Zhou Xiaoyun, Boellaard Ronald, Ishiwata Kiichi, Sakata Muneyuki, Dierckx Rudi A J O, de Jong Johan R, Nishiyama Shingo, Ohba Hiroyuki, Tsukada Hideo, de Vries Erik F J, Elsinga Philip H
University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
J Nucl Med. 2017 May;58(5):762-767. doi: 10.2967/jnumed.116.182410. Epub 2017 Jan 6.
C-preladenant was developed as a novel PET ligand for the adenosine A receptors (ARs). The present study aimed to evaluate the suitability of C-preladenant PET for the quantification of striatal ARs and the assessment of AR occupancy in the conscious monkey brain. C-preladenant was intravenously injected into conscious monkeys ( = 4, 18 PET scans), and a 91-min dynamic scan was started. Arterial blood samples in combination with metabolite analysis were obtained during the scan to provide the input function for kinetic modeling. The distribution volume () was obtained by kinetic modeling with a 2-tissue-compartment model. The simplified reference tissue model (SRTM) with selected reference regions (cerebellum, cingulate, parietal cortex, and occipital cortex) was tested to estimate the binding potential () in AR-rich regions. obtained from the SRTM was compared with distribution volume ratio (DVR)-1. The effects of blood volume, blood delay, and scan duration on and DVR-1 were investigated. and were also obtained after preblocking with unlabeled preladenant (1 mg/kg), AR-selective KW-6002 (0.5-1 mg/kg), and nonselective adenosine receptor antagonist caffeine (2.5-10 mg/kg). AR occupancy was studied with caffeine blockade. Regional uptake of C-preladenant was consistent with the distribution of ARs in the monkey brain, with the highest uptake in the putamen, followed by the caudate, and the lowest uptake in the cerebellum. Tracer kinetics were well described by the 2-tissue-compartment model with a lower constraint on to stabilize fits. The highest was observed in AR-rich regions (∼5.8-7.4) and lowest value in the cerebellum (∼1.3). values estimated from the SRTM with different scan durations were comparable and were in agreement with DVR-1 (∼4.3-5.3 in AR-rich regions). Preladenant preinjection decreased the tracer uptake in AR-rich regions to the level of the reference regions. Caffeine pretreatment reduced the tracer uptake in the striatum in a dose-dependent manner. C-preladenant PET is suitable for noninvasive quantification of ARs and assessment of AR occupancy in AR-rich regions in the monkey brain. SRTM using the cerebellum as the reference tissue is the applicable model for AR quantification.
C-预拉丹宁作为一种新型的用于腺苷A受体（ARs）的正电子发射断层扫描（PET）配体而被开发出来。本研究旨在评估C-预拉丹宁PET用于定量纹状体ARs以及评估清醒猴脑中AR占有率的适用性。将C-预拉丹宁静脉注射到清醒猴（n = 4，进行18次PET扫描）体内，并开始91分钟的动态扫描。在扫描过程中采集动脉血样本并结合代谢物分析，以提供动力学建模的输入函数。通过用双组织隔室模型进行动力学建模来获得分布容积（Vd）。测试了采用选定参考区域（小脑、扣带回、顶叶皮质和枕叶皮质）的简化参考组织模型（SRTM），以估计富含AR区域的结合潜能（BP）。将从SRTM获得的BP与分布容积比（DVR）-1进行比较。研究了血容量、血液延迟和扫描持续时间对Vd和DVR-1的影响。在用未标记的预拉丹宁（1mg/kg）、AR选择性KW-6002（0.5 - 1mg/kg）和非选择性腺苷受体拮抗剂咖啡因（2.5 - 10mg/kg）进行预阻断后，也获得了Vd和BP。用咖啡因阻断来研究AR占有率。C-预拉丹宁的区域摄取与猴脑中AR的分布一致，壳核摄取最高，其次是尾状核，小脑摄取最低。双组织隔室模型能很好地描述示踪剂动力学，对Vd的约束较低以稳定拟合。在富含AR的区域观察到最高的BP（约5.8 - 7.4），在小脑中最低（约1.3）。用不同扫描持续时间从SRTM估计的BP值具有可比性，并且与DVR-1一致（在富含AR的区域约为4.3 - 5.3）。预注射预拉丹宁使富含AR区域的示踪剂摄取降低到参考区域的水平。咖啡因预处理以剂量依赖的方式降低了纹状体中的示踪剂摄取。C-预拉丹宁PET适用于对猴脑中富含AR区域的AR进行无创定量和评估AR占有率。以小脑作为参考组织的SRTM是用于AR定量的适用模型。
