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Purpose: The treatment of complex neurological diseases often requires the administration of large therapeutic drugs, such as antisense oligonucleotide (ASO), by lumbar puncture into the intrathecal space in order to bypass the blood-brain barrier. Despite the growing number of ASOs in clinical development, there are still uncertainties regarding their dosing, primarily around their distribution and kinetics in the brain following intrathecal injection. The challenge of taking measurements within the delicate structures of the central nervous system (CNS) necessitates the use of non-invasive nuclear imaging, such as positron emission tomography (PET). Herein, an emergent strategy known as "pretargeted imaging" is applied to image the distribution of an ASO in the brain by developing a novel PET tracer, [18F]F-537-Tz. This tracer is able to undergo an in vivo "click" reaction, covalently binding to a trans-cyclooctene conjugated ASO.Procedures: A novel small molecule tracer for pretargeted PET imaging of ASOs in the CNS is developed and tested in a series of in vitro and in vivo experiments, including biodistribution in rats and non-human primates.Results: In vitro data and extensive in vivo rat data demonstrated delivery of the tracer to the CNS, and its successful ligation to its ASO target in the brain. In an NHP study, the slow tracer kinetics did not allow for specific binding to be determined by PET.Conclusion: A CNS-penetrant radioligand for pretargeted imaging was successfully demonstrated in a proof-of-concept study in rats, laying the groundwork for further optimization. [ABSTRACT FROM AUTHOR]