Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, MA, 02129, USA.
Department of Pharmacology, University of North Carolina Chapel Hill School of Medicine, Chapel Hill, NC, 27514, USA.
Mol Imaging Biol. 2021 Aug;23(4):527-536. doi: 10.1007/s11307-021-01586-0. Epub 2021 Feb 8.
Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [C]7 as a PET radioligand for imaging mGluR2. Herein, [F]JNJ-46356479 ([F]8) was synthesized and characterized as the first F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.
JNJ-46356479 (8) was radiolabeled via the copper (I)-mediated radiofluorination of organoborane 9. In vivo PET imaging experiments with [F]8 were conducted first in C57BL/6 J mice and Sprague-Dawley rats to obtain whole body biodistribution and brain uptake profile. Subsequent PET studies were done in a cynomolgus monkey (Macaca fascicularis) to investigate the uptake of [F]8 in the brain, its metabolic stability, as well as pharmacokinetic properties.
JNJ-46356479 (8) exhibited excellent selectivity against other mGluRs. In vivo PET imaging studies showed reversible and specific binding characteristic of [F]8 in rodents. In the non-human primate, [F]8 displayed good in vivo metabolic stability, excellent brain permeability, fast and reversible kinetics with moderate heterogeneity across brain regions. Pre-treatment studies with compound 7 revealed time-dependent decrease of [F]8 accumulation in mGluR2 rich regions based on SUV values with the highest decrease in the nucleus accumbens (18.7 ± 5.9%) followed by the cerebellum (18.0 ± 7.9%), the parietal cortex (16.9 ± 7.8%), and the hippocampus (16.8 ± 6.9%), similar to results obtained in the rat studies. However, the volume of distribution (V) results derived from 2T4k model showed enhanced V from a blocking study with compound 7. This is probably because of the potentiating effect of compound 7 as an mGluR2 PAM as well as related non-specific binding in the tissue data.
[F]8 readily crosses the blood-brain barrier and demonstrates fast and reversible kinetics both in rodents and in a non-human primate. Further investigation of [F]8 on its binding specificity would warrant translational study in human.
代谢型谷氨酸受体 2（mGluR2）与精神分裂症和阿尔茨海默病等各种精神和神经疾病有关。我们之前开发了 [C]7 作为用于成像 mGluR2 的 PET 放射性配体。本文合成并表征了 [F]JNJ-46356479（[F]8）作为第一个 F 标记的 mGluR2 成像配体，以增强与 mGluR2 相关疾病的诊断方法。
通过有机硼烷 9 的铜（I）介导的放射性氟化作用对 JNJ-46356479（8）进行放射性标记。首先在 C57BL/6 J 小鼠和 Sprague-Dawley 大鼠中进行 [F]8 的体内 PET 成像实验，以获得全身生物分布和脑摄取曲线。随后在食蟹猴（Macaca fascicularis）中进行 PET 研究，以研究 [F]8 在大脑中的摄取、代谢稳定性以及药代动力学特性。
JNJ-46356479（8）对其他 mGluR 表现出优异的选择性。体内 PET 成像研究表明，[F]8 在啮齿动物中具有可逆和特异性结合特征。在非人类灵长类动物中，[F]8 显示出良好的体内代谢稳定性、优异的脑通透性、快速和可逆的动力学以及跨脑区的中等异质性。用化合物 7 进行的预处理研究表明，基于 SUV 值，[F]8 积累与时间呈依赖性下降，在纹状体（18.7±5.9%）后，小脑（18.0±7.9%）、顶叶皮层（16.9±7.8%）和海马体（16.8±6.9%），与大鼠研究结果相似。然而，2T4k 模型的分布容积（V）结果显示，用化合物 7 进行阻断研究后 V 增加。这可能是由于化合物 7 作为 mGluR2 PAM 的增效作用以及组织数据中的相关非特异性结合所致。
[F]8 很容易穿过血脑屏障，在啮齿动物和非人类灵长类动物中均表现出快速和可逆的动力学。进一步研究 [F]8 的结合特异性将需要在人类中进行转化研究。
