Klein Pieter J, Schuit Robert C, Metaxas Athanasios, Christiaans Johannes A M, Kooijman Esther, Lammertsma Adriaan A, van Berckel Bart N M, Windhorst Albert D
Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Nucl Med Biol. 2017 Aug;51:25-32. doi: 10.1016/j.nucmedbio.2017.05.003. Epub 2017 May 8.
Presently available PET ligands for the NMDAr ion channel generally suffer from fast metabolism. The purpose of this study was to develop a metabolically more stable ligand for the NMDAr ion channel, taking [C]GMOM ([C]1) as the lead compound.
[C]1, its fluoralkyl analogue [F]PK209 ([F]2) and the newly synthesized fluorovinyloxy analogue [C]7b were evaluated ex vivo in male Wistar rats for metabolic stability. In addition, [C]7b was subjected to a biodistribution study and its affinity (K) and lipophilicity (logD) values were determined.
The addition of a vinyl chain in the fluoromethoxy moiety did not negatively alter the affinity of [C]7b for the NMDAr, while lipophilicity was increased. Biodistribution studies showed higher uptake of [C]7b in forebrain regions compared with cerebellum. Pre-treatment with MK-801 decreased the overall brain uptake significantly, but not in a region-specific manner. 45min after injection 78, 90 and 87% of activity in the brain was due to parent compound for [C]1, [F]2 and [C]7b, respectively. In plasma, 26-31% of activity was due to parent compound.
Complete substitution of the alpha-carbon increased lipophilicity to more favorable values. Substitution of one or more hydrogens of the alpha-carbon atom in the methoxy moiety improved metabolic stability. In plasma, more parent compound was found for [F]2 and [C]7b then for [C]1, although differences were not significant. At 45min, significantly more parent [F]2 and [C]7b was measured in the brain compared with [C]1.
目前用于NMDAr离子通道的PET配体通常存在代谢过快的问题。本研究的目的是以[C]GMOM（[C]1）为先导化合物，开发一种代谢更稳定的NMDAr离子通道配体。
在雄性Wistar大鼠体内对[C]1、其氟烷基类似物[F]PK209（[F]2）和新合成的氟乙烯氧基类似物[C]7b进行代谢稳定性的体外评估。此外，对[C]7b进行生物分布研究，并测定其亲和力（K）和亲脂性（logD）值。
在氟甲氧基部分添加乙烯链不会对[C]7b与NMDAr的亲和力产生负面影响，同时亲脂性增加。生物分布研究表明，与小脑相比，[C]7b在前脑区域的摄取更高。用MK-801预处理可显著降低整体脑摄取，但无区域特异性。注射后45分钟，[C]1、[F]2和[C]7b在脑中的活性分别有78%、90%和87%归因于母体化合物。在血浆中，26 - 31%的活性归因于母体化合物。
α-碳的完全取代使亲脂性增加到更有利的值。甲氧基部分α-碳原子上一个或多个氢的取代提高了代谢稳定性。在血浆中，[F]2和[C]7b的母体化合物比[C]1多，尽管差异不显著。在45分钟时，与[C]1相比，脑中检测到的母体[F]2和[C]7b明显更多。
