Development of novel PET probes targeting phosphatidylinositol 3-kinase (PI3K) in tumors

Here we report the synthesis of three candidate compounds, FMTA-1, 2 and 3, and evaluate their capacity to detect PI3K expression levels with positron emission tomography (PET). Among the three candidates, FMTA-2 showed a lower IC50 value for PI3K. 18F Radiolabeling of FMTA-2 to produce [18F]FMTA-2 was accomplished and its capacity for detecting PI3K expression levels was evaluated in vitro and in vivo. Cell uptake of [18F]FMTA-2 correlated well with cellular PI3K expression levels, and was suppressed by the ATP-competitive PI3K inhibitor ZSTK474. In an in vivo experiment using tumor-transplanted model mice, a higher signal-to-noise ratio (S/N) was seen with [18F]FMTA-2 in animals transplanted with DMS114 cells (expressing high PI3K levels) relative to DU145 cells (expressing low PI3K levels). However, in vivo pharmacokinetics of [18F]FMTA-2 was undesirable and the absolute amount of this compound that accumulated at the tumor region was low. To the best of our knowledge, this study represents the first trial of a PET tracer for detecting PI3K. Although further improvement of the probe is required prior to clinical application, these results should encourage future work.