Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain,ACS Chemical Neuroscience

当前位置： X-MOL 学术 › ACS Chem. Neurosci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-11-13 00:00:00 , DOI: 10.1021/acschemneuro.7b00340
Jonas Malmquist ₁ , Katarina Varnäs ₁ , Marie Svedberg ₁ , Frédéric Vallée ₂ , Jeffrey S. Albert ₂ , Sjoerd J. Finnema ₁ , Magnus Schou _{1,

3}

Affiliation

Positron emission tomography (PET), together with a suitable radioligand, is one of the more prominent methods for measuring changes in synaptic neurotransmitter concentrations in vivo. The radioligand of choice for such measurements on the cholinergic system is the muscarinic receptor antagonist N-[1-¹¹C]propyl-3-piperidyl benzilate (PPB). In an effort to overcome the shortcomings with the technically cumbersome synthesis of [¹¹C]PPB, we designed and synthesized four structurally related analogues of PPB, of which (S,R)-1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate (1) was found to bind muscarinic receptors with similar affinity as PPB (3.5 vs 7.9 nM, respectively). (S,R)-1 was radiolabeled via N-¹¹C-methylation at high radiochemical purity (>99%) and high specific radioactivity (>130 GBq/μmol). In vitro studies by autoradiography on human brain tissue and in vivo studies by PET in nonhuman primates demonstrated excellent signal-to-noise ratios and a kinetic profile in brain comparable to that of [¹¹C]PBB. (S,R)-[¹¹C]1 is a promising candidate for measuring changes in endogenous acetylcholine concentrations.

中文翻译：

在猴脑中发现具有快速动力学的新型毒蕈碱受体PET放射性配体

正电子发射断层扫描（PET）与合适的放射性配体一起，是测量体内突触神经递质浓度变化的最主要方法之一。所选择的用于这种测量的胆碱能系统的放射性配体是毒蕈碱受体拮抗剂ñ - [1- ¹¹ C]丙基-3-哌啶基二苯乙醇酸（PPB）。为了克服技术上繁琐的[ ¹¹ C] PPB合成的缺点，我们设计并合成了四种结构上相关的PPB类似物，其中（S，R）-1-甲基哌啶-3-基）2-环戊基- 2-羟基-2-苯基乙酸酯（1）被发现以与PPB相似的亲和力结合毒蕈碱受体（分别为3.5 vs 7.9 nM）。（S，R）-1通过N - ¹¹ C-甲基化以高放射化学纯度（> 99％）和高比放射性（> 130 GBq /μmol）进行放射性标记。通过放射自显影在人脑组织上进行的体外研究以及在非人灵长类动物中通过PET进行的体内研究表明，与[ ¹¹ C] PBB相比，脑中具有出色的信噪比和动力学特性。（S，R）-[ ¹¹ C] 1是用于测量内源性乙酰胆碱浓度变化的有希望的候选者。

更新日期：2017-11-14

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11