Journal of Medicinal Chemistry vol:50 issue:26 pages:6627-6637
We recently reported a new positron emission tomography (PET) reporter gene, namely, varicella-zoster virus thymidine kinase (VZV-tk) in combination, with carbon-11 or fluorine-18 labeled m-alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as PET reporter probes. We now report the synthesis and evaluation of p-alkoxyphenyl-BCNA tracers ([ (11)C]- 4 and [ (18)F]- 5), which are found to be superior to the m-alkoxyphenyl-BCNA tracers. In particular, the fluorine-18 labeled tracer ([ (18)F]- 5, IC 50 of 5 is 4.2 muM) shows a higher accumulation in VZV-tk expressing cells than the previously reported m-methoxyphenyl BCNA. [ (11)C]- 4 and [ (18)F]- 5 were synthesized by heating the phenol precursor 3 with (11)CH 3I and (18)FCH 2CH 2Br, respectively, as alkylating agents. In vitro evaluation of [ (11)C]- 4 and [ (18)F]- 5 in 293T cells showed about 14- and 54-fold higher uptake, respectively, into VZV-tk gene-transduced cells compared to control cells. LC-MS analysis confirmed the formation of monophosphate derivative of 5 upon catalysis by VZV TK. In vivo studies of this new reporter gene/probe system are in progress.