Lehto Jussi, Johansson Jarkko, Vuorilehto Lauri, Luoto Pauliina, Arponen Eveliina, Scheinin Harry, Rouru Juha, Scheinin Mika
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
Clinical Research Services Turku CRST, University of Turku, Itäinen Pitkäkatu 4 B, 20520, Turku, Finland.
Psychopharmacology (Berl). 2015 Nov;232(21-22):4169-78. doi: 10.1007/s00213-015-3941-y. Epub 2015 Apr 29.
No validated methods have been available for studying brain noradrenergic neurotransmission in vivo in humans. Positron emission tomography (PET) radiotracers are widely used in clinical drug development targeted to brain receptors and can also in some cases be employed to monitor extracellular (synaptic) neurotransmitter concentrations.
The objective of this study is to test the sensitivity of [(11)C]ORM-13070 uptake to increased concentrations of extracellular (synaptic) noradrenaline in the human brain.
Eight subjects underwent a control PET scan with [(11)C]ORM-13070, a subtype-selective α2C-adrenoceptor antagonist radioligand, and two PET scans after two different noradrenaline challenges, i.e. during ketamine infusion and after a dose of atomoxetine combined with cold stimulation. Tracer uptake in the caudate nucleus and putamen was described with AUC values in scan time windows of 10-20 and 5-30 min post injection and quantified with the ratio method. Voxel-based analysis was performed with average bound per free (B/F) ratio images.
Both noradrenaline challenges were consistently associated with 10-20 % (p < 0.05) reductions in tracer uptake in the dorsal striatum, as determined with region-of-interest-based analysis. Voxel-based analysis revealed significant reductions in B/F ratios in the dorsal striatum, in the brain stem and in several cortical areas. Reductions of 24 and 23 % were detected in the peak putamen clusters with ketamine and atomoxetine + cold, respectively.
Direct experimental support was gained for the suitability of [(11)C]ORM-13070 for imaging of brain noradrenergic neurotransmission.
目前尚无经过验证的方法可用于在人体中体内研究脑去甲肾上腺素能神经传递。正电子发射断层扫描（PET）放射性示踪剂广泛应用于针对脑受体的临床药物研发，并且在某些情况下还可用于监测细胞外（突触）神经递质浓度。
本研究的目的是测试[(11)C]ORM-13070摄取对人脑中细胞外（突触）去甲肾上腺素浓度升高的敏感性。
8名受试者接受了一次使用[(11)C]ORM-13070（一种亚型选择性α2C-肾上腺素能受体拮抗剂放射性配体）的对照PET扫描，以及在两次不同的去甲肾上腺素激发后进行的两次PET扫描，即在氯胺酮输注期间和一剂托莫西汀联合冷刺激后。在注射后10 - 20分钟和5 - 30分钟的扫描时间窗内，用AUC值描述尾状核和壳核中的示踪剂摄取情况，并采用比值法进行定量。使用平均结合与游离（B/F）比值图像进行基于体素的分析。
基于感兴趣区域的分析确定，两次去甲肾上腺素激发均与背侧纹状体中示踪剂摄取减少10 - 20%（p < 0.05）一致。基于体素的分析显示，背侧纹状体、脑干和几个皮质区域的B/F比值显著降低。氯胺酮和托莫西汀 + 冷刺激分别在壳核峰值簇中检测到24%和23%的降低。
获得了直接的实验支持，证明[(11)C]ORM-13070适用于脑去甲肾上腺素能神经传递成像。
