11C-Labeled Radiotracer for Noninvasive and Quantitative Assessment of the Thiocyanate Efflux System in the Brain
11C-Labeled Radiotracer for Noninvasive and Quantitative Assessment of the Thiocyanate Efflux System in the Brain
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11C 标记放射性示踪剂，用于对大脑中硫氰酸盐流出系统进行无创定量评估
DOI：
10.1021/acs.bioconjchem.2c00277
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发表时间：
2022
影响因子：
4.7
通讯作者：
Zhang Ming-Rong
中科院分区：
文献类型：
--
作者：
Okamura Toshimitsu;Tsukamoto Satoshi;Okada Maki;Kikuchi Tatsuya;Aizawa Ryutaro;Wakizaka Hidekatsu;Nengaki Nobuki;Ogawa Masanao;Ishii Hideki;Zhang Ming-Rong
硫氰酸盐（SCN-）改变α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的某些激动剂的效力，并且AMPA受体信号传导的功能障碍被认为是许多神经系统疾病的基础。虽然人类可能暴露于来自环境（包括食物来源）的SCN-，但载体介导的系统将SCN-从大脑转运到血液中，并且是SCN-在中枢神经系统中分布的重要调节剂。因此，对脑中SCN-外排系统的评估将有助于了解SCN-神经毒性的机制，并阐明外排系统与脑疾病之间的关系。然而，目前可用于研究SCN-外排的技术受到其侵入性的严重限制。在这里，我们描述了SCN-前体示踪剂，9-戊基-6-[11 C]硫氰酸嘌呤（[11 C]1），以克服这一限制的发展。[11 C] 1是由碘代前体与[11 C] SCN-或二硫代前体与[11 C] NH 4CN反应合成的。前示踪剂[11 C] 1经静脉注射进入小鼠脑内后迅速代谢为[11 C]SCN-，然后从脑中消除。[11 C] SCN-的外排被一价阴离子高氯酸盐剂量依赖性地抑制，最高剂量导致外排率降低82%。我们的研究结果表明，[11 C] 1可用于非侵入性和定量评估的SCN-流出系统在大脑中。
Thiocyanate (SCN–) alters the potency of certain agonists for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and dysfunctions in AMPA receptor signaling are considered to underlie a number of neurological diseases. While humans may be exposed to SCN–from the environment, including food sources, a carrier-mediated system transports SCN–from the brain into the blood and is an important regulator of SCN–distribution in the central nervous system. The assessment of this SCN–efflux system in the brain would thus be useful for understanding the mechanisms underlying the neurotoxicity of SCN–and for elucidating the relationship between the efflux system and brain diseases. However, the currently available technique for studying SCN–efflux is severely limited by its invasiveness. Here, we describe the development of a SCN–protracer, 9-pentyl-6-[11C]thiocyanatopurine ([11C]1), to overcome this limitation. [11C]1was synthesized by the reaction of the iodo-precursor and [11C]SCN–or the reaction of the disulfide precursor with [11C]NH4CN. The protracer [11C]1entered the brain after intravenous injection into mice and was rapidly metabolized to [11C]SCN–, which was then eliminated from the brain. The efflux of [11C]SCN–was dose-dependently inhibited by perchlorate, a monovalent anion, and the highest dose caused an 82% reduction in the efflux rate. Our findings demonstrate that [11C]1can be used for the noninvasive and quantitative assessment of the SCN–efflux system in the brain.