AUTHOR=Kaur Tanpreet , Brooks Allen F. , Lapsys Alex , Desmond Timothy J. , Stauff Jenelle , Arteaga Janna , Winton Wade P. , Scott Peter J. H. 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=15

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.766176

DOI=10.3389/fnins.2021.766176

ISSN=1662-453X

ABSTRACT=<p>Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (<italic>m</italic>HTT), which is the hallmark pathology of neurodegenerative Huntington’s disease (HD). Development of a high affinity <sup>18</sup>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-<sup>18</sup>F)ethoxy)pyridin-2-yl)methoxy)benzo[<italic>d</italic>]oxazol-2-yl)-2-methylpyridazin-3(2<italic>H</italic>)-one ([<sup>18</sup>F]1), a radioligand for HD and its preclinical evaluation <italic>in vitro</italic> (autoradiography of post-mortem HD brains) and <italic>in vivo</italic> (rodent and non-human primate brain PET). [<sup>18</sup>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). [<sup>18</sup>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 <italic>m</italic>HTT aggregates identified by immunohistochemistry.</p>