Golla Sandeep S V, Klein Pieter J, Bakker Jaco, Schuit Robert C, Christiaans Johannes A M, van Geest Leo, Kooijman Esther J M, Oropeza-Seguias Gisela M, Langermans Jan A M, Leysen Josée E, Boellaard Ronald, Windhorst Albert D, van Berckel Bart N M, Metaxas Athanasios
Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
Biomedical Primate Research Centre, Rijswijk, the Netherlands.
Nucl Med Biol. 2015 Feb;42(2):205-12. doi: 10.1016/j.nucmedbio.2014.09.006. Epub 2014 Sep 30.
The present study was designed to assess whether [(18)F]PK-209 (3-(2-chloro-5-(methylthio)phenyl)-1-(3-([(18)F]fluoromethoxy)phenyl)-1-methylguanidine) is a suitable ligand for imaging the ion-channel site of N-methyl-D-aspartate receptors (NMDArs) using positron emission tomography (PET).
Dynamic PET scans were acquired from male rhesus monkeys over 120min, at baseline and after the acute administration of dizocilpine (MK-801, 0.3mg/kg; n=3/condition). Continuous and discrete arterial blood samples were manually obtained, to generate metabolite-corrected input functions. Parametric volume-of-distribution (VT) images were obtained using Logan analysis. The selectivity profile of PK-209 was assessed in vitro, on a broad screen of 79 targets.
PK-209 was at least 50-fold more selective for NMDArs over all other targets examined. At baseline, prolonged retention of radioactivity was observed in NMDAr-rich cortical regions relative to the cerebellum. Pretreatment with MK-801 reduced the VT of [(18)F]PK-209 compared with baseline in two of three subjects. The rate of radioligand metabolism was high, both at baseline and after MK-801 administration.
PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [(18)F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.
本研究旨在评估[(18)F]PK - 209（3 - (2 - 氯 - 5 - (甲硫基)苯基)-1 - (3 - ([(18)F]氟甲氧基)苯基)-1 - 甲基胍）是否是一种适合使用正电子发射断层扫描（PET）对N - 甲基 - D - 天冬氨酸受体（NMDArs）的离子通道位点进行成像的配体。
对雄性恒河猴进行120分钟的动态PET扫描，分别在基线期以及急性给予地佐环平（MK - 801，0.3mg/kg；每种情况n = 3）后进行。手动采集连续和离散的动脉血样本，以生成代谢物校正的输入函数。使用洛根分析法获得分布容积（VT）参数图像。在体外对79种靶点进行广泛筛选，评估PK - 209的选择性概况。
与所有其他检测靶点相比，PK - 209对NMDArs的选择性至少高50倍。在基线期，相对于小脑，在富含NMDArs的皮质区域观察到放射性的长时间滞留。在三名受试者中的两名中，与基线相比，MK - 801预处理降低了[(18)F]PK - 209的VT。在基线期和给予MK - 801后，放射性配体的代谢率都很高。
PK - 209以高选择性靶向离子通道位点。尽管[(18)F]PK - 209代谢迅速，但对NMDAr进行成像仍是可行的。有必要在人体中进行进一步的体内评估。
