title: Development of novel PET probes targeting phosphatidylinositol 3-kinase (PI3K) in tumors.
abstract: Phosphatidylinositol 3-kinase (PI3K) activity and protein expression levels are often increased in tumor regions. Since PI3K plays a crucial role in regulating cell growth and proliferation, inhibiting PI3K-dependent pathways could be a promising approach for cancer treatment. In clinical practice, however, evaluation of PI3K expression levels is limited to immunohistochemistry of patient samples, which requires invasive biopsies. 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. (18)F Radiolabeling of FMTA-2 to produce [(18)F]FMTA-2 was accomplished and its capacity for detecting PI3K expression levels was evaluated in vitro and in vivo. Cell uptake of [(18)F]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 [(18)F]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 [(18)F]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.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501; Biomedical Imaging Research Center (BIRC), University of Fukui, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193. Electronic address: amakino@u-fukui.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Makino
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Arai
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Ohmomo
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501. Electronic address: hsaji@pharm.kyoto-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D055808:Drug Discovery; D005462:Fluorine Radioisotopes; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D014227:Triazines; D019869:Phosphatidylinositol 3-Kinases
keywords: (18)F; Molecular imaging; PET; Phosphatidylinositol 3-kinase (PI3K)