Title | Development of a PET radioligand for potassium channels to image CNS demyelination. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Brugarolas P, Sánchez-RodrÃguez JE, Tsai H-M, Basuli F, Cheng S-H, Zhang X, Caprariello AV, Lacroix JJ, Freifelder R, Murali D, DeJesus O, Miller RH, Swenson RE, Chen C-T, Herscovitch P, Reich DS, Bezanilla F, Popko B |
Journal | Sci Rep |
Volume | 8 |
Issue | 1 |
Pagination | 607 |
Date Published | 2018 Jan 12 |
ISSN | 2045-2322 |
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 F for PET imaging. Additionally, we demonstrate that [F]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 [F]3-F-4-AP may be a valuable PET tracer for detecting CNS demyelination noninvasively. |
DOI | 10.1038/s41598-017-18747-3 |
Alternate Journal | Sci Rep |
PubMed ID | 29330383 |
PubMed Central ID | PMC5766510 |
Grant List | R21 NS084382 / NS / NINDS NIH HHS / United States R00 EB020075 / EB / NIBIB NIH HHS / United States R37 GM030376 / GM / NIGMS NIH HHS / United States U54 GM087519 / GM / NIGMS NIH HHS / United States K99 EB020075 / EB / NIBIB NIH HHS / United States R01 GM030376 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:13pm