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

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

doi:10.3389/fnins.2021.766176

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

Front Neurosci. 2021 Dec 2:15:766176. doi: 10.3389/fnins.2021.766176. eCollection 2021.

Authors

Tanpreet Kaur¹, Allen F Brooks¹, Alex Lapsys¹, Timothy J Desmond¹, Jenelle Stauff¹, Janna Arteaga¹, Wade P Winton¹, Peter J H Scott¹

Affiliation

¹ Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, United States.

Abstract

Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (mHTT), 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[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one ([¹⁸F]1), a radioligand for HD and its preclinical evaluation in vitro (autoradiography of post-mortem HD brains) and in vivo (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 mHTT aggregates identified by immunohistochemistry.

Keywords: Huntington’s disease; PET imaging; [11C]CHDI; fluorine-18; radiotracer.