Department of Radiology & Nuclear Medicine, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands.
Centre for Human Drug Research, Leiden, The Netherlands.
Mol Imaging Biol. 2019 Aug;21(4):676-685. doi: 10.1007/s11307-018-1284-x.
There are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brain N-methyl-D-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5-(4-fluoro-2-[C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamin ([C]HACH242). This paper reports the evaluation of [C]HACH242 PET in non-human primates at baseline and following administration of the GluN2B negative allosteric modulator radiprodil.
Eight 90-min dynamic [C]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.
[C]HACH242 entered the brain and displayed fairly uniform uptake. The mean (± standard deviation, SD) T was 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 [C]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 %.
The present results show that [C]HACH242 has a suitable kinetic profile in the brain and low accumulation of lipophilic radiometabolites. Radiprodil did not consistently change [C]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 for in vivo imaging of the ionotropic NMDA receptor.
目前尚无用于脑 N-甲基-D-天冬氨酸 (NMDA) 受体 GluN2B（NR2B）结合部位的正电子发射断层扫描 (PET) 放射性示踪剂。在大鼠中，GluN2B 拮抗剂 Ro25-6981 降低了 N-((5-(4-氟-2-[C]甲氧基苯基)吡啶-3-基)甲基)环戊烷胺 ([C]HACH242) 的结合。本文报告了非人类灵长类动物中 [C]HACH242 PET 在基线和 GluN2B 负变构调节剂 radiprodil 给药后 10 分钟的评估。
在 3 只麻醉恒河猴中进行了 8 次 90 分钟的动态 [C]HACH242 PET 扫描，包括第 1 只动物的重测，在基线和静脉注射 10mg/kg radiprodil 后 10 分钟。计算了 9 个脑区的标准化摄取值 (SUV)。在六个时间点采集动脉血样，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变异性，无法生成可靠的用于动力学建模的输入函数。
[C]HACH242 进入大脑并显示出相当均匀的摄取。基线扫描中 T 的平均值（±标准偏差，SD）为 17±7 分钟，而 radiprodil 扫描中为 24±15 分钟。血浆中放射性配体代谢（主要转化为极性代谢物）速度很快，20 分钟时母体分数平均为 26±10%，85 分钟时为 8±5%。Radiprodil 分别使第 1、2、3 只动物和第 1 只动物的重测最后一个 PET 帧的 [C]HACH242 全脑 SUV 增加了 25%、1%、3%和 17%。脑与血浆的比值为 5.4±2.6，在 radiprodil 条件下增加 39%至 110%，部分原因是母体血浆放射性降低 -11 至 -56%。
目前的结果表明，[C]HACH242 在大脑中具有合适的动力学特征，并且脂溶性放射性代谢物的积累较少。Radiprodil 并未一致改变 [C]HACH242 的大脑摄取。这些发现可能是由于脑血流的变化、特异性结合示踪剂的分数低，或与结合部位的内源性 NMDA 受体配体相互作用所致。需要进一步进行配体相互作用的实验，以促进用于 NMDA 受体离子型体内成像的放射性示踪剂的开发。
