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用于正电子发射断层成像的18F放射性配体的合成与评价，用于亨廷顿蛋白聚集体成像

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

作者信息

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

机构信息

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

出版信息

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

DOI:10.3389/fnins.2021.766176
PMID:34924935
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8675899/
Abstract

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.

摘要

亨廷顿蛋白基因（HTT）的突变会引发亨廷顿蛋白（HTT）的聚集，这是神经退行性疾病亨廷顿舞蹈症（HD）的标志性病理特征。开发一种高亲和力的F放射性示踪剂将能够使用正电子发射断层扫描（PET）成像这种非侵入性成像方式来研究亨廷顿舞蹈症的病理。在此，我们报告了氟-18成像剂6-(5-((5-(2,2-二氟-2-(氟-F)乙氧基)吡啶-2-基)甲氧基)苯并[]恶唑-2-基)-2-甲基哒嗪-3(2)-酮([F]1)的首次合成，它是一种用于HD的放射性配体及其临床前评估（死后HD大脑的放射自显影）和（啮齿动物和非人类灵长类动物大脑PET）。[F]1的合成产率为4.1%（衰变校正），平均摩尔活度为16.5±12.5 GBq/μmol（445±339 Ci/mmol）。[F]1穿透了啮齿动物和灵长类动物的血脑屏障，并且在死后脑切片中观察到特异性可饱和结合，这与免疫组织化学鉴定的HTT聚集物相关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/66fb833236fb/fnins-15-766176-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/fbf3d3ea664d/fnins-15-766176-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/8f4a5944b22b/fnins-15-766176-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/919e4ab937bb/fnins-15-766176-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/350d0241ad1f/fnins-15-766176-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/4f9a110e49d4/fnins-15-766176-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/66fb833236fb/fnins-15-766176-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/fbf3d3ea664d/fnins-15-766176-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/8f4a5944b22b/fnins-15-766176-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/919e4ab937bb/fnins-15-766176-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/350d0241ad1f/fnins-15-766176-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/4f9a110e49d4/fnins-15-766176-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/269e/8675899/66fb833236fb/fnins-15-766176-g005.jpg

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