schuurkes, Jan AJ verfasserin aut Lammertsma, Adriaan A verfasserin aut Leysen, Josée E verfasserin aut Enthalten in EJNMMI Research Berlin : Springer, 2011 3(2013), 1 vom: 04. Apr. (DE-627)664970265 (DE-600)2619892-7 2191-219X nnns volume:3 year:2013 number:1 day:04 month:04 https://dx.doi.org/10.1186/2191-219X-3-24 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2013 1 04 04 |
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Enthalten in EJNMMI Research 3(2013), 1 vom: 04. Apr. volume:3 year:2013 number:1 day:04 month:04 |
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Buiter, Hans JC @@aut@@ Windhorst, Albert D @@aut@@ Huisman, Marc C @@aut@@ De Maeyer, Joris H @@aut@@ Schuurkes, Jan AJ @@aut@@ Lammertsma, Adriaan A @@aut@@ Leysen, Josée E @@aut@@ |
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The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. 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Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor |
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Buiter, Hans JC Windhorst, Albert D Huisman, Marc C De Maeyer, Joris H Schuurkes, Jan AJ Lammertsma, Adriaan A Leysen, Josée E |
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radiosynthesis and preclinical evaluation of [11c]prucalopride as a potential agonist pet ligand for the 5-$ ht_{4} $ receptor |
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Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-$ HT_{4} $ receptor |
| abstract |
Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. |
| abstractGer |
Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. |
| abstract_unstemmed |
Background Serotonin 5-$ HT_{4} $ receptor (5-$ HT_{4} $-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-$ HT_{4} $-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-$ HT_{4} $-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its $ LogD_{oct,pH7.4} $ was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its $ LogD_{oct,pH7.4} $ was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·$ g^{−1} $) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut. Conclusion [11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-$ HT_{4} $-R is worthwhile, in view of the therapeutic applications of 5-$ HT_{4} $ agonists for treatment of gastrointestinal motility disorders. |
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