Development of [Carbonyl-11C]AZ13198083, a Novel Histamine Type-3 Receptor Radioligand with Favorable Kinetics,ACS Chemical Neuroscience

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Development of [Carbonyl-11C]AZ13198083, a Novel Histamine Type-3 Receptor Radioligand with Favorable Kinetics
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-01-23 00:00:00 , DOI: 10.1021/acschemneuro.7b00493
Kenneth Dahl ₁ , Ryuji Nakao ₁ , Nahid Amini ₁ , Mohammad Mahdi Moein ₁ , Sjoerd Finnema ₁ , Jonas Malmquist ₂ , Katarina Varnäs ₁ , Magnus Schou _{1,

2}

Affiliation

The histamine subtype-3 receptor (H₃R) is implicated in a range of central nervous system disorders, and several radioligands have been developed for H₃R positron emission tomography imaging. However, a limitation of currently used PET radioligands for H₃R is the slow binding kinetics in high density brain regions. To address this, we herein report the development of three novel candidate H₃R radioligands, namely, [carbonyl-¹¹C]AZ13153556 ([carbonyl-¹¹C]4), [carbonyl-¹¹C]AZD5213([carbonyl-¹¹C]5), and [carbonyl-¹¹C]AZ13198083 ([carbonyl-¹¹C]6), and their subsequent preclinical evaluation in nonhuman primates (NHP). Radioligands [carbonyl-¹¹C]4–6 were produced and isolated in high radioactivity (>1000 MBq), radiochemical purity (>99%), and moderate molar activity (19–28 GBq/μmol at time of injection) using a palladium-mediated ¹¹C-aminocarbonylation protocol. All three radioligands showed high brain permeability as well as a regional brain radioactivity distribution in accordance with H₃R expression (striatum > cortex > cerebellum). [Carbonyl-¹¹C]6 displayed the most favorable in vivo kinetics and brain uptake, with an early peak in the striatal time–activity curve followed by a progressive washout from the brain. The specificity and on-target kinetics of [carbonyl-¹¹C]6 were next investigated in pretreatment and displacement studies. After pretreatment or displacement with 5 (0.1 mg/kg), a uniformly low distribution of radioactivity across the NHP brain was observed. Collectively, this work demonstrates that [carbonyl-¹¹C]6 is a promising candidate for H₃R imaging in human subjects.

中文翻译：

具有良好动力学的新型组胺3型受体放射性配体[ Carbonyl - ¹¹ C] AZ13198083的开发

组胺亚型3受体（H ₃ R）与一系列中枢神经系统疾病有关，并且已经为H ₃ R正电子发射断层显像开发了几种放射性配体。但是，当前使用的PET放射性配体对H ₃ R的局限性是高密度大脑区域的缓慢结合动力学。为了解决这个问题，我们在此报告的三种新的候选H发展₃ - [R放射性配体，即，[羰基- ¹¹ C] AZ13153556（[羰基- ¹¹ C] 4），[羰基- ¹¹ C] AZD5213（[羰基- ¹¹ C ^ ]5）和[羰基- ¹¹ C] AZ13198083（[羰基- ¹¹ C] 6），以及在非人灵长类动物及其随后的临床前评估（NHP）。放射性配体[羰基- ¹¹ C] 4 - 6中制作的，在高放射性分离（> 1000活度），放射化学纯度（> 99％），并使用钯中度摩尔活性（在注射时间19-28吉贝/微摩尔） -介导的¹¹ C-氨基羰基化方案。所有三种放射性配体均显示出高的脑通透性以及符合H ₃的局部脑放射性分布R表达（纹状体>皮层>小脑）。[羰基- ¹¹ C] 6显示体内动力学和脑摄取的最有利的，随着时间纹状体-活性曲线，接着从大脑的渐进冲洗早期峰。特异性和对靶动力学[羰基- ¹¹ C] 6在预处理和位移研究，接着研究。在用5（0.1 mg / kg）进行预处理或置换后，在整个NHP脑中观察到放射性的均匀分布较低。总之，这项工作表明，[羰基- ¹¹ C] 6是H A前途的候选人类受试者的₃ R成像。

更新日期：2018-01-23

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