Silicon-based building blocks for one-step 18F-radiolabeling of peptides for PET imaging
Silicon-based building blocks for one-step 18F-radiolabeling of peptides for PET imaging
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DOI：
10.1002/anie.200705854
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Klar, Ulrich
中科院分区：
文献类型：
--
作者：
Mu, Linjing;Hoehne, Aileen;Klar, Ulrich
正电子发射断层扫描 (PET) 是现代医学中的重要诊断工具，因为它能够定位和评估神经病学、[1a-e] 肿瘤学、[1f-j] 和心脏病学中的异常情况。[1k, l] 18F 标记的小生物活性肽在诊断成像中的应用已成为核医学中一个重要且有趣的领域。 [2]然而，目前建立的18F标记程序需要严格干燥、高温下的强碱性反应条件，这不适合肽和蛋白质等生物分子。因此，肽和蛋白质的标记通常是通过使用合适的18F标记辅基来实现。然而，这种方法需要多步反应序列并且非常耗时。[3]由于 18F 的半衰期短（110 分钟）和生物分子的化学性质，需要一种在温和条件下更有效的一步式定点标记方法。基于高硅氟键能（CÀF 为 135 kcal mol-1 与 116 kcal mol-1）和 Whitmore 等人的实验结果，[4] 不同的研究小组已经讨论和测试了利用硅上的氟化物取代来标记生物分子的 18F 的概念。 [5]到目前为止，在温和条件下对有机硅烷进行位点特异性18F放射性标记已经实现，然而，大多数方法仍然需要至少两步程序。最近，乔杜里等人。评估了四种模型三烷基氟硅烷的水解稳定性，并建议使用最稳定的化合物作为直接 18F 标记生物分子的构建模块。 [6]席尔马赫等人。还报道了通过同位素交换反应对有机硅修饰的肽进行直接放射性标记，[7a]，但产物主要含有相应的非放射性 19F 化合物，这导致比放射性相对较低。最近，同一小组使用高效标记试剂对（二叔丁基氟硅基）苯甲醛与 N 端氨氧基 (N-AO) 衍生肽偶联，通过两步程序实现高比活性。 [7b] Ting 等人。发表了带有多个氟原子的三烷氧基硅烷的载体添加 18F 标记，[8] 并且烷基四氟硅酸盐在水性介质中具有中等稳定性。利用硅氟化学对生物分子（例如肽）进行一步无载体添加的亲核 18F 氟化是我们研究的主要目标。为了使硅基 18F 显像剂能够有效地用作 PET 探针，SiÀF 键需要在生理条件下足够稳定。众所周知，硅-卤素键的水解稳定性是由硅原子上取代基的性质决定的。因此，设计并合成了一系列双功能硅结构单元，其中包含适合氟化的不同取代基和离去基团以及适合随后与生物分子偶联的连接基。还制备了使用非放射性氟化物 (19FÀ) 的模型氟硅烷。这些化合物用于稳定性研究并作为标准参考化合物。酰胺3a和3b分别由市售的二甲基甲硅烷基胺1a和二异丙基甲硅烷基胺1b合成。用 BF3·OEt2 氟化 3a 和 3b，得到化合物 I 和 II 作为标准参考（方案 1）。
Positron emission tomography (PET) is an important diagnostic tool in modern medicine due to its ability to locate and assess abnormalities in neurology,[1a–e] oncology,[1f–j] and cardiology.[1k, l] The application of 18F-labeled small bioactive peptides for diagnostic imaging has emerged as an important and interesting field in nuclear medicine.[2] However, currently established 18F-labeling procedures require scrupulously dry, strongly basic reaction conditions at high temperature, which are not suitable for biomolecules such as peptides and proteins. Therefore, the labeling of peptides and proteins is usually achieved by using suitable prosthetic groups labeled with 18F. This approach, however, requires a multistep reaction sequence and is time-consuming.[3] Owing to the short half-life (110min) of 18F and the chemical properties of biomolecules, a more efficient, one-step method for site-specific labeling under mild conditions is required. Based on the high silicon–fluorine bond energy (135 kcal molÀ1 vs. 116 kcal molÀ1 for CÀF) and the experimental results of Whitmore et al.,[4] the concept of exploiting the fluoride substitution at silicon for the 18F-labeling of biomolecules has been discussed and tested by different research groups.[5] Up to now, site-specific 18F-radiolabeling of organosilanes under mild conditions has been achieved, however, most methods still require at least a two-step procedure. Recently, Choudhry et al. evaluated the hydrolytic stability of four model trialkylfluorosilanes and proposed to use the most stable compound as a building block for the direct 18F-labeling of biomolecules.[6] Schirrmacher et al. also reported on the direct radiolabeling of an organosilicon-modified peptide by an isotope exchange reaction,[7a] but the product contains predominantly the corresponding non-radioactive 19F compound, which leads to relatively low specific radioactivity. Very recently, the same group used the highly effective labeling reagent p-(di-tertbutylfluorosilyl) benzaldehyde for coupling to N-terminal aminooxy (N-AO) derivatized peptides to achieve high specific activities with a two-step procedure.[7b] Ting et al. published the carrier-added 18F-labeling of trialkoxysilanes with multiple fluorine atoms attached to silicon,[8] and the alkyltetrafluorosilicate was moderately stable in aqueous media.A one-step no-carrier-added nucleophilic 18F-fluorination of biomolecules such as peptides using silicon–fluorine chemistry is the main goal of our study. For the siliconbased 18F imaging agent to be effective as a PET probe, the SiÀF bond needs to be sufficiently stable under physiological conditions. It is known that the hydrolytic stability of the silicon–halogen bond is determined by the nature of the substituents on the silicon atom. Therefore, a series of bifunctional silicon building blocks were designed and synthesized, which contained different substituents and leaving groups suitable for fluorination and linkers suitable for subsequent coupling to a biomolecule. Model fluorosilanes using non-radioactive fluoride (19FÀ) were also prepared. These compounds were used for stability studies and as standard reference compounds. The amides 3a and 3b were synthesized from commercially available dimethyl-and diisopropylsilylamines 1a and 1b, respectively. Fluorination of 3a and 3b with BF3· OEt2 afforded compounds I and II as standard references (Scheme 1).