Gravel Paul, Gu Jiwei, Wang Chao, Volpi Tommaso, Gallezot Jean-Dominique, Holden Daniel, Fowles Krista, Zheng Ming-Qiang, Zhang Li, Borroni Edilio, Honer Michael, Gobbi Luca, Tamagnan Gilles, Huang Yiyun, Carson Richard E
PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut;
PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
J Nucl Med. 2025 Oct 1;66(10):1652-1658. doi: 10.2967/jnumed.125.270332.
The main inhibitory neurotransmitter in the central nervous system is γ-aminobutyric acid (GABA). GABA transporter type 1 (GAT-1) is the principal GABA transporter in the brain, and it plays a crucial role in modulating GABA signaling. Its potential role in several neuropsychiatric disorders makes it an important target to study. Although PET radiotracers exist for the GABA receptors, none have been successful for imaging GAT-1. The focus of this work was to evaluate the kinetic behavior of 4 novel F-labeled PET radiotracers (F-GATT-31, F-GATT-34, F-GATT-39, and F-GATT-44) for imaging GAT-1 in nonhuman primates and to select the best radiotracer to progress to human studies. Twenty scans were acquired from 4 rhesus monkeys (). Each monkey received 0.5 mg/kg of tiagabine given approximately 20 min before radiotracer injection and underwent baseline and blocking scans with F-GATT-31, F-GATT-34, F-GATT-39, or F-GATT-44 on a small-animal PET scanner. During each scan, arterial blood was collected for measurement of the input function. Kinetic analysis was performed using a 1-tissue compartment model, 2-tissue reversible model ( > 0), and 2-tissue irreversible model ( = 0), including a blood volume fraction term and a time-delay term. All radiotracers exhibited good, albeit slow, brain uptake within the cortical and subcortical gray matter regions and cerebellum. Peripheral metabolism was slow for F-GATT-34, F-GATT-39, and F-GATT-44, with greater than 75% remaining as the parent compound, but was somewhat faster for F-GATT-31 (63%) over the 3-h scans. The 1-tissue compartment model delivered a reliable performance on the basis of the overall lowest Akaike information criterion and an SE of less than 10% for the volume of distribution. F-GATT-39 and F-GATT-34 were eliminated from progressing to human studies because of low brain uptake or low specific binding. The 2 remaining radiotracers had similar characteristics, with F-GATT-44 showing slightly superior performance over F-GATT-31, with more consistent tiagabine blocking results (65%-71%) and with nondisplaceable binding potential (BP) values ranging from 1.2 to 4.2 across gray matter structures. We successfully developed 4 GAT-1 selective radiotracers and evaluated them in nonhuman primates with kinetic analysis and blocking studies with tiagabine. Of these compounds, F-GATT-44 exhibited consistent results and reasonable BP values and will progress to human studies.
中枢神经系统中的主要抑制性神经递质是γ-氨基丁酸（GABA）。1型GABA转运体（GAT-1）是大脑中主要的GABA转运体，在调节GABA信号传导中起关键作用。其在几种神经精神疾病中的潜在作用使其成为一个重要的研究靶点。尽管存在用于GABA受体的PET放射性示踪剂，但尚无用于GAT-1成像的成功示踪剂。这项工作的重点是评估4种新型F标记的PET放射性示踪剂（F-GATT-31、F-GATT-34、F-GATT-39和F-GATT-44）在非人灵长类动物中成像GAT-1的动力学行为，并选择最佳的放射性示踪剂推进到人体研究。从4只恒河猴身上进行了20次扫描（）。每只猴子在注射放射性示踪剂前约20分钟给予0.5mg/kg的噻加宾，并在小动物PET扫描仪上用F-GATT-31、F-GATT-34、F-GATT-39或F-GATT-44进行基线和阻断扫描。在每次扫描期间，采集动脉血用于测量输入函数。使用单组织隔室模型、双组织可逆模型（>0）和双组织不可逆模型（=0）进行动力学分析，包括血容量分数项和时间延迟项。所有放射性示踪剂在皮质和皮质下灰质区域以及小脑中均表现出良好的、尽管较慢的脑摄取。F-GATT-34、F-GATT-39和F-GATT-44的外周代谢较慢，在3小时扫描中超过75%保留为母体化合物，但F-GATT-31（63%）的外周代谢稍快。基于总体最低的赤池信息准则和分布体积的标准误差小于10%，单组织隔室模型表现出可靠的性能。由于脑摄取低或特异性结合低，F-GATT-39和F-GATT-34被排除在推进到人体研究之外。剩下的2种放射性示踪剂具有相似的特征，F-GATT-44的性能略优于F-GATT-31，噻加宾阻断结果更一致（65%-71%），并且在灰质结构中的不可置换结合潜力（BP）值范围为1.2至4.2。我们成功开发了4种GAT-1选择性放射性示踪剂，并通过动力学分析和噻加宾阻断研究在非人灵长类动物中对其进行了评估。在这些化合物中，F-GATT-44表现出一致的结果和合理的BP值，并将推进到人体研究。
