Design, Synthesis, and Evaluation of Fluorinated Radioligands for Myelin Imaging

Myelination is one of the fundamental processes in vertebrates. A major challenge is to quantitatively image myelin distribution in the central nervous system. For this reason, we designed and synthesized a series of fluorinated radioligands that can be radiolabeled as radiotracers for positron emission tomography (PET) imaging of myelin. These newly developed radioligands readily penetrate the blood–brain barrier and selectively bind to myelin membranes in the white matter region. Structure–activity relationship studies of such ligands suggested that optimal permeability could be achieved with calculated lipophilicty in the range of 3–4. After radiolabeling with fluorine-18, the brain uptake and retention of each radioligand were determined by microPET/CT imaging studies. These pharmacokinetic studies led us to identify a lead compound ([18F]­FMeDAS, 32) with promising in vivo binding properties, which was subsequently validated by ex vivo autoradiography.