Evaluation of an image-derived input function for kinetic modeling of nicotinic acetylcholine receptor-binding PET ligands in mice
Evaluation of an image-derived input function for kinetic modeling of nicotinic acetylcholine receptor-binding PET ligands in mice
Date
2023-10-24
Authors
Zammit, Matthew
Kao, Chien-Min
Zhang, Hannah J.
Tsai, Hsiu-Ming
Holderman, Nathanial
Mitchell, Samuel
Tanios, Eve
Bhuiyan, Mohammed
Freifelder, Richard
Kucharski, Anna
Green, William N.
Mukherjee, Jogeshwar
Chen, Chin-Tu
Kao, Chien-Min
Zhang, Hannah J.
Tsai, Hsiu-Ming
Holderman, Nathanial
Mitchell, Samuel
Tanios, Eve
Bhuiyan, Mohammed
Freifelder, Richard
Kucharski, Anna
Green, William N.
Mukherjee, Jogeshwar
Chen, Chin-Tu
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DOI
10.3390/ijms242115510
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Keywords
Kinetic modeling
Nicotine
Addiction
PET
Nifene
2-FA85380
Nicotine
Addiction
PET
Nifene
2-FA85380
Abstract
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-[18F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [18F]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.
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© The Author(s), 2023. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Zammit, M., Kao, C.-M., Zhang, H. J., Tsai, H.-M., Holderman, N., Mitchell, S., Tanios, E., Bhuiyan, M., Freifelder, R., Kucharski, A., Green, W. N., Mukherjee, J., & Chen, C.-T. (2023). Evaluation of an image-derived input function for kinetic modeling of nicotinic acetylcholine receptor-binding PET ligands in mice. International Journal of Molecular Sciences, 24(21), https://doi.org/10.3390/ijms242115510.
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Zammit, M., Kao, C.-M., Zhang, H. J., Tsai, H.-M., Holderman, N., Mitchell, S., Tanios, E., Bhuiyan, M., Freifelder, R., Kucharski, A., Green, W. N., Mukherjee, J., & Chen, C.-T. (2023). Evaluation of an image-derived input function for kinetic modeling of nicotinic acetylcholine receptor-binding PET ligands in mice. International Journal of Molecular Sciences, 24(21).