Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: potential PET imaging agents for tumor detection

Two novel pyrazolo1,5-a]pyrimidine derivatives, 7-(2-¹⁸F]fluoroethylamino)-5-methylpyrazolo1,5-a]pyrimidine-3-carbonitrile (¹⁸F]FEMPPC, ¹⁸F]1) and N-(2-(3-cyano-5-methylpyrazolo1,5-a]pyrimidin-7-ylamino)ethyl)-2-¹⁸F]fluoro-4-nitrobenzamide (¹⁸F]FCMPPN, ¹⁸F]2), have been designed and successively labeled with ¹⁸F by the nucleophilic substitution employing tosylate and nitryl as leaving groups, respectively. The radiochemical synthesis of both compounds was completed within 60 min with final high-performance liquid chromatography purification included. The corresponding radiochemical yields (without decay correction) were approximately 35% and 30%, respectively. Meanwhile, we compared the uptake characteristics of ¹⁸F]1 and ¹⁸F]2 with those of ¹⁸F]FDG and L-¹⁸F]FET in S180 tumor cells. Furthermore, the tumor uptake of ¹⁸F]1 and ¹⁸F]2 was assessed in mice bearing S180 tumor and compared with ¹⁸F]FDG and L-¹⁸F]FET in the same animal model. In vitro cell uptake studies showed ¹⁸F]1 had higher uptake than ¹⁸F]FDG, ¹⁸F]2 and L-¹⁸F]FET over the 2 h period. In ex vivo biodistribution showed tumor/brain uptake ratios of ¹⁸F]2 were 12.35, 10.44, 8.69 and 5.13 at 15 min, 30 min, 60 min and 120 min post-injection, much higher than those of L-¹⁸F]FET (2.43, 2.54, 2.93 and 2.95) and ¹⁸F]FDG (0.59, 0.61, 1.02 and 1.33) at the same time point. What’s more, the uptake of ¹⁸F]1 in tumor was 1.88, 4.37, 5.51, 2.95 and 2.88 at 5 min, 15 min, 30 min, 60 min and 120 min post-injection, respectively. There was a remarkable increasing trend before 30 min. The same trend was present for L-¹⁸F]FET before 30 min and ¹⁸F]FDG before 60 min. Additionally, the tumor/brain uptake ratios of ¹⁸F]1 were superior to those of ¹⁸F]FDG at all the selected time points, the tumor/muscle and tumor/blood uptake ratios of ¹⁸F]1 at 30 min were higher than those of L-¹⁸F]FET at the same time point. MicroPET image of ¹⁸F]1 administered into S180 tumor-bearing mouse acquired at 30 min post-injection illustrated that the uptake in S180 tumor was obvious. These results suggest that compound ¹⁸F]1 could be a new probe for PET tumor imaging.