Myelin pathology is present in many neurological conditions such as multiple sclerosis (MS) and traumatic spinal cord injury (SCI). To facilitate development of novel therapies aimed at myelin repair, we set out to develop imaging agents that permit direct quantification of myelination in vivo. In this work, we designed and synthesized a series of fluorescent fluorinated myelin imaging agents that can be used for in vivo positron emission tomography (PET) imaging combined with subsequent post-mortem fluorescent cryoimaging. Structure–activity relationship (SAR) studies of the newly developed myelin imaging agents led us to identify a lead compound (TAFDAS, 21) that readily enters the brain and spinal cord and selectively binds to myelin. By conducting sequential PET and 3D cryoimaging in an SCI rat model, we demonstrated for the first time that PET and cryoimaging can be combined as a novel technique to image the spinal cord with high sensitivity and spatial resolution.

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.