title: Radiofluorinated probe for PET imaging of fatty acid binding protein 4 in cancer.
abstract: BACKGROUND
  Cancer-associated adipocytes metabolically interact with adjacent cancer cells to promote tumor proliferation and metastasis. Fatty acid binding protein 4 (FABP4) participates in this interaction, and is gathering attention as a therapeutic and diagnostic target. Positron emission tomography (PET) is a useful diagnostic method that enables noninvasive in vivo quantitative imaging of biofunctional molecules with probes labeled with positron-emitting radioisotopes. Here a novel (18)F labeled probe for PET FABP4 imaging developed through dedicated drug design from a radioiodinated probe we recently reported is evaluated in vitro and in vivo.
  
  
  METHODS
  We designed the [(18)F]-labeled FTAP1 and FTAP3 probe, composed of a single or triple oxyethylene linker and a triazolopyrimidine scaffold derived from an FABP4 inhibitor. FABP4 binding affinities for chemically synthesized FTAP1 and FTAP3 were measured using FABP4 and 8-anilino-1-naphthalene sulfonic acid. Cell membrane permeability was measured using a commercially available plate assay system. After radiosynthesis, [(18)F]FTAP1 affinity and selectivity were evaluated using immobilized FABP3, FABP4, and FABP5. Cell uptake was investigated using differentiated adipocytes expressing FABP4 with inhibitor treatment. Following biodistribution studies in C6 glioblastoma-bearing mice, ex vivo autoradiography and immunohistochemistry were performed using thin sliced tumor sections. PET/CT imaging was then performed on C6 tumor bearing mice.
  
  
  RESULTS
  FTAP1 showed high FABP4 affinity (Ki=68±8.9 nM) and adequate cell permeability. [(18)F]FTAP1 with ≥98% radiochemical purity was shown to selectively bind to FABP4 (16.3- and 9.3-fold higher than for FABP3 and FABP5, respectively). [(18)F]FTAP1 was taken up by FABP4 expressing cells, and this uptake could be blocked by an inhibitor, indicating very low non-specific cell binding. [(18)F]FTAP1 showed high tumor accumulation, which demonstrates its potential use for in vivo tumor PET imaging, and the intratumoral radioactivity distribution corresponded to the FABP4 expression profile.
  
  
  CONCLUSIONS
  [(18)F]FTAP1 is a promising PET probe to target FABP4.
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Temma
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kantaro
authors.initials: K
authors.lastname: Nishigori
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Onoe
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Sotaro
authors.initials: S
authors.lastname: Sampei
authors.affiliation: Department of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-Shi, Tokyo 183-8509, Japan; Department of Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kimura
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.affiliation: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hsaji@pharm.kyoto-u.ac.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D005910:Glioma / Q000000981:diagnostic imaging* / Q000473:pathology; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry; D010539:Permeability; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D051381:Rats; D014018:Tissue Distribution; D014230:Triazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D050556:Fatty Acid-Binding Proteins; D005462:Fluorine Radioisotopes; D009281:Naphthalenes; D014230:Triazoles; C031721:naphthalene
keywords: Fatty acid binding protein 4; Nuclear imaging; PET; Positron emission tomography; Radiolabeled probe