title: Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: potential PET imaging agents for tumor detection.
abstract: Two novel pyrazolo[1,5-a]pyrimidine derivatives, 7-(2-[(18)F]fluoroethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile ([(18)F]FEMPPC, [(18)F]1) and N-(2-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[(18)F]fluoro-4-nitrobenzamide ([(18)F]FCMPPN, [(18)F]2), have been designed and successively labeled with (18)F by the nucleophilic substitution employing tosylate and nitryl as leaving groups, respectively. The radiochemical synthesis of both compounds was completed within 60min 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 [(18)F]1 and [(18)F]2 with those of [(18)F]FDG and L-[(18)F]FET in S180 tumor cells. Furthermore, the tumor uptake of [(18)F]1 and [(18)F]2 was assessed in mice bearing S180 tumor and compared with [(18)F]FDG and L-[(18)F]FET in the same animal model. In vitro cell uptake studies showed [(18)F]1 had higher uptake than [(18)F]FDG, [(18)F]2 and L-[(18)F]FET over the 2h period. In ex vivo biodistribution showed tumor/brain uptake ratios of [(18)F]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-[(18)F]FET (2.43, 2.54, 2.93 and 2.95) and [(18)F]FDG (0.59, 0.61, 1.02 and 1.33) at the same time point. What's more, the uptake of [(18)F]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-[(18)F]FET before 30 min and [(18)F]FDG before 60 min. Additionally, the tumor/brain uptake ratios of [(18)F]1 were superior to those of [(18)F]FDG at all the selected time points, the tumor/muscle and tumor/blood uptake ratios of [(18)F]1 at 30 min were higher than those of L-[(18)F]FET at the same time point. MicroPET image of [(18)F]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 [(18)F]1 could be a new probe for PET tumor imaging.
authors.affiliation: Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Xu
authors.forename: Hang
authors.initials: H
authors.lastname: Liu
authors.forename: Guixia
authors.initials: G
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.forename: Rui
authors.initials: R
authors.lastname: Ding
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: Man
authors.initials: M
authors.lastname: Feng
authors.forename: Shuting
authors.initials: S
authors.lastname: Zhang
authors.forename: Yurong
authors.initials: Y
authors.lastname: Chen
authors.forename: Shilei
authors.initials: S
authors.lastname: Li
authors.forename: Mingxia
authors.initials: M
authors.lastname: Zhao
authors.forename: Chuanmin
authors.initials: C
authors.lastname: Qi
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Dang
mesh_terms: D000818:Animals; D005462:Fluorine Radioisotopes; D051379:Mice; D008968:Molecular Conformation; D009369:Neoplasms / Q000175:diagnosis*; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D011720:Pyrazoles; D011743:Pyrimidines; C527752:pyrazolo(1,5-a)pyrimidine