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用于脑内代谢型谷氨酸受体4成像的氟-18标记的-(4-氯-3-((氟甲基)硫代)苯基)吡啶甲酰胺的合成与表征

Synthesis and Characterization of Fluorine-18-Labeled -(4-Chloro-3-((fluoromethyl-)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain.

作者信息

Wang Junfeng, Qu Xiying, Shoup Timothy M, Yuan Gengyang, Afshar Sepideh, Pan Chuzhi, Zhu Aijun, Choi Ji-Kyung, Kang Hye Jin, Poutiainen Pekka, El Fakhri Georges, Zhang Zhaoda, Brownell Anna-Liisa

机构信息

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 125 Nashua Street, Suite 660, Boston, Massachusetts 02114, United States.

The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.

出版信息

J Med Chem. 2020 Mar 26;63(6):3381-3389. doi: 10.1021/acs.jmedchem.0c00201. Epub 2020 Mar 4.

DOI:10.1021/acs.jmedchem.0c00201
PMID:32081008
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7261135/
Abstract

We have synthesized and characterized [F]--(4-chloro-3-((fluoromethyl-)thio)phenyl)-picolinamide ([F]) as a potential ligand for the positron emission tomography (PET) imaging of mGluR4 in the brain. Radioligand [F] displays central nervous system drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity, and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was carried out in two steps. The radiochemical yield of [F] was 11.6 ± 2.9% ( = 7, decay corrected) with a purity of 99% and a molar activity of 84.1 ± 11.8 GBq/μmol. Ex vivo biodistribution studies showed reversible binding of [F] in all investigated tissues including the brain, liver, heart, lungs, and kidneys. PET imaging studies in male Sprague Dawley rats showed that [F] accumulates in the brain regions known to express mGluR4. Pretreatment with the unlabeled mGluR4 PAM compounds (methylthio analogue) and showed significant dose-dependent blocking effects. These results suggest that [F] is a promising radioligand for PET imaging mGluR4 in the brain.

摘要

我们已经合成并表征了[F] - (4 - 氯 - 3 - ((氟甲基)硫代)苯基) - 吡啶甲酰胺([F])，它是一种用于脑内代谢型谷氨酸受体4（mGluR4）正电子发射断层扫描（PET）成像的潜在配体。放射性配体[F]具有类似中枢神经系统药物的特性，包括对mGluR4的亲和力、强大的mGluR4正向变构调节剂（PAM）活性、对其他mGluRs的选择性以及足够的代谢稳定性。放射性合成分两步进行。[F]的放射化学产率为11.6±2.9%（n = 7，衰变校正），纯度为99%，摩尔活度为84.1±- 11.8 GBq/μmol。体外生物分布研究表明，[F]在所有研究的组织（包括脑、肝、心、肺和肾）中均有可逆性结合。对雄性Sprague Dawley大鼠进行的PET成像研究表明，[F]在已知表达mGluR4的脑区中蓄积。用未标记的mGluR4 PAM化合物（甲硫基类似物）和进行预处理显示出显著的剂量依赖性阻断作用。这些结果表明，[F]是一种用于脑内mGluR4 PET成像的有前景的放射性配体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/be7c139a9277/nihms-1585700-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/b25492d64ffc/nihms-1585700-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/3b78baaf8ba1/nihms-1585700-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/675ae15c12a3/nihms-1585700-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/bae2ddfc377a/nihms-1585700-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/8ae7bf22486d/nihms-1585700-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/4b7e0e80ab3f/nihms-1585700-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/e70989d2edbc/nihms-1585700-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/0a5f08f5326a/nihms-1585700-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/c44fc52e2056/nihms-1585700-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/be7c139a9277/nihms-1585700-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/b25492d64ffc/nihms-1585700-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/3b78baaf8ba1/nihms-1585700-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/675ae15c12a3/nihms-1585700-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/bae2ddfc377a/nihms-1585700-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/8ae7bf22486d/nihms-1585700-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/4b7e0e80ab3f/nihms-1585700-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/e70989d2edbc/nihms-1585700-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/0a5f08f5326a/nihms-1585700-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/c44fc52e2056/nihms-1585700-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4bd4/7261135/be7c139a9277/nihms-1585700-f0010.jpg

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