Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice
Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/15510 |
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| author | Matthew Zammit Chien-Min Kao Hannah J. Zhang Hsiu-Ming Tsai Nathanial Holderman Samuel Mitchell Eve Tanios Mohammed Bhuiyan Richard Freifelder Anna Kucharski William N. Green Jogeshwar Mukherjee Chin-Tu Chen |
| author_facet | Matthew Zammit Chien-Min Kao Hannah J. Zhang Hsiu-Ming Tsai Nathanial Holderman Samuel Mitchell Eve Tanios Mohammed Bhuiyan Richard Freifelder Anna Kucharski William N. Green Jogeshwar Mukherjee Chin-Tu Chen |
| author_sort | Matthew Zammit |
| collection | DOAJ |
| description | Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[<sup>18</sup>F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [<sup>18</sup>F]Nifene, displaying similar pKa and binding affinity to nicotine. Time–activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies. |
| first_indexed | 2024-03-11T11:29:37Z |
| format | Article |
| id | doaj.art-529a1aeb78e440c383ad1f97ae4b8642 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:29:37Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-529a1aeb78e440c383ad1f97ae4b86422023-11-10T15:04:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124211551010.3390/ijms242115510Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in MiceMatthew Zammit0Chien-Min Kao1Hannah J. Zhang2Hsiu-Ming Tsai3Nathanial Holderman4Samuel Mitchell5Eve Tanios6Mohammed Bhuiyan7Richard Freifelder8Anna Kucharski9William N. Green10Jogeshwar Mukherjee11Chin-Tu Chen12Department of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USADepartment of Neurobiology, University of Chicago, Chicago, IL 60637, USADepartment of Radiological Sciences, University of California, Irvine, CA 92697, USADepartment of Radiology, University of Chicago, Chicago, IL 60637, USAPositron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[<sup>18</sup>F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [<sup>18</sup>F]Nifene, displaying similar pKa and binding affinity to nicotine. Time–activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.https://www.mdpi.com/1422-0067/24/21/15510kinetic modelingnicotineaddictionPETNifene2-FA85380 |
| spellingShingle | Matthew Zammit Chien-Min Kao Hannah J. Zhang Hsiu-Ming Tsai Nathanial Holderman Samuel Mitchell Eve Tanios Mohammed Bhuiyan Richard Freifelder Anna Kucharski William N. Green Jogeshwar Mukherjee Chin-Tu Chen Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice International Journal of Molecular Sciences kinetic modeling nicotine addiction PET Nifene 2-FA85380 |
| title | Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice |
| title_full | Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice |
| title_fullStr | Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice |
| title_full_unstemmed | Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice |
| title_short | Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice |
| title_sort | evaluation of an image derived input function for kinetic modeling of nicotinic acetylcholine receptor binding pet ligands in mice |
| topic | kinetic modeling nicotine addiction PET Nifene 2-FA85380 |
| url | https://www.mdpi.com/1422-0067/24/21/15510 |
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