18F-labeling of peptides by means of an organosilicon-based fluoride acceptor
18F-labeling of peptides by means of an organosilicon-based fluoride acceptor
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DOI：
10.1002/anie.200600795
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Jurkschat, Klaus
中科院分区：
文献类型：
--
作者：
Schirrmacher, Ralf;Bradtmoeller, Gerrit;Jurkschat, Klaus
氟-18是正电子发射断层扫描（PET）中最常用的放射性核素之一这种非侵入性成像技术能够通过1808巧合检测正电子湮灭同时发射的两个光子来提供关于放射性标记生物分子分布的体内信息。虽然许多不同的放射性示踪剂已经成功地应用于PET，但只有少数几种示踪剂，如2-[18F]氟-2-脱氧-d-葡萄糖（FDG）[2]和[18F]氟吡啶，[3]在核医学中得到了广泛的应用。这是因为18F在示踪分子中的区域选择性引入通常是非特异性的，而且18F标记产物的放射化学产率（RCY）很低。将18FÀ引入示踪分子需要高温，并且经常导致不希望的副产物过去十年的研究清楚地表明，PET在核医学中的成功证明了为合成18f -放射性药物而大力寻找通用标记配方是合理的。特别是开发合理的肽18f标记策略，迄今为止以多步骤程序为特征，被认为是最重要的任务之一作为传统18F标记化学的替代品，使用[18F]氟硅烷作为标记合成子最早是由Rosenthal等人提出的，他们在乙腈水溶液中用nca（不添加载体）18FÀ处理氯三甲基硅烷，以65%的收率分离出相应的[18F]氟硅烷初步的体内评价显示，该化合物的快速水解伴随着高放射性（18F）被骨骼吸收，使其不适合作为标记合成物。另一种方法是基于Pilcher等人的工作，他们用非放射性HF高产量氟化有机硅烷。一个类似的标注策略在研讨会摘要中被提出然而，到目前为止，还没有使用18FÀ/[18F] HF水溶液进行标记实验的报道。最近，Ting等人使用有机三乙氧基硅烷作为合成氟硅烷的标记前体[18F]，但尚未证明其在潜在放射性药物合成中的实际应用本文报道了以有机氯硅烷为标记前体的取代[18F]有机氟硅烷的合成及其体外和体内稳定性。作为一种替代标记方法，我们还使用[19F]二叔丁基苯氟硅烷作为高效硅基氟受体（SiFA化合物）来描述18F-19F同位素交换。作为适用性的证明，我们将SiFA方法转移到一种简单实用的配方的开发中，用于合成一种18f标记的SiFA衍生的Tyr3-octreotate，一种用于肿瘤神经内分泌肿瘤可视化的肽我们合成了三种[18F]有机氟硅烷，即[18F]氟三苯基硅烷(1)、[18F]氟叔丁基二苯基硅烷(2)和[18F]氟二叔丁基苯基硅烷(3)，并通过动物pet研究了它们在人血清中的体外稳定性和在大鼠体内的稳定性。这些数据对于寻找最合适的化合物和评估标签概念至关重要。三有机氯硅烷（5-11.8 μmol mLÀ1） Ph3SiCl、tBuPh2SiCl和tBu2PhSiCl与共沸干燥配合物18FÀ/Kryptofix2在乙腈中反应。2.2./K+在室温下几乎可以定量地提供相应的[18F]三有机氟硅烷1 - 3（图1），通过放射性高效液相色谱证实。他们的身份是通过在放射性探针中加入相关的…
Fluorine-18 is among the most commonly used radionuclides for positron emission tomography (PET).[1] This non-invasive imaging technique is capable of providing in vivo information about the distribution of radiolabeled biomolecules by 1808 coincidence detection of two simultaneously emitted photons from positron–electron annihilation. Although a number of different radiotracers have been successfully employed in PET, only a few, such as 2-[18F] fluoro-2-deoxy-d-glucose (FDG)[2] and [18F] fluorodopa,[3] have gained widespread application in nuclear medicine. The reason for this is that the regioselective introduction of 18F into tracer molecules is often non-specific and radiochemical yields (RCY) of the 18F-labelled product are low. The introduction of 18FÀ into tracer molecules requires high temperatures and often leads to undesired by-products.[1] The research over the last decade clearly indicates that the success of PET in nuclear medicine justifies the intense search for versatile labeling formulations for the syntheses of 18F-radiopharmaceuticals. Especially the development of rational 18F-labelling strategies for peptides, until now characterized by multistep procedures, is considered to be one of the most important tasks.[4] As an alternative to conventional 18F-labelling chemistry, the use of [18F] fluorosilanes as labeling synthons was first proposed by Rosenthal et al. who treated chlorotrimethylsilane with nca (no carrier added) 18FÀ in aqueous acetonitrile isolating the corresponding [18F] fluorosilane in 65% yield.[5] A preliminary in vivo evaluation revealed fast hydrolysis of the compound accompanied by high radioactivity (18F) uptake by the bone making it unsuitable as a labeling synthon. Another approach is based on the work by Pilcher et al.[6] who fluorinated organosilanoles with nonradioactive HF in high yields. An analogous labeling strategy was proposed in a symposium abstract.[7] However, so far no labeling experiments using aqueous 18FÀ/[18F] HF solutions have been reported. Most recently Ting et al. used organotriethoxysilanes as labeling precursors for the synthesis of [18F] fluorosilanes but no practical application for the synthesis of potential radiopharmaceuticals has been demonstrated.[8] Herein we report the syntheses of substituted [18F] organofluorosilanes using organochlorosilanes as labeling precursors and their in vitro and in vivo stability. As an alternative labeling approach we also describe the 18F–19F isotopic exchange using [19F] di-tert-butylphenyl fluorosilane as a highly efficient silicon-based fluoride acceptor (SiFA compound). As proof of applicability we transferred the SiFA approach to the development of a simple and practical formulation for the synthesis of a 18F-labelled SiFA derivatized Tyr3-octreotate, a peptide used in oncology for the visualization of neuro-endocrine tumors.[9] We synthesized three [18F] organofluorosilanes, namely [18F] fluorotriphenylsilane (1),[18F] fluoro-tert-butyldiphenylsilane (2), and [18F] fluorodi-tert-butylphenylsilane (3), and evaluated their in vitro stability in human serum as well as their in vivo stability in rats, studied by animal-PET. These data are essential for finding the most suitable compound and for evaluating the labeling concept. The reaction in acetonitrile of the triorganochlorosilanes (5–11.8 μmol mLÀ1) Ph3SiCl, tBuPh2SiCl, and tBu2PhSiCl, with the azeotropically dried complex 18FÀ/Kryptofix2. 2.2./K+ at room temperature provided almost quantitatively the corresponding [18F] triorganofluorosilanes 1–3 (Figure 1), as demonstrated by means of radio-HPLC. Their identities were confirmed by coelution of the radioactive probes spiked with the related …