title: Alkyl-fluorinated thymidine derivatives for imaging cell proliferation I. The in vitro evaluation of some alkyl-fluorinated thymidine derivatives.
abstract: Derivatives of 2'-deoxyuridine that contain fluoroalkyl groups at the C5 position and derivatives of thymidine that contain fluoroalkyl groups at the N3 position were synthesized and examined in three in vitro assays designed to evaluate their potential as radiopharmaceuticals for imaging cellular proliferation. Three of the former nucleosides and five of the latter were synthesized. The three assays were as follows: (a) phosphoryl transfer assay, which showed that all three of the former nucleosides and four of the latter ones were phosphorylated by recombinant human thymidine kinase 1 (TK1) and that N(3)-(2-fluoroethyl)-thymidine (NFT202) was the most potent substrate of the eight nucleosides studied; (b) transport assay, which indicated that all eight nucleosides had good affinity for an 6-[(4-nitrobenzyl)thio]-9-beta-d-ribofuranosylpurine-sensitive mouse erythrocyte nucleoside transporter, with inhibition constants in the range of 0.02-0.55 mM; and (c) degradation assay, which showed that all but one of the former nucleosides and none of the latter were degraded by recombinant Escherichia coli thymidine phosphorylase (an enzyme that catalyzes the glycosidic bond of thymidine and 2'-deoxyuridine derivatives). From these in vitro screening assays, we selected NFT202 as a candidate for subsequent in vivo evaluation because this compound met the three minimum requirements of the in vitro screening assays and had the most potent phosphorylation activity as a substrate for recombinant human TK1.
authors.affiliation: Probe Research Section, Department of Molecular Probe, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan. toyohara@nirs.go.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Toyohara
authors.forename: Akio
authors.initials: A
authors.lastname: Hayashi
authors.forename: Akie
authors.initials: A
authors.lastname: Gogami
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hamada
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamashima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Katoh
authors.forename: Manabu
authors.initials: M
authors.lastname: Node
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujibayashi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D015195:Drug Design; D005461:Fluorine; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013868:Thioinosine / Q000031:analogs & derivatives / Q000378:metabolism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism*; D013937:Thymidine Kinase / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000378:metabolism
chemical_list: D019275:Radiopharmaceuticals; D005461:Fluorine; D013868:Thioinosine; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase; C001789:4-nitrobenzylthioinosine; D013936:Thymidine