Novel F-18 labeled Radioligands for PET imaging of myelination in CNS

614 Objectives: Myelination lination is a fundamental process of the vertebrate nervous system, in which a myelin membrane is generated to protect axons and thereby facilitate impulse conduction through the nervous system. Disruption of the myelin sheath is associated with many neurodegenerative diseases such as spinal cord injury (SCI), which often leads to apoptosis of oligodendrocyte cells, and subsequent demyelination of axonal tracts along the spinal cord. In vivo monitoring of myelination in the spinal cord has been a daunting challenge, particularly in the spinal cord due to its small and mobile structure. To meet this challenge, we designed and synthesized a series of novel fluorinated imaging agents and conducted systematic structure-activity relationship (SAR) studies for potential positron Emission Tomography (PET) imaging of myelin. All of the newly synthesized compounds were found to be permeable across the blood-brain barrier (BBB) and to specifically bind to myelin in the spinal cord as well as the brain. Following our in vitro and ex vivo evaluations, a lead agent termed [18F]PenDAS ([18F]5a) has been identified that can be used in conjunction with PET imaging to delineate myelin status in the spinal cord. Subsequent in vivo PET imaging studies of [18F]5a in traumatic SCI rat models showed promising pharmacokinetics that justify its further development as a novel imaging marker for the diagnosis of myelin-related diseases and efficacy evaluation of novel therapies that are currently under development (Fig1).