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Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS

[Image: see text] Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium...

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Autores principales: Sun, Yang, Guehl, Nicolas J., Zhou, Yu-Peng, Takahashi, Kazue, Belov, Vasily, Dhaynaut, Maeva, Moon, Sung-Hyun, El Fakhri, Georges, Normandin, Marc D., Brugarolas, Pedro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732819/
https://www.ncbi.nlm.nih.gov/pubmed/36417797
http://dx.doi.org/10.1021/acschemneuro.2c00364
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author Sun, Yang
Guehl, Nicolas J.
Zhou, Yu-Peng
Takahashi, Kazue
Belov, Vasily
Dhaynaut, Maeva
Moon, Sung-Hyun
El Fakhri, Georges
Normandin, Marc D.
Brugarolas, Pedro
author_facet Sun, Yang
Guehl, Nicolas J.
Zhou, Yu-Peng
Takahashi, Kazue
Belov, Vasily
Dhaynaut, Maeva
Moon, Sung-Hyun
El Fakhri, Georges
Normandin, Marc D.
Brugarolas, Pedro
author_sort Sun, Yang
collection PubMed
description [Image: see text] Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels K(v)1.1 and K(v)1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe a novel tracer for K(v)1 channels, [(11)C]3-methyl-4-aminopyridine ([(11)C]3Me4AP). [(11)C]3Me4AP was efficiently synthesized via Pd(0)–Cu(I) comediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [(11)C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a one-tissue compartment model can accurately model the regional brain time–activity curves. Compared to the related tracers [(18)F]3-fluoro-4-aminopyridine ([(18)F]3F4AP) and [(11)C]3-methoxy-4-aminopyridine ([(11)C]3MeO4AP), [(11)C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood–brain barrier and slower kinetics, suggesting higher binding affinity consistent with in vitro studies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic.
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spelling pubmed-97328192022-12-10 Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS Sun, Yang Guehl, Nicolas J. Zhou, Yu-Peng Takahashi, Kazue Belov, Vasily Dhaynaut, Maeva Moon, Sung-Hyun El Fakhri, Georges Normandin, Marc D. Brugarolas, Pedro ACS Chem Neurosci [Image: see text] Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels K(v)1.1 and K(v)1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe a novel tracer for K(v)1 channels, [(11)C]3-methyl-4-aminopyridine ([(11)C]3Me4AP). [(11)C]3Me4AP was efficiently synthesized via Pd(0)–Cu(I) comediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [(11)C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a one-tissue compartment model can accurately model the regional brain time–activity curves. Compared to the related tracers [(18)F]3-fluoro-4-aminopyridine ([(18)F]3F4AP) and [(11)C]3-methoxy-4-aminopyridine ([(11)C]3MeO4AP), [(11)C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood–brain barrier and slower kinetics, suggesting higher binding affinity consistent with in vitro studies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic. American Chemical Society 2022-11-23 /pmc/articles/PMC9732819/ /pubmed/36417797 http://dx.doi.org/10.1021/acschemneuro.2c00364 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Sun, Yang
Guehl, Nicolas J.
Zhou, Yu-Peng
Takahashi, Kazue
Belov, Vasily
Dhaynaut, Maeva
Moon, Sung-Hyun
El Fakhri, Georges
Normandin, Marc D.
Brugarolas, Pedro
Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS
title Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS
title_full Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS
title_fullStr Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS
title_full_unstemmed Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS
title_short Radiochemical Synthesis and Evaluation of 3-[(11)C]Methyl-4-aminopyridine in Rodents and Nonhuman Primates for Imaging Potassium Channels in the CNS
title_sort radiochemical synthesis and evaluation of 3-[(11)c]methyl-4-aminopyridine in rodents and nonhuman primates for imaging potassium channels in the cns
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732819/
https://www.ncbi.nlm.nih.gov/pubmed/36417797
http://dx.doi.org/10.1021/acschemneuro.2c00364
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