ABSTRACT
Myelin is the protective sheath that surrounds nerves in vertebrates to protect axons, which thereby facilitates impulse conduction. Damage to myelin is associated with many neurodegenerative diseases such as multiple sclerosis and also includes spinal cord injury (SCI). The small size of the spinal cord poses formidable challenges to in vivo monitoring of myelination, which we investigated via conducting a structure-activity relationship study to determine the optimum positron-emitting agent to use for imaging myelin using positron emission tomography (PET). From these studies, [18F]PENDAS was identified as the lead agent to use in conjunction with PET imaging to delineate the integrity of spinal cord myelin. A subsequent in vivo PET imaging study of [18F]PENDAS in rats with SCI showed promising pharmacokinetic results that justify further development of imaging markers for diagnosing myelin-related diseases. Additionally, [18F]PENDAS could be valuable in determining the efficacy of therapies that are currently under development.
Subject(s)
Brain/diagnostic imaging , Fluorine Radioisotopes , Myelin Sheath/pathology , Positron-Emission Tomography/methods , Small Molecule Libraries/chemical synthesis , Spinal Cord/diagnostic imaging , Animals , Brain/metabolism , Ligands , Mice , Molecular Structure , Myelin Sheath/metabolism , Rats , Rats, Sprague-Dawley , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Spinal Cord/metabolism , Structure-Activity RelationshipABSTRACT
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.
