Extension of PET radiochemistry toolkit. Novel 18F-fluorinated building blocks and procedures for indirect labeling

PET 放射化学工具包的扩展。

• 批准号: 429729215
• 负责人: Professor Dr. Boris Zlatopolskiy
• 金额: --
• 依托单位: Russian Foundation for Basic Research
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/429729215?language=en
• 关键词: Extension; PET; radiochemistry; toolkit.; Novel

Emerging late-stage radiofluorination methods significantly improved the accessibility of numerous PET probes in recent years. However, reaction conditions are often incompatible with sensitive compounds, like secondary metabolites and proteins. Furthermore, owing to the often challenging synthesis of radiolabeling substrates, late-stage fluorination methods are not always well suited for the optimization of in vivo parameters of PET-tracers (stability, selectivity for the target, modulation of pharmacokinetics like elimination rate and route, blood albumin binding, etc.). In this case a modular approach using the same building blocks for the preparation of different radiolabeled compounds is preferable. Furthermore, whereas numerous 18F-fluorinated building blocks are already known only a few of them are easily accessible. One of the most critical points is the necessity of the HPLC isolation of the majority of prosthetic groups increasing the production time, lowering RCYs and complicating synthesis transfer into a remote-controlled synthesis unit impeding the cGMP production and clinical application of radiotracers. The purpose of this project is the further development of a modular (indirect) approach to radiofluorination with the aim to simplify and accelerate the development of the novel PET probes. Consequently, one focus of this application is the application of already established radiolabeled building blocks like [18F]fluorobenzonitrile oxides and [18F]fluorobenzaldehydes. Another important aim of planned work is to develop novel easily accessible prosthetic groups with versatile reactivities and coupling properties. Ideally these prosthetic groups will be isolated by SPE purification avoiding the application of cumbersome and time consuming HPLC purification. To this end simplified 18F-fluorination methods like the “minimalist” and “on-cartridge” protocols will be used for radiolabeling of the highly activated pyridine-substituted quaternary ammonium salt precursors. The highly polar and positively charged onium tag will enable the simple purification of the prepared prosthetic groups by solid phase extraction. A further emphasis of this project is the development of radiolabeling protocols for a site-specific radiolabeling of unmodified peptides and proteins. Here for the novel approaches the introduction of the 18F label is planned by coupling of the prosthetic group with the N-terminus, disulfide bonds or peptide backbone, as well as with Cys and Tyr residues. The practicality of the novel prosthetic groups and novel radiolabeling protocols will be confirmed by the preparation of clinically relevant probes as well as by labeling of model peptides and proteins. Importantly, the developed protocols should be translated into automated synthesis modules enabling finally the application of the novel procedures for the preparation of clinically relevant tracers.

近年来，新兴的晚期放射治疗方法显著改善了许多PET探头的可及性。然而，反应条件通常与敏感化合物如次级代谢产物和蛋白质不相容。此外，由于放射性标记底物的合成通常具有挑战性，因此后期PCR方法并不总是很好地适用于PET示踪剂的体内参数的优化（稳定性、对靶标的选择性、药代动力学如消除速率和途径的调节、血液白蛋白结合等）。在这种情况下，优选使用相同结构单元制备不同放射性标记化合物的模块化方法。此外，尽管许多18F-氟化结构单元是已知的，但其中只有少数是容易获得的。最关键的一点是需要HPLC分离大部分辅基，这增加了生产时间，降低了RCY，并使合成转移到远程控制的合成单元中变得复杂，阻碍了cGMP的生产和放射性示踪剂的临床应用。该项目的目的是进一步开发模块化（间接）方法，以简化和加速新型PET探头的开发。因此，本申请的一个焦点是已经建立的放射性标记的结构单元如[18F]氟苄腈氧化物和[18F]氟苯甲醛的应用。计划工作的另一个重要目标是开发具有多功能反应性和偶联性质的新型易于获得的辅基。理想地，这些辅基将通过SPE纯化分离，避免应用繁琐且耗时的HPLC纯化。为此，将使用简化的18F-NMR方法如“极简”和“筒上”方案来放射性标记高度活化的吡啶取代的季铵盐前体。高极性和带正电荷的鎓标签将使得能够通过固相萃取简单纯化所制备的辅基。该项目的另一个重点是开发用于未修饰肽和蛋白质的位点特异性放射性标记的放射性标记方案。在此，对于新方法，计划通过辅基与N-末端、二硫键或肽骨架以及与Cys和Tyr残基的偶联来引入18F标记。 新型辅基和新型放射性标记方案的实用性将通过制备临床相关探针以及通过标记模型肽和蛋白质来证实。重要的是，开发的协议应转化为自动化的合成模块，使最终的应用程序的新程序的准备临床相关的示踪剂。