Synthesis of [18F]-labeled (2-(2-fluoroethoxy)ethyl)tris(4-methoxyphenyl) phosphonium cation as a potential agent for positron emission tomography myocardial imaging
Synthesis of [18F]-labeled (2-(2-fluoroethoxy)ethyl)tris(4-methoxyphenyl) phosphonium cation as a potential agent for positron emission tomography myocardial imaging
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DOI：
10.1016/j.nucmedbio.2012.03.008
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发表时间：
2012-10-01
影响因子：
3.1
通讯作者：
Min, Jung-Joon
中科院分区：
文献类型：
--
作者：
Kim, Dong-Yeon;Kim, Hee-Jung;Min, Jung-Joon
简介：用于正电子发射断层扫描（PET）心肌灌注研究的放射性示踪剂通常使用短寿命放射性同位素标记，限制了其广泛的临床应用。因此，我们合成了（2-（2-[F-18]氟乙氧基）乙基）三（4-甲氧基苯基）鏻盐（[F-18]FETMP）作为一种新型心肌灌注剂，可穿透质膜和线粒体膜的疏水屏障，并在心肌细胞线粒体中积累，以响应负的跨膜内电位。[F-18]FETMP是由无载体的[F-18]氟化物与前体2，2 ′-氧代双（2，2 ′-bis）通过两步亲核取代反应合成的在Kryptofix 2.2.2和K2 CO 3的存在下，（乙烷-2，1-二基）双（4-甲基苯磺酸盐）。在大鼠胚胎心肌母细胞（H9 c2）和小鼠正常成纤维细胞（NIH/3 T3）细胞系的细胞培养物中测定[F-18]FETMP蓄积。使用经羰基氰化物间氯苯腙（CCCP）处理的H9 c2细胞进一步评估[F-18]FETMP的线粒体膜电位依赖性细胞摄取，CCCP是一种选择性消除线粒体膜电位的质子载体。在正常BALB/c小鼠中进行生物分布和micro-PET研究以测试和优化放射性标记的鏻阳离子的动力学。通过分析型HPLC，放射化学纯度>98%，比活度>5.92 TBq/urnol。细胞摄取试验显示心肌细胞优先摄取[F-18]FETMP。[F-18]FETMP在小鼠和大鼠体内的生物分布和微型PET成像研究结果显示，[F-18] FETMP优先在心肌中积聚。结论：结果表明，[F-18]FETMP将成为心肌成像的有希望的候选药物，并可能用于临床心脏PET/CT应用。(c)2012 Elsevier Inc. All rights reserved.
Introduction: Established radiotracers for positron emission tomography (PET) myocardial perfusion study are commonly labeled with short-lived radio-isotopes that limit their widespread clinical use. Thus, we synthesized (2-(2[F-18]fluoroethoxy)ethyl)tris(4-methoxyphenyl)phosphonium salt ([F-18]FETMP) as a novel myocardial perfusion agent that penetrates the hydrophobic barriers of the plasma and mitochondrial membranes and accumulate in mitochondria of cardiomyocytes in response to the negative inner-transmembrane potentials.Methods: The [F-18]FETMP was synthesized via two-step nucleophilic substitution reactions of no-carrier-added [F-18]fluoride with the precursor 2,2'-oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) in the presence of Kryptofix 2.2.2 and K2CO3. The [F-18]FETMP accumulation was measured in cell culture with rat embryonic cardiomyoblast (H9c2) and mouse normal fibroblast (NIH/3T3) cell lines. The mitochondrial membrane potential-dependent cellular uptake of [F-18]FETMP was further assessed using the H9c2 cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) which is a protonophore that selectively abolishes the mitochondrial membrane potential. Biodistribution and micro-PET studies were performed in normal BALB/c mice to test and optimize the kinetics for radiolabeled phosphonium cation.Results: The radiolabeled compound was synthesized with 10%-20% yield. The radiochemical purity was >98% by analytical HPLC, and the specific activity was >5.92 TBq/urnol. The cellular uptake assay showed preferential uptake of [F-18]FETMP in cardiomyocytes. The results of biodistribution and micro-PET imaging studies of [F-18]FETMP in mice and rats showed preferential accumulation in the myocardium.Conclusions: The results suggest that [F-18]FETMP would be a promising candidate for myocardial imaging and might be useful for clinical cardiac PET/CT applications. (c) 2012 Elsevier Inc. All rights reserved.