A fluorine-labeled methotrexate as a probe for monitoring tumor antifolate pharmacokinetics: synthesis, in vitro cytotoxicity, and pilot in vivo 19F magnetic resonance spectra.
The synthesis and characterization of 3'-fluoromethotrexate (FMTX), a novel fluorine-labeled analogue of methotrexate, are presented. Molecular modeling studies indicate that the fluorine atom causes only minimal changes in the structure/binding in the complex of the antifolate with thymidine synthetase and dihydrofolate reductase (DHFR). The in vitro cytotoxicity of this compound is shown to be equivalent to that of the parent antifolate compound. While the focus of this report is the synthetic technique of FMTX, it is also demonstrated that tumor accumulation of the labeled compound in vivo can be observed via 19F magnetic resonance spectroscopy (MRS) in a human tumor xenograft model.
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
William M
WM
Spees
Guangli
G
Yang
Darren
D
Veach
Maria Belen
MB
Rubio
Jason A
JA
Koutcher
William
W
Bornmann
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes / Q000627:therapeutic use*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008727:Methotrexate / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D005462:Fluorine Radioisotopes; D013762:Tetrahydrofolate Dehydrogenase; D013936:Thymidine; D008727:Methotrexate