Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging
Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the...
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doaj-17b4441fca844fc5810e15f51f8372992020-11-24T23:58:48ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2016-07-011010.3389/fnins.2016.00350204916Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET ImagingAhmed Haider0Adrienne Müller Herde1Roger Slavik2Markus Weber3Claudia Mugnaini4Alessia Ligresti5Roger Schibli6Linjing Mu7Simon Mensah Ametamey8Swiss Federal Institute of Technology (ETH Zurich)Swiss Federal Institute of Technology (ETH Zurich)University of CaliforniaKantonsspital St. GallenUniversity of SienaNational Research Counsil of ItalySwiss Federal Institute of Technology (ETH Zurich)University Hospital ZurichSwiss Federal Institute of Technology (ETH Zurich)Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 µM (CB1) for AAT-015. AAT-778 showed similar Ki values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 µM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 - 449 GBq/µmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015 and [11C]AAT-778 could not be demonstrated.http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00350/fullNeuroinflammationNeurodegenerative disordersCannabinoid receptor type 2Positron Emission 13 TomographyThiophene-Based Structures |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ahmed Haider Adrienne Müller Herde Roger Slavik Markus Weber Claudia Mugnaini Alessia Ligresti Roger Schibli Linjing Mu Simon Mensah Ametamey |
spellingShingle |
Ahmed Haider Adrienne Müller Herde Roger Slavik Markus Weber Claudia Mugnaini Alessia Ligresti Roger Schibli Linjing Mu Simon Mensah Ametamey Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging Frontiers in Neuroscience Neuroinflammation Neurodegenerative disorders Cannabinoid receptor type 2 Positron Emission 13 Tomography Thiophene-Based Structures |
author_facet |
Ahmed Haider Adrienne Müller Herde Roger Slavik Markus Weber Claudia Mugnaini Alessia Ligresti Roger Schibli Linjing Mu Simon Mensah Ametamey |
author_sort |
Ahmed Haider |
title |
Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging |
title_short |
Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging |
title_full |
Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging |
title_fullStr |
Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging |
title_full_unstemmed |
Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging |
title_sort |
synthesis and biological evaluation of thiophene-based cannabinoid receptor type 2 radiotracers for pet imaging |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2016-07-01 |
description |
Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based 11C-labeled PET ligands designated [11C]AAT-015 and [11C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki values of 3.3 ± 0.5 nM (CB2) and 1.0 ± 0.2 µM (CB1) for AAT-015. AAT-778 showed similar Ki values of 4.3 ± 0.7 nM (CB2) and 1.1 ± 0.1 µM (CB1). Radiosynthesis was carried out under basic conditions using [11C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 - 449 GBq/µmol for both tracers. In order to demonstrate CB2 specificity of [11C]AAT-015 and [11C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [11C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2-positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [11C]AAT-015 and [11C]AAT-778 could not be demonstrated. |
topic |
Neuroinflammation Neurodegenerative disorders Cannabinoid receptor type 2 Positron Emission 13 Tomography Thiophene-Based Structures |
url |
http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00350/full |
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