Impacting Neuroscience With Chemistry: HDAC Neuroimaging Enabled by [18F]-Fluorination Methodology

Abstract

In this dissertation, innovative radiochemical methodology was leveraged to systematically advance radiotracer development. A novel organometallic radiofluorination was established, as well as two fluorinated radiotracers, [18F]MGS3 and [18F]Bavarostat, for imaging histone deacetylases (HDACs) in the living brain using Positron Emission Tomography (PET). First, to overcome the practical hurdles of [18F]radiofluorination, a ruthenium-mediated deoxyfluorination was developed. This innovative radiochemical transformation benefits from readily available phenols as starting materials, tolerance of moisture and ambient atmosphere, large substrate scope, and translatability to generate doses appropriate for PET imaging. The successful development of [18F]MGS3, a class I and IIb selective HDAC imaging agent, illustrated limitations of traditional radiolabeling methods. The ability of ruthenium-mediated radiofluorination to resolve these existing challenges in radiosynthesis was demonstrated with a cGMP compliant, fully automated synthetic process for human radiopharmaceutical production of [18F]MGS3. The discussion concludes with an outlook on state-of-the-art target validation platform design for HDAC inhibitors. To validate the prospective value of target-oriented radiolabeling methodology, the de novo development of an HDAC6 PET tracer was accomplished. [18F]Bavarostat was identified as a tracer candidate from a pool of HDAC6 selective small molecules based on computational predictions and validated by biochemical assays. Ruthenium-mediated radiofluorination enabled the study of [18F]Bavarostat with PET imaging in rodents and non-human primates, highlighting its translational potential for human HDAC6 neuroimaging. The timeframe of de novo development of Bavarostat in comparison to the adaptation of [18F]MGS3 demonstrates the efficiency of molecule-oriented method development in radiochemistry.