Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Ebert, Kristin; Wiemer, Jens; Caballero, Julio; Köckerling, Martin; Steinbach, Jörg; Pietzsch, Jens; Mamat, Constantin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 6025
• Page End: 6035
• Publication Date: 2015-09-01
• Subjects: In silico studies -- Radiolabeling -- Carbon-11 -- Fluorine-18 -- Spiro precursor -- Eph receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.040
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Due to their essential role in the pathogenesis of cancer, members of the Eph (erythropoietin-producing hepatoma cell line-A2) receptor tyrosine kinase family represent promising candidates for molecular imaging. Thus, the development and preparation of novel radiotracers for the noninvasive imaging of the EphB4 receptor via positron emission tomography (PET) is described. First in silico investigations with the indazolylpyrimidine lead compound which is known to be highly affine to EphB4 were executed to identify favorable labeling positions for an introduction of fluorine-18 to retain the affinity. Based on this, reference compounds as well as precursors were developed and labeled with carbon-11 and fluorine-18, respectively. For this purpose, a protecting group strategy essentially had to be generated to prevent unwanted methylation and to enable the introduction of fluorine-18. Further, a convenient radiolabeling strategy using [ 11 C]methyl iodide was established which afforded the isotopically labeled radiotracer in 30–35% RCY (d.c.) which is identical with the original inhibitor molecule. A spiro ammonium precursor was prepared for radiolabeling with fluorine-18. Unfortunately, the labeling did not lead to the desired 18 F-radiotracer under the chosen conditions.