title: Synthesis, biological evaluation, and molecular dynamics (MD) simulation studies of three novel F-18 labeled and focal adhesion kinase (FAK) targeted 5-bromo pyrimidines as radiotracers for tumor.
abstract: Focal adhesion kinase (FAK) is considered as an attractive target for oncology. A series of F-18 labeled 5-bromo-N2-(4-(2-fluoro-pegylated (FPEG))-3,5-dimethoxyphenyl)-N4-(4-methoxyphenyl)pyrimidine-2,4-diamine derivatives were prepared and evaluated as the FAK targeted radiotracers for the early diagnoses of tumor. For the study of the FAK targeted drug molecules, this was the first attempt to develop the tumor diagnostic imaging agents on the radiopharmaceutical level. They inhibited the activity of FAK with IC50in the range of 91.4-425.7 nM, and among which the result of the [19F]2 was relatively good and had a modest IC50of 91.4 nM. The [19F]2 was also profiled in vitro against some other kinds of cancer-related kinases (including two kinds of non-receptor tyrosine kinase: PYK2 and JAK2, and three kinds of receptor tyrosine kinase: IGF-1R, EGFR and PDGFRβ). It displayed 25.2 folds selectivity against PYK2, 35.1 folds selectivity against EGFR, and more than 100 folds selectivity against IGF-1R, JAK2 and PDGFRβ. For the biodistribution in S180 bearing mice, the corresponding [18F]2 were also relatively good, with modest tumor uptake of 5.47 ± 0.19 and 5.80 ± 0.06 %ID/g at 15 and 30 min post-injection, respectively. Furthermore, its tumor/muscle, tumor/bone and tumor/blood ratio at 15 min post-injection were 3.16, 2.53 and 4.52, respectively. And its tumor/muscle, tumor/bone and tumor/blood ratio at 30 min post-injection were 3.14, 2.76 and 4.43, respectively. In addition, coronal micro-PET/CT images of a mouse bearing S180 tumor clearly confirmed that [18F]2 could be accumulated in tumor, especially at 30 min post-injection. Besides, for the [18F]2, both the biodistribution data and the micro-PET/CT imaging study showed significantly reduced uptake of the radiotracer in the tumor tissue at 30 min post-injection in mice that received PF-562,271 (one of the reported best selective FAK inhibitor which was developed by Pfitzer Inc. and inhibited the activity of FAK with IC50value of 1.5 nM) at 1 h before the injection of radiotracer. In combination with the above kinase profiling assay, it could be indicated that the uptake of [18F]2 in tumor of the mouse model was due to FAK expression, and that [18F]2 might be a kind of selectively FAK targeted tumor imaging agents. What's more, the results of the MD (molecular dynamics) simulations were in agreement with the changing trends of the interaction between the different F-19 standards and the FAK (expressed as the in vitro inhibitory abilities of enzymatic activities of FAK in this article), which was also in agreement with and had great effect on the changing trends of the uptake of the corresponding F-18 labeled tracers in tumor and some of theirs target/non-target ratios.
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Wu
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Xue
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China.
authors.forename: Hang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China. Electronic address: hbzhang@bnu.edu.cn.
authors.forename: Huabei
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005260:Female; D005462:Fluorine Radioisotopes; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D056004:Molecular Dynamics Simulation; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011849:Radioactive Tracers; D014018:Tissue Distribution
chemical_list: D005462:Fluorine Radioisotopes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011849:Radioactive Tracers; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: F-18 labeled; Focal adhesion kinase (FAK); Molecular dynamics (MD) simulation; Radiotracers; Tumor imaging