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高对比度正电子发射断层扫描成像技术与[F]NT160，一种用于中枢神经系统中表观遗传学机制的体内成像的 IIa 类组蛋白去乙酰化酶探针。

High-Contrast PET Imaging with [F]NT160, a Class-IIa Histone Deacetylase Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System.

机构信息

Stony Brook Cancer Center, Stony Brook, Long Island, New York 11794, United States.

Department of Radiology, School of Medicine, Stony Brook University, Long Island, New York 11794, United States.

出版信息

J Med Chem. 2023 Apr 27;66(8):5611-5621. doi: 10.1021/acs.jmedchem.2c02064. Epub 2023 Apr 17.

DOI:10.1021/acs.jmedchem.2c02064
PMID:37068265
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10150721/
Abstract

We utilized positron emission tomography (PET) imaging in vivo to map the spatiotemporal biodistribution/expression of class-IIa histone deacetylases (class-IIa HDACs) in the central nervous system (CNS). Herein we report an improved radiosynthesis of [F]NT160 using 4-hydroxy-TEMPO which led to a significant improvement in radiochemical yield and molar activity. PET imaging with [F]NT160, a highly potent class-IIa HDAC inhibitor, led to high-quality and high-contrast images of the brain. [F]NT160 displayed excellent pharmacokinetic and imaging characteristics: brain uptake is high in gray matter regions, tissue kinetics are appropriate for a F-tracer, and specific binding for class-IIa HDACs is demonstrated by self-blockade. Higher uptake with [F]NT160 was observed in the hippocampus, thalamus, and cortex while the uptake in the cerebellum was relatively low. Overall, our current studies with [F]NT160 will likely facilitate the development and clinical translation of PET tracers for imaging of class-IIa HDACs biodistribution/expression in cancer and the CNS.

摘要

我们利用正电子发射断层扫描（PET）成像在体内对 IIa 类组蛋白去乙酰化酶（class-IIa HDACs）在中枢神经系统（CNS）中的时空生物分布/表达进行了定位。在此，我们报告了一种使用 4-羟基-TEMPO 改进的 [F]NT160 的放射合成方法，这导致放射化学产率和摩尔活性有了显著提高。使用 [F]NT160（一种高活性的 IIa 类 HDAC 抑制剂）进行 PET 成像，可得到高质量和高对比度的脑部图像。[F]NT160 表现出优异的药代动力学和成像特性：在灰质区域的脑摄取量高，组织动力学适合 F 示踪剂，并且通过自阻断证明了对 IIa 类 HDACs 的特异性结合。与小脑相比，在海马体、丘脑和皮层中观察到 [F]NT160 的摄取更高。总体而言，我们目前使用 [F]NT160 的研究可能会促进用于成像癌症和中枢神经系统中 IIa 类 HDACs 生物分布/表达的 PET 示踪剂的开发和临床转化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/f725997af459/jm2c02064_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/7321502b39e2/jm2c02064_0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/198ffc1cdf1e/jm2c02064_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/585ae9d036f1/jm2c02064_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/41bc51b0b7e5/jm2c02064_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/b38509c2fa09/jm2c02064_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/6a5ab9d7d01a/jm2c02064_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/e0100bf5bdce/jm2c02064_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/f725997af459/jm2c02064_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/7321502b39e2/jm2c02064_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/6af63eedfe5d/jm2c02064_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/198ffc1cdf1e/jm2c02064_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/585ae9d036f1/jm2c02064_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/41bc51b0b7e5/jm2c02064_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/b38509c2fa09/jm2c02064_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/6a5ab9d7d01a/jm2c02064_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/e0100bf5bdce/jm2c02064_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5964/10150721/f725997af459/jm2c02064_0008.jpg

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