Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging

Abstract

Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (<i>m</i>HTT), which is the hallmark pathology of neurodegenerative Huntington's disease (HD). Development of a high affinity ¹⁸F radiotracer would enable the study of Huntington's disease pathology using a non-invasive imaging modality, positron emission tomography (PET) imaging. Herein, we report the first synthesis of fluorine-18 imaging agent, 6-(5-((5-(2,2-difluoro-2-(fluoro-¹⁸F)ethoxy)pyridin-2-yl)methoxy)benzo[<i>d</i>]oxazol-2-yl)-2-methylpyridazin-3(2<i>H</i>)-one ([¹⁸F]1), a radioligand for HD and its preclinical evaluation <i>in vitro</i> (autoradiography of post-mortem HD brains) and <i>in vivo</i> (rodent and non-human primate brain PET). [¹⁸F]1 was synthesized in a 4.1% RCY (decay corrected) and in an average molar activity of 16.5 ± 12.5 GBq/μmol (445 ± 339 Ci/mmol). [¹⁸F]1 penetrated the blood-brain barrier of both rodents and primates, and specific saturable binding in post-mortem brain slices was observed that correlated to <i>m</i>HTT aggregates identified by immunohistochemistry.