基于氟膦类多肽探针一步法[18F]标记系统的构建及其在肿瘤早期诊断中的应用

18F is the most ideal radionuclide for PET imaging. Research on its labeling method is one of the research hotspots in recent decades. We recently developed a non-carbon 18F labeling method based on the P-F bond that can be prepared in the aqueous phase. The pioneering concept of a large sterically hindered substituent to improve the stability of the P-F bond in the aqueous phase allows the modified peptide probe to have certain stability both in vivo and in vitro, and can be specifically taken up by the tumor tissue.The distinct advantage of the reaction is that it can be labeled in one step in the aqueous phase at room temperature. However, the shortcoming is that the 18F-19F isotope exchange method was applied and the prepared peptide probe has a lower specific activity. Based on this, the project intends to break through the bottleneck of the specific activity of the probe prepared by the original method through the 18F substitution reaction of different substrates such as P-S, P-Se and P-SCF3. Furthermore, fluorophosphines with high thermodynamic stability, such as cage-like rigid structure, electron absorption and large steric resistance, were proposed to improve the stability of P-18F modified peptide probes and further enrich the P-18F labeling system with distinct characteristics. The novel labeling method was applied to the 18F modification of tumor targeting peptides, and the in vivo and in vitro properties and PET imaging were investigated to develop a number of novel tumor-targeted PET probes with clinical application potential.

18F是最理想的PET显像核素，其标记方法研究是核医学研究的热点。我们最近发展了一种基于P-F键的18F标记方法，首创性地提出用大位阻的取代基来提高P-F键在水相中的稳定性的概念，使得其修饰的18F多肽探针在体内外都具备一定的稳定性，能被肿瘤组织特异性摄取，该反应鲜明的优势是可以在室温下，水相中一步标记。然而其不足之处是使用了18F-19F同位素交换的方法，制备的多肽探针比活度较低。基于此，本项目拟通过P-S、P-Se和P-SCF3等不同底物的18F取代反应来突破原有方法制备的探针比活度不高的瓶颈，提出金刚烷笼状刚性结构、带吸电子和大位阻等具有高热力学稳定的氟代膦烷结构来提高P-18F修饰的多肽探针的稳定性，进一步丰富具有鲜明特色的P-18F标记体系。并将该新型标记方法用于肿瘤靶向多肽的18F修饰，进行体内外性质评价及PET显像考察，开发一批具有临床应用潜力的新型肿瘤靶向PET探针。

18F是PET成像最理想的放射性核素。对其标记方法的研究是近几十年来的研究热点之一。在本项目中，我们开发了一种基于P-F键的18F标记方法，该方法可以特异性地与半胱氨酸结合硫醇，并用于c (RGDfC)和FAPI多肽的放射合成和PET成像。这种简单而快速的放射性氟化反应具有极好的放射化学产率，并能够获得很好的放射化学纯度的18F放射性标记氟化物。大位阻的金刚烷全氟苯基氟化膦的标记辅基在体内外均表现出良好的稳定性。通过在金刚基上添加磺酸基或选择适当的多肽来改善前驱体的水溶性有待进一步探讨。我们期望该方法能够在更多的活性多肽的18F辐射标记中得到应用。

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