Sakata Muneyuki, Ishibashi Kenji, Imai Masamichi, Wagatsuma Kei, Ishii Kenji, Zhou Xiaoyun, de Vries Erik F J, Elsinga Philip H, Ishiwata Kiichi, Toyohara Jun
Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Department of Radiology, Toranomon Hospital, Tokyo, Japan.
J Nucl Med. 2017 Sep;58(9):1464-1470. doi: 10.2967/jnumed.116.188474. Epub 2017 Mar 9.
C-preladenant is a selective antagonist for mapping of cerebral adenosine A receptors (ARs) by PET. This is a first-in-human study to examine the safety, radiation dosimetry, and brain imaging of C-preladenant in healthy human subjects. Dynamic C-preladenant PET scans (90 min) were obtained in 5 healthy male subjects. During the scan, arterial blood was sampled at various time intervals, and the fraction of the parent compound in plasma was determined. For anatomic coregistration, T1-weighted MRI was performed. The total distribution volume () was estimated using 1- and 2-tissue-compartment models (1T and 2T, respectively). The distribution volume ratio (DVR) was calculated from of target and reference region and obtained with a noninvasive Logan graphical reference tissue method (* = 30 min). The applicability of a shortened protocol as an alternative to the 90-min PET scan was investigated. Tracer biodistribution and dosimetry were determined in 3 healthy male subjects, using serial whole-body PET scans acquired over 2 h after C-preladenant injection. There were no serious adverse events in any of the subjects throughout the study period. C-preladenat readily entered the brain, with a peak uptake in the putamen and head of the caudate nucleus 30-40 min after tracer injection. Other brain regions showed rapid clearance of radioactivity. The regional distribution of C-preladenant was consistent with known AR densities in the brain. At pseudoequilibrium (reached at 40 min after injection), stable target-to-cerebellar cortex ratios of around 3.8-10.0 were obtained. The 2T fit better than the 1T in the low-density AR regions. In contrast, there were no significant differences between 1T and 2T in the high-AR-density regions. DVRs in the putamen and head of the caudate nucleus were around 3.8-10.3 when estimated using a Logan graphical reference tissue method with cerebellum as the reference region. PET scanning at 50 or 70 min can provide the stable DVR estimates within 10% or 5% differences at most, respectively. The radioactivity was mainly excreted through the hepatobiliary system after C-preladenant injection. As a result, the absorbed dose (μGy/MBq) was highest in the gallbladder wall (mean ± SD, 17.0 ± 2.5) and liver (11.7 ± 2.1). The estimated effective dose for C-preladenant was 3.7 ± 0.4 μSv/MBq. This initial evaluation indicated that C-preladenat is suitable for imaging of ARs in the brain.
C-预负荷拮抗剂是一种用于通过正电子发射断层扫描（PET）绘制脑腺苷A受体（ARs）图谱的选择性拮抗剂。这是一项在健康人类受试者中研究C-预负荷拮抗剂的安全性、辐射剂量学和脑成像的首例人体研究。对5名健康男性受试者进行了动态C-预负荷拮抗剂PET扫描（90分钟）。在扫描过程中，在不同时间间隔采集动脉血样，并测定血浆中母体化合物的分数。为进行解剖配准，进行了T1加权磁共振成像（MRI）。使用单组织室模型和双组织室模型（分别为1T和2T）估计总分布容积（）。分布容积比（DVR）由靶区和参考区的计算得出，并采用非侵入性洛根图形参考组织法（* = 30分钟）获得。研究了缩短方案作为90分钟PET扫描替代方案的适用性。在3名健康男性受试者中，在注射C-预负荷拮抗剂后2小时内进行系列全身PET扫描，以确定示踪剂生物分布和剂量学。在整个研究期间，所有受试者均未出现严重不良事件。C-预负荷拮抗剂很容易进入大脑，在示踪剂注射后30 - 40分钟，壳核和尾状核头部摄取达到峰值。其他脑区放射性迅速清除。C-预负荷拮抗剂的区域分布与大脑中已知的AR密度一致。在假平衡状态（注射后40分钟达到），获得的靶区与小脑皮质的稳定比值约为3.8 - 10.0。在低密度AR区域，2T模型比1T模型拟合得更好。相比之下，在高AR密度区域，1T和2T之间没有显著差异。当以小脑作为参考区域，采用洛根图形参考组织法估计时，壳核和尾状核头部的DVR约为3.8 - 10.3。在50分钟或70分钟进行PET扫描，分别最多可提供差异在10%或5%以内的稳定DVR估计值。注射C-预负荷拮抗剂后，放射性主要通过肝胆系统排泄。因此，胆囊壁（均值±标准差，17.0±2.5）和肝脏（11.7±2.1）的吸收剂量（μGy/MBq）最高。C-预负荷拮抗剂的估计有效剂量为3.7±0.4μSv/MBq。这项初步评估表明，C-预负荷拮抗剂适用于脑内ARs的成像。
