Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates
Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates
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DOI：
10.1007/s11307-018-1284-x
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发表时间：
2018-10
影响因子：
3.1
通讯作者：
Jasper van der Aart;M. Yaqub;E. Kooijman;J. Bakker;J. Langermans;R. Schuit;M. Hofman;J. Christiaans;A. Lammertsma;A. Windhorst;B. V. van Berckel
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文献类型：
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作者：
Jasper van der Aart;M. Yaqub;E. Kooijman;J. Bakker;J. Langermans;R. Schuit;M. Hofman;J. Christiaans;A. Lammertsma;A. Windhorst;B. V. van Berckel
目的目前还没有针对脑n -甲基-d-天冬氨酸（NMDA）受体GluN2B （NR2B）结合位点的正电子发射断层扫描（PET）示踪剂。在大鼠中，GluN2B拮抗剂Ro25-6981降低了N-（（5-（4-氟-2-[11C]甲氧基苯基）吡啶-3-基）甲基）环戊胺（[11C]HACH242）的结合。本文报道了非人类灵长类动物在基线和给药GluN2B阴性变构调节剂radiprodil后[11C]HACH242 PET的评估。对3只雄性麻醉恒河猴进行8次90分钟动态[11C]HACH242 PET扫描，包括受试者1在基线和静脉注射10mg /kg雷地尔后10分钟的重新测试。计算9个脑区的标准化摄取值（SUV）。在六个时间点采集动脉血样本，以表征血液和血浆中的药代动力学。由于全血放射性测量的可变性，无法生成可靠的动力学建模输入函数。结果[11C]HACH242进入大脑并表现出相当均匀的摄取。基线扫描的平均（±标准差，SD） tmax为17±7 min， radiprodil扫描为24±15 min。血浆中放射性配体代谢率（主要是极性代谢物）很高，平均亲本组分在20分钟为26±10%，在85分钟为8±5%。在受试者1、受试者2、受试者3和受试者1的复测中，Radiprodil使[11C]HACH242在最后一个PET帧的全脑SUV分别增加25%、1%、3%和17%。平均脑与血浆比值为5.4±2.6，在放射地尔组中增加了39% ~ 110%，部分原因是母体血浆放射性较低，为- 11 ~ - 56%。结论[11C]HACH242在脑内具有合适的动力学谱，且亲脂性放射性代谢物蓄积量低。雷地尔并没有持续改变HACH242脑摄取[11C]。这些发现可能是由于脑血流的变化，特异性结合示踪剂的低比例，或与内源性NMDA受体配体在结合部位的相互作用。配体相互作用的进一步实验是必要的，以促进放射性示踪剂的发展，为体内成像的电离性NMDA受体。
PurposeThere are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brainN-methyl-d-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamin ([11C]HACH242). This paper reports the evaluation of [11C]HACH242 PET in non-human primates at baseline and following administration of the GluN2B negative allosteric modulator radiprodil.ProceduresEight 90-min dynamic [11C]HACH242 PET scans were acquired in three male anaesthetised rhesus monkeys, including a retest session of subject 1, at baseline and 10 min after intravenous 10 mg/kg radiprodil. Standardised uptake values (SUV) were calculated for 9 brain regions. Arterial blood samples were taken at six timepoints to characterise pharmacokinetics in blood and plasma. Reliable input functions for kinetic modelling could not be generated due to variability in the whole-blood radioactivity measurements.Results[11C]HACH242 entered the brain and displayed fairly uniform uptake. The mean (± standard deviation, SD)Tmaxwas 17 ± 7 min in baseline scans and 24 ± 15 min in radiprodil scans. The rate of radioligand metabolism in plasma (primarily to polar metabolites) was high, with mean parent fractions of 26 ± 10 % at 20 min and 8 ± 5 % at 85 min. Radiprodil increased [11C]HACH242 whole-brain SUV in the last PET frame by 25 %, 1 %, 3 and 17 % for subjects 1, 2, 3 and retest of subject 1, respectively. The mean brain to plasma ratio was 5.4 ± 2.6, and increased by 39 to 110 % in the radiprodil condition, partly due to lower parent plasma radioactivity of −11 to −56 %.ConclusionsThe present results show that [11C]HACH242 has a suitable kinetic profile in the brain and low accumulation of lipophilic radiometabolites. Radiprodil did not consistently change [11C]HACH242 brain uptake. These findings may be explained by variations in cerebral blood flow, a low fraction of specifically bound tracer, or interactions with endogenous NMDA receptor ligands at the binding site. Further experiments of ligand interactions are necessary to facilitate the development of radiotracers forin vivoimaging of the ionotropic NMDA receptor.