In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT_1A receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT_1A-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT_1A radiotracer, [¹⁸F]MPPF. Drug occupancy was evaluated after injection at 50 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT_1A receptor occupancy was found to be dose-dependent for both agonists, but differed in magnitude and spatial distribution at equal doses with distinct BOLD patterns. Functional connectivity, as measured by BOLD signal temporal correlations between regions, was also differently modified by NLX-112 or NLX-101. Voxel-based correlation analyses between PET and fMRI suggested that NLX-112 stimulates both 5-HT_1A autoreceptors and post-synaptic receptors, whereas NLX-101 preferentially stimulates post-synaptic cortical receptors. In cingulate cortex, the agonists induced opposite BOLD signal changes in response to receptor occupancy. These data constitute the first simultaneous exploration of 5-HT_1A occupancy and its consequences in terms of brain activation, and demonstrates differential signalling by two 5-HT_1A-biased agonists. Combined PET/fMRI represents a powerful tool in neuropharmacology, and opens new ways to address the concept of biased agonism by translational approaches.

中文翻译：

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对5-HT1A受体的体内偏向激动作用：通过同时进行PET / MR成像进行表征。

在神经药理学中，“偏向激动作用”的最新概念表示某些激动剂对特定大脑区域中给定受体的靶标特定细胞内途径的能力。在5-羟色胺药物治疗的背景下，偏向5-HT _1A受体的激动剂可能会引起多种神经精神疾病。这项研究的目的是确定是否可以通过同时使用功能磁共振成像（fMRI）和正电子发射断层扫描（PET）脑成像来区分偏向激动剂是否在区域靶向方面有所区别。我们比较了两个5-HT _1A麻醉的猫（n = 4）以三种不同的剂量注射了偏向性的激动剂NLX-112和NLX-101。大剂量给药后90分钟进行PET成像，然后持续输注5-HT _1A放射性示踪剂[ ¹⁸ F] MPPF。注射50分钟后评估药物占用情况，同时获取BOLD fMRI评估随后的大脑激活模式。5-HT _1A发现两种激动剂的受体占用均与剂量有关，但是在等剂量下具有明显的BOLD模式的幅度和空间分布不同。通过区域之间的BOLD信号时间相关性来衡量的功能连接性，也被NLX-112或NLX-101进行了不同的修改。PET和fMRI之间基于体素的相关性分析表明，NLX-112刺激5-HT _1A自身受体和突触后受体，而NLX-101优先刺激突触后皮质受体。在扣带回皮层中，激动剂响应受体占用而诱导相反的BOLD信号变化。这些数据构成了对5-HT _1A的首次同步探索占用和它对大脑激活的影响，并显示了由两个5-HT _1A偏向激动剂产生的差异信号。结合的PET / fMRI代表了神经药理学中的强大工具，并开辟了新的途径来解决通过平移方法产生的激动性激动的概念。