Abstract

Central nervous system (CNS) demyelination represents the pathological hallmark of multiple sclerosis (MS) and contributes to other neurological conditions. Quantitative and specific imaging of demyelination would thus provide critical clinical insight. Here, we investigated the possibility of targeting axonal potassium channels to image demyelination by positron emission tomography (PET). These channels, which normally reside beneath the myelin sheath, become exposed upon demyelination and are the target of the MS drug, 4-aminopyridine (4-AP). We demonstrate using autoradiography that 4-AP has higher binding in non-myelinated and demyelinated versus well-myelinated CNS regions, and describe a fluorine-containing derivative, 3-F-4-AP, that has similar pharmacological properties and can be labeled with 18F for PET imaging. Additionally, we demonstrate that [18F]3-F-4-AP can be used to detect demyelination in rodents by PET. Further evaluation in Rhesus macaques shows higher binding in non-myelinated versus myelinated areas and excellent properties for brain imaging. Together, these data indicate that [18F]3-F-4-AP may be a valuable PET tracer for detecting CNS demyelination noninvasively.

Details

Title
Development of a PET radioligand for potassium channels to image CNS demyelination
Author
Brugarolas, Pedro 1 ; Sánchez-Rodríguez, Jorge E 2 ; Tsai, Hsiu-Ming 3 ; Basuli, Falguni 4 ; Cheng, Shih-Hsun 3 ; Zhang, Xiang 4 ; Caprariello, Andrew V 5 ; Lacroix, Jerome J 6 ; Freifelder, Richard 3 ; Dhanabalan Murali 7 ; DeJesus, Onofre 7 ; Miller, Robert H 8 ; Swenson, Rolf E 4 ; Chin-Tu, Chen 3 ; Herscovitch, Peter 9 ; Reich, Daniel S 10   VIAFID ORCID Logo  ; Bezanilla, Francisco 11 ; Popko, Brian 12 

1  Department of Neurology, University of Chicago, Chicago, IL, USA; Massachusetts General Hospital, Boston, MA, USA 
2  Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA; Universidad de Guadalajara, Guadalajara, Jalisco, Mexico 
3  Department of Radiology, University of Chicago, Chicago, IL, USA 
4  Imaging Probe Development Center, NIH/NHLBI, Bethesda, MD, USA 
5  Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA; University of Calgary, Calgary, Alberta, Canada 
6  Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA; Western University of Health Sciences, Pomona, CA, USA 
7  Department of Medical Physics, University of Wisconsin at Madison, Madison, WI, USA 
8  Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA; George Washington University, Washington, DC, USA 
9  Positron Emission Tomography Department, NIH/CC, Bethesda, MD, USA 
10  Translational Neuroradiology Section, NIH/NINDS, Bethesda, MD, USA 
11  Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA 
12  Department of Neurology, University of Chicago, Chicago, IL, USA 
Pages
1-16
Publication year
2018
Publication date
Jan 2018
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-18747-3
ProQuest document ID
1986974303
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.