Synthesis and in vitro evaluation of 5-fluoro-6-[(2-iminopyrrolidin-1-YL)methyl]uracil, TPI(F): an inhibitor of human thymidine phosphorylase (TP).

An investigation was conducted to determine if the 5-fluoro analog of TPI (5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]uracil), a potent inhibitor of human thymidine phosphorylase (TP), has an IC(50) in a range that might allow to use it labeled for imaging of TP expression in vivo. The previously unreported fluoro analog, TPI(F), was prepared and tested against TPI and TPI(Br) using an inhibition assay of [H-3]thymidine cleavage. An assay, performed in the presence of 0.4 mg/ml of human TP, yielded IC(50) values of 2.5 nM, 2.7 nM, and 9.0 nM for TPI, TPI(Br), and TPI(F), respectively. The results indicate that further studies to develop (18)F-labeled TPI(F) as a potential radiopharmaceutical for PET imaging of TP expression in vivo are warranted.