First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors.
First in human evaluation of [(18)F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors.
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DOI：
10.1186/s13550-018-0424-2
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发表时间：
2018-07-27
期刊：
影响因子：
3.2
通讯作者：
van Berckel BNM
中科院分区：
文献类型：
--
作者：
van der Aart J;Golla SSV;van der Pluijm M;Schwarte LA;Schuit RC;Klein PJ;Metaxas A;Windhorst AD;Boellaard R;Lammertsma AA;van Berckel BNM
为人类N-甲基-d-天冬氨酸（NMDA）受体的离子通道位点开发合适的正电子发射断层扫描（PET）示踪剂的努力取得了有限的成功。[18F]PK-209是一种甘精胰岛素衍生物，以高亲和力和选择性结合通道内苯环利定位点。灵长类动物PET研究表明，给予NMDA受体拮抗剂MK-801可降低脑中的分布容积，这与大量特异性结合一致。本研究的目的是通过评估S-氯胺酮静脉给药（0.5 mg/kg−1）后的重测重现性和结合特异性，在10名健康人中评价[18 F]PK-209。五名健康受试者接受了测试-重测方案，另外五名受试者接受了基线-氯胺酮方案。在所有情况下，动态，120分钟PET扫描与代谢物校正的动脉血浆输入功能一起采集。根据受试者内和人群平均父母分数测试其他输入函数。使用具有额外血容量参数的不可逆两组织室模型获得脑时间-活性曲线的最佳拟合。净流入率Ki的平均重测变异性在7 - 24%之间变化，取决于输入函数。氯胺酮给药后，[18 F]PK-209 PET参数无一致变化，这可能是影响通道门控的复杂内源性配体过程的结果。[18 F]PK-209与NMDA受体离子通道内结合位点之间的分子相互作用的重现性和特异性不足，无法作为可靠的显像剂进行定量。EudraCT 2014-001735-36。2014年4月28日注册
Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-d-aspartate (NMDA) receptors have had limited success. [18F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding. The purpose of the present study was to evaluate [18F]PK-209 in 10 healthy humans by assessing test–retest reproducibility and binding specificity following intravenous S-ketamine administration (0.5 mg ∙ kg−1). Five healthy subjects underwent a test–retest protocol, and five others a baseline-ketamine protocol. In all cases dynamic, 120-min PET scans were acquired together with metabolite-corrected arterial plasma input functions. Additional input functions were tested based on within-subject and population-average parent fractions. Best fits of the brain time-activity curves were obtained using an irreversible two-tissue compartment model with additional blood volume parameter. Mean test–retest variability of the net rate of influx Ki varied between 7 and 24% depending on the input function. There were no consistent changes in [18F]PK-209 PET parameters following ketamine administration, which may be a consequence of the complex endogenous ligand processes that affect channel gating. The molecular interaction between [18F]PK-209 and the binding site within the NMDA receptor ion channel is insufficiently reproducible and specific to be a reliable imaging agent for its quantification. EudraCT 2014-001735-36. Registered 28 April 2014
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影响因子：
6.7
作者：
HARTVIG, P;VALTYSSON, J;LANGSTROM, B
通讯作者：
LANGSTROM, B
影响因子：
5.6
作者：
Kumlien, E;Hartvig, P;Långström, B
通讯作者：
Långström, B
影响因子：
3.4
作者：
Stone, James M.;Erlandsson, Kjell;Pilowsky, Lyn S.
通讯作者：
Pilowsky, Lyn S.
影响因子：
9.3
作者：
van der Aart, Jasper;van der Doef, Thalia F.;Lammertsma, Adriaan A.
通讯作者：
Lammertsma, Adriaan A.
影响因子：
3.1
作者：
Ametamey, SM;Bruehlmeier, M;Schubiger, PA
通讯作者：
Schubiger, PA