Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography
The cerebral expression of the A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further in...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/15/5/516 |
| _version_ | 1797496973190758400 |
|---|---|
| author | Daniel Gündel Magali Toussaint Thu Hang Lai Winnie Deuther-Conrad Paul Cumming Susann Schröder Rodrigo Teodoro Rareş-Petru Moldovan Francisco Pan-Montojo Bernhard Sattler Klaus Kopka Osama Sabri Peter Brust |
| author_facet | Daniel Gündel Magali Toussaint Thu Hang Lai Winnie Deuther-Conrad Paul Cumming Susann Schröder Rodrigo Teodoro Rareş-Petru Moldovan Francisco Pan-Montojo Bernhard Sattler Klaus Kopka Osama Sabri Peter Brust |
| author_sort | Daniel Gündel |
| collection | DOAJ |
| description | The cerebral expression of the A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A<sub>2A</sub>AR–specific antagonist radiotracer [<sup>18</sup>F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (<i>BP</i><sub>ND</sub>) of [<sup>18</sup>F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (<i>V</i><sub>T</sub>) at baseline and under blocking conditions with tozadenant. The MRT of [<sup>18</sup>F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A<sub>2A</sub>AR antagonist istradefylline. Mouse results showed the highest <i>BP<sub>ND</sub></i> (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A<sub>2A</sub>AR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the <i>V</i><sub>T</sub> (14.6 vs. 8.5 mL · g<sup>−1</sup>) and <i>BP</i><sub>ND</sub> values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high <i>BP</i><sub>ND</sub> of [<sup>18</sup>F]FLUDA in the striatum. We conclude that [<sup>18</sup>F]FLUDA is a suitable tool for the non–invasive quantitation of altered A<sub>2A</sub>AR expression in neurodegenerative diseases such as PD and HD, by PET. |
| first_indexed | 2024-03-10T03:10:56Z |
| format | Article |
| id | doaj.art-e2058fe7ee934c008d6cd4ac33ced1b4 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T03:10:56Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-e2058fe7ee934c008d6cd4ac33ced1b42023-11-23T12:33:47ZengMDPI AGPharmaceuticals1424-82472022-04-0115551610.3390/ph15050516Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission TomographyDaniel Gündel0Magali Toussaint1Thu Hang Lai2Winnie Deuther-Conrad3Paul Cumming4Susann Schröder5Rodrigo Teodoro6Rareş-Petru Moldovan7Francisco Pan-Montojo8Bernhard Sattler9Klaus Kopka10Osama Sabri11Peter Brust12Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment of Nuclear Medicine, Bern University Hospital, 3010 Bern, SwitzerlandDepartment of Research and Development, ROTOP Pharmaka Ltd., 01328 Dresden, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment of Psychiatry, University Hospital Munich, Ludwig–Maximilians–Universität (LMU) Munich, 80336 Munich, GermanyDepartment for Nuclear Medicine, University Hospital Leipzig, 04103 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyDepartment for Nuclear Medicine, University Hospital Leipzig, 04103 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz–Zentrum Dresden–Rossendorf, 04308 Leipzig, GermanyThe cerebral expression of the A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A<sub>2A</sub>AR–specific antagonist radiotracer [<sup>18</sup>F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (<i>BP</i><sub>ND</sub>) of [<sup>18</sup>F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (<i>V</i><sub>T</sub>) at baseline and under blocking conditions with tozadenant. The MRT of [<sup>18</sup>F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A<sub>2A</sub>AR antagonist istradefylline. Mouse results showed the highest <i>BP<sub>ND</sub></i> (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A<sub>2A</sub>AR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the <i>V</i><sub>T</sub> (14.6 vs. 8.5 mL · g<sup>−1</sup>) and <i>BP</i><sub>ND</sub> values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high <i>BP</i><sub>ND</sub> of [<sup>18</sup>F]FLUDA in the striatum. We conclude that [<sup>18</sup>F]FLUDA is a suitable tool for the non–invasive quantitation of altered A<sub>2A</sub>AR expression in neurodegenerative diseases such as PD and HD, by PET.https://www.mdpi.com/1424-8247/15/5/5167–(3–(4–(2–[<sup>18</sup>F]fluoroethoxy–1,1,2,2–d4)phenyl)propyl)–2–(furan–2–yl)–7H–pyrazolo[4,3–e][1,2,4]triazolo–[1,5–c]pyrimidin–5–amine ([<sup>18</sup>F]FLUDA)A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR)Parkinson’s disease (PD)Huntington’s disease (HD)kinetic analysispreclinical positron emission tomography (PET) |
| spellingShingle | Daniel Gündel Magali Toussaint Thu Hang Lai Winnie Deuther-Conrad Paul Cumming Susann Schröder Rodrigo Teodoro Rareş-Petru Moldovan Francisco Pan-Montojo Bernhard Sattler Klaus Kopka Osama Sabri Peter Brust Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography Pharmaceuticals 7–(3–(4–(2–[<sup>18</sup>F]fluoroethoxy–1,1,2,2–d4)phenyl)propyl)–2–(furan–2–yl)–7H–pyrazolo[4,3–e][1,2,4]triazolo–[1,5–c]pyrimidin–5–amine ([<sup>18</sup>F]FLUDA) A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR) Parkinson’s disease (PD) Huntington’s disease (HD) kinetic analysis preclinical positron emission tomography (PET) |
| title | Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography |
| title_full | Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography |
| title_fullStr | Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography |
| title_full_unstemmed | Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography |
| title_short | Quantitation of the A<sub>2A</sub> Adenosine Receptor Density in the Striatum of Mice and Pigs with [<sup>18</sup>F]FLUDA by Positron Emission Tomography |
| title_sort | quantitation of the a sub 2a sub adenosine receptor density in the striatum of mice and pigs with sup 18 sup f fluda by positron emission tomography |
| topic | 7–(3–(4–(2–[<sup>18</sup>F]fluoroethoxy–1,1,2,2–d4)phenyl)propyl)–2–(furan–2–yl)–7H–pyrazolo[4,3–e][1,2,4]triazolo–[1,5–c]pyrimidin–5–amine ([<sup>18</sup>F]FLUDA) A<sub>2A</sub> adenosine receptor (A<sub>2A</sub>AR) Parkinson’s disease (PD) Huntington’s disease (HD) kinetic analysis preclinical positron emission tomography (PET) |
| url | https://www.mdpi.com/1424-8247/15/5/516 |
| work_keys_str_mv | AT danielgundel quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT magalitoussaint quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT thuhanglai quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT winniedeutherconrad quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT paulcumming quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT susannschroder quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT rodrigoteodoro quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT rarespetrumoldovan quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT franciscopanmontojo quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT bernhardsattler quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT klauskopka quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT osamasabri quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography AT peterbrust quantitationoftheasub2asubadenosinereceptordensityinthestriatumofmiceandpigswithsup18supffludabypositronemissiontomography |