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

我将开发新型的有机硅支架，可以方便地用同位素氟-18进行放射性标记，以设计用于正电子发射断层扫描(PET)的新一代显像剂。PET是一种活体成像方式，它依赖于检测嵌入在称为示踪剂的生物活性分子中的同位素的放射性衰变，给患者或研究对象使用。由于其理想的核性质，氟-18是应用最广泛的PET同位素。然而，由于C-18F键形成所需的苛刻反应条件，其后期融入某些生物相关化合物，特别是大分子和脆弱小分子，仍然具有挑战性。这往往阻碍新的PET示踪剂的开发、在制造环境中的实施以及临床应用。硅上的氟同位素交换反应(Si-18F为Si-19F)，以下称为SiFex，为将放射性18F掺入到PET示踪剂候选中提供了一种高产率、操作简单和可靠的方法。适用于这种放射性标记技术的氟硅烷支架被称为氟化硅受体(SIFA)。尽管最近取得了重大进展，但苯基和两个叔丁基取代基在硅上的大碳足迹导致了当前一代SIFA支架的不良药代动力学特性。这一缺点限制了它们的应用于标记较大的大分子，如多肽和蛋白质，并阻碍了含硅小分子PET示踪剂的开发。后者对于脑PET成像示踪剂的设计尤其有利。我的计划旨在改善Sifa分子的药代动力学特性，主要目标是设计新一代含硅的18F标记PET示踪剂。我们将首先寻求用代表药物化学中常见主题的杂芳环来取代苯基。接下来，我们将通过电子和空间因素来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笨重的叔丁基来减小硅上取代基的大小，并将硅结合到致密的药物类6元或8元硅环支架中。我的计划将解决当前SIFA技术的关键限制，并导致类药物有机硅化合物的开发朝着合理设计新型PET示踪剂的方向发展。新一代[18F]氟硅烷支架将结合SIFA技术前所未有的放射性标记效率和重复性，以及调整PET示踪剂的关键药代动力学特性的可能性，并在脑成像方面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，将其结合到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.