Novel organosilicon molecular scaffolds as a platform to design positron emission tomography tracers via Si-18F bond formation (SiFEx).

我将开发新的有机硅支架，适合用同位素氟-18进行简单的放射性标记，以设计新一代的正电子发射断层扫描（PET）成像剂。PET是一种体内成像模式，其依赖于对被施用于患者或研究受试者的被称为示踪剂的生物活性分子内嵌入的同位素的放射性衰变的检测。由于其理想的核性质，氟-18是最广泛使用的PET同位素。然而，由于C-18 F键形成所需的苛刻反应条件，其后期掺入某些类别的生物相关化合物，特别是大分子和脆弱的小分子，仍然具有挑战性。这通常会阻碍新PET示踪剂的开发、其在制造环境中的实施以及向临床的转化。 硅上的氟同位素交换反应（Si-19 F交换Si-18F），下文称为SiFEx，提供了一种高产、操作简单且稳健的方法，用于将放射性18F掺入PET示踪剂候选物中。适合这种放射性标记技术的氟硅烷支架类别被称为氟化硅受体（SiFA）。尽管最近取得了重大进展，但硅上苯基和两个叔丁基取代基的大碳足迹导致当前一代SiFA支架的不利药代动力学性质。这一缺点限制了它们在放射性标记较大大分子（如肽和蛋白质）方面的应用，并阻碍了含硅小分子PET示踪剂的开发。后者对于脑PET成像的示踪剂的设计将是特别有利的。 我的项目旨在改善SiFA分子的药代动力学特性，主要目标是设计新一代含硅18F标记的PET示踪剂。我们将首先寻求用代表药物化学中常见基序的杂芳环取代苯基。接下来，我们将通过电子和空间因素研究杂芳环上的远程取代基对Si-F和C-Si键稳定性的影响。然后，我们将通过用较小的烷基取代庞大的叔丁基来减小硅上取代基的大小，并将硅引入到紧凑的药物状6-或8-元硅杂环丁烷支架中。 我的计划将解决当前SiFA技术的关键限制，并导致药物样有机硅化合物的开发，以合理设计新型PET示踪剂。新一代[18 F]氟硅烷支架将结合联合收割机前所未有的放射性标记效率和SiFA技术的可重复性，以及调整PET示踪剂的关键药代动力学特性的可能性，这些特性在脑成像中具有潜在的令人兴奋的应用。我的计划还将扩大硅在药物化学中的作用，并开发新的合成方法，将其纳入适合药物设计的分子支架中。

I will develop novel organosilicon scaffolds amenable for facile radiolabeling with an isotope fluorine-18 to design the new generation of imaging agents for positron emission tomography (PET). PET is an in vivo imaging modality which relies on the detection of radioactive decay of isotopes embedded within biologically active molecules, called tracers, administered to a patient or study subject. Fluorine-18 is the most widely used PET isotope due to its ideal nuclear properties. However, its late-stage incorporation into certain classes of biologically relevant compounds, especially macromolecules and fragile small molecules, remains challenging due to the harsh reaction conditions required for C-18F bond formation. This often impedes development of new PET tracers, their implementation in manufacturing settings and translation to the clinic. The fluorine isotope exchange reaction on silicon (Si-19F for Si-18F), hereafter termed SiFEx, offers a high-yielding, operationally simple and robust method for the incorporation of radioactive 18F into PET tracer candidates. The class of fluorosilane scaffolds amenable for this radiolabeling technique was coined silicon fluoride acceptors (SiFA). Despite significant recent advances, the large carbon footprint of the phenyl and two tert-butyl substituents on silicon results in unfavorable pharmacokinetic properties of the current generation of SiFA scaffolds. This drawback has limited their applications to radiolabeling larger macromolecules, such as peptides and proteins, and precluded the development of small silicon-containing molecule PET tracers. The latter would be especially advantageous for the design of tracers for brain PET imaging. My program aims to improve pharmacokinetic properties of SiFA molecules with a primary goal of designing new generation of silicon-containing 18F-labeled PET tracers. We will first seek to substitute the phenyl with heteroaromatic rings that represent common motifs in medicinal chemistry. Next, we will investigate the remote substituent effect on the heteroaromatic ring on stability of Si-F and C-Si bonds via electronic and steric factors. We will then reduce the size of the substituents on the silicon by replacing the bulky tert-butyls with smaller alkyl groups and incorporate silicon into compact druglike 6- or 8-membered silacycle scaffolds. My program will address the key limitations of the current SiFA technology and lead to development of druglike organosilicon compounds towards rational design of novel PET tracers. A new generation of [18F]fluorosilane scaffolds will combine the unprecedented radiolabeling efficiency and reproducibility of SiFA technology with the possibility to tune key pharmacokinetic properties of PET tracers with potential exciting applications in brain imaging. My program will also expand the role of silicon in medicinal chemistry and develop new synthetic methods for its incorporation into molecular scaffolds suitable for drug design.