Synthesis and evaluation of two positron-labeled nitric oxide synthase inhibitors, S-[11C]methylisothiourea and S-(2-[18F]fluoroethyl)isothiourea, as potential positron emission tomography tracers.
Synthesis and evaluation of two positron-labeled nitric oxide synthase inhibitors, S-[11C]methylisothiourea and S-(2-[18F]fluoroethyl)isothiourea, as potential positron emission tomography tracers.
复制标题
两种正电子标记的一氧化氮合酶抑制剂 S-[11C]甲基异硫脲和 S-(2-[18F]氟乙基)异硫脲作为潜在正电子发射断层扫描示踪剂的合成和评估。
DOI：
10.1021/jm960481q
复制
发表时间：
1996
影响因子：
7.3
通讯作者：
Welch,MJ
中科院分区：
文献类型：
--
作者：
Zhang,J;McCarthy,TJ;Moore,WM;Currie,MG;Welch,MJ
为了开发一种用于探测诱导型一氧化氮合酶（iNOS）水平的示踪剂，我们合成并评价了两种正电子发射型iNOS选择性抑制剂：S-[11 C]甲基异硫脲（1b）和S-（2-[18 F]氟乙基）异硫脲（3b）。在氟-18标记之前，制备了非放射性氟代衍生物S-（2-氟乙基）异噻唑烷（3a），并确定其对iNOS的选择性是内皮NOS（eNOS）的9倍。这两种化合物的放射化学合成，在高放射化学纯度和高比活度，完成了标记的前体（11 CH 3 I或18 FCH 2 CH 2 OTf）与硫脲的S-烷基化反应。采用体外模型J774巨噬细胞，在细胞水平上评价iNOS诱导对放射性标记的iNOS抑制剂的摄取。观察到在刺激的iNOS水平下，细胞对这两种标记化合物的摄取增加，以及在体外条件下的受控阻断。报告了两种化合物的亲脂性（logPo/w）、稳定性和组织生物分布数据。血清稳定性研究表明，3b在体内和体外代谢比相对稳定的1快得多。基于体外细胞摄取数据，在脂多糖（LPS）预处理的大鼠中进一步评估这两种示踪剂。据报道，LPS可诱导肝、肺、心和肾等组织中的iNOS蛋白表达。LPS预处理的大鼠（治疗后6小时）的摄取显着增加，在肝脏，肾脏和心脏为3蝙蝠10分钟，在肝脏和肺为1蝙蝠30分钟。结果表明，这第一代放射性标记的抑制剂可能是有用的评估诱导iNOSin体内PET。
In an effort to develop a tracer for probing inducible nitric oxide synthase (iNOS) levelsin vivoutilizing positron emission tomography, we have synthesized and evaluated two positron-emitting iNOS selective inhibitors:S-[11C]methylisothiourea (1b) andS-(2-[18F]fluoroethyl)isothiourea (3b). Prior to fluorine-18 labeling, the nonradioactive fluoro derivativeS-(2-fluoroethyl)isothiourea (3a) was prepared and determined to have a 9-fold higher selectivity for iNOS compared to endothelial NOS (eNOS). Radiochemical synthesis of both compounds, in high radiochemical purity and at high specific activity, was accomplished by the S-alkylation reaction of labeled precursors (11CH3I or18FCH2CH2OTf) with thiourea. Anin vitromodel, J774 macrophage cell line, was used to assess the uptake of radiolabeled iNOS inhibitor in response to iNOS induction at the cellular level. Increased cell uptake of these two labeled compounds at stimulated iNOS levels, as well as blocking under controlledin vitroconditions, was observed. Lipophilicity (logPo/w), stability, and tissue biodistribution data of both compounds are reported. Serum stability studies indicate that3bmetabolized much more rapidly compared to the relatively stable1bin vitroandin vivo. Based onin vitrocell uptake data, both tracers were further evaluated in lipopolysaccharide (LPS)-pretreated rats. LPS has been reported to induce iNOS protein expression in the liver, lung, heart, and kidney and other tissues. The uptake for LPS-pretreated rats (6 h post-treatment) was significantly increased in the liver, kidney, and heart for3bat 10 min and in the liver and lung for1bat 30 min. The results suggest that this first generation of radiolabeled inhibitors may be useful for assessing induction of iNOSin vivowith PET.