Abstract

1. A challenge in the development of novel ¹⁸F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the ¹⁸F radioisotope. Metabolic loss of ¹⁸F from PET probes in vivo can lead to misleading biodistribution data as displaced ¹⁸F can accumulate in various tissues.

2. In this study we report on in vitro hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C₈-6-I, C₈-6-N, C₈-6-C₈) that can prevent in vitro aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson’s disease. The metabolic profile obtained guided us to synthesize stable isotope ¹⁹F-labelled analogues in which the fluorine was introduced at the metabolically stable N7 of the caffeine moiety.

3. An in vitro hepatic microsomal metabolism study of the ¹⁹F-labelled analogues resulted in similar metabolites to the unlabelled compounds and demonstrated that the fluorine was metabolically stable, suggesting that these analogues are appropriate PET imaging probes. This straightforward in vitro strategy is valuable for avoiding costly stability failures when designing radiolabelled compounds for PET imaging.

摘要

1. 开发新型¹⁸ F 标记正电子发射断层扫描 (PET) 成像探针的一个挑战是识别代谢稳定位点以纳入¹⁸ F 放射性同位素。体内PET 探针的¹⁸ F代谢损失会导致误导性的生物分布数据，因为置换的¹⁸ F 可以在各种组织中积累。

2. 在这项研究中，我们报告了新型含咖啡因的双功能化合物（C ₈ -6-I、C ₈ -6-N、C ₈ -6-C ₈）的体外肝微粒体代谢，这些化合物可以防止α-突触核蛋白的体外聚集，这与帕金森病的病理生理学有关。获得的代谢谱指导我们合成稳定同位素¹⁹ F 标记的类似物，其中氟被引入咖啡因部分的代谢稳定 N7。

3. 的体外的的肝微粒体代谢研究¹⁹ F-标记的类似物导致类似的代谢物未标记的化合物和证明了氟是代谢稳定的，这表明这些类似物是适当PET成像探针。在设计用于 PET 成像的放射性标记化合物时，这种直接的体外策略对于避免代价高昂的稳定性故障很有价值。