@article{092cd02df35b4dcb960f925190a046a5,
title = "Development of a PET radioligand for potassium channels to image CNS demyelination",
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.",
author = "Pedro Brugarolas and S{\'a}nchez-Rodr{\'i}guez, {Jorge E.} and Tsai, {Hsiu Ming} and Falguni Basuli and Cheng, {Shih Hsun} and Xiang Zhang and Caprariello, {Andrew V.} and Lacroix, {Jerome J.} and Richard Freifelder and Dhanabalan Murali and Onofre DeJesus and Miller, {Robert H.} and Swenson, {Rolf E.} and Chen, {Chin Tu} and Peter Herscovitch and Reich, {Daniel S.} and Francisco Bezanilla and Brian Popko",
note = "Funding Information: We would like to thank Prof. Chuan He and Dr. Yunus Turkmen for help with chemical syntheses, Dr. Sharon Way for experimental assistance and for editing the manuscript, Mr. Ani Solanki for assistance with animal procedures and Dr. Maria Traka for guidance with the DTA model. We also thank the Integrated Small Animal Imaging Research Resource and the Integrated Light Microscopy Facility at The University of Chicago for their services. This work was partially supported by NIH/NIBIB K99EB020075 (P.B.), NIH/NINDS R21NS084382 and the National Multiple Sclerosis Society through special funds from the Illinois Lottery (B.P.), an Innovation Fund Award from the Chicago Innovation Exchange (B.P. and P.B.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (D.S.R. and B.P.) and NIH GM030376 (F.B.). JESR was a recipient of a postdoctoral fellowship from Consejo Nacional de Ciencia y Tecnolog{\'i}a (Mexico) and partially supported by the glue-grant (U54GM087519). D.S.R. is supported by the Intramural Research Program of NINDS. Funding Information: Competing Interests: The University of Chicago has filed a patent application related to this technology where P.B., C.-T.C. and B.P. are listed as inventors. D.S.R. wishes to disclose funding from MRF and Vertex to develop methods for imaging demyelination using MRI. Other authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-017-18747-3",
language = "English (US)",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}