Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (HTT), which is the hallmark pathology of neurodegenerative Huntington's disease (HD). Development of a high affinity F 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-F)ethoxy)pyridin-2-yl)methoxy)benzo[]oxazol-2-yl)-2-methylpyridazin-3(2)-one ([F]1), a radioligand for HD and its preclinical evaluation (autoradiography of post-mortem HD brains) and (rodent and non-human primate brain PET). [F]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). [F]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 HTT aggregates identified by immunohistochemistry.
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| http://dx.doi.org/10.3389/fnins.2021.766176 | DOI Listing |
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