title: Fluoro-, bromo-, and iodopaclitaxel derivatives: synthesis and biological evaluation.
abstract: Paclitaxel (Taxol) is a clinically important chemotherapeutic agent. We describe the synthesis of fluoro-, bromo-, and iodopaclitaxel and their [(18)F]fluoro-, [(76)Br]bromo-, and [(124)I]iodo- analogues. [(18)F]Fluoropaclitaxel shows high uptake and rapid clearance from tissues in rats. Preadministration of paclitaxel in normal rats significantly increases (p < 0.005) retention of [(18)F]fluoropaclitaxel and [(76)Br]bromopaclitaxel in blood (33.0%), heart (32.0%), lung (37.6%) kidney (142.4%); and blood (33.4%), lung (42.3%), kidney (62.4%), respectively. [(18)F]Fluoropaclitaxel uptake in the brain of mdr1a/1b(-/-) mice is increased 1400% (p < 1.3e-07) relative to wild-type controls. Preadministration of paclitaxel or XR9576, a modulator, had little effect on the biodistribution in these mdr1a/1b(-/-) mice. As a result, [(18)F]fluoropaclitaxel will be a useful radiopharmaceutical for the study of multidrug resistant tumors.
authors.affiliation: Positron Emission Tomography Department, Clinical Center, NIH, Bethesda, MD 20892, USA.
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Jagoda
authors.forename: Chih-Hao K
authors.initials: CH
authors.lastname: Kao
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Laura
authors.initials: L
authors.lastname: Ravasi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimoji
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Szajek
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
mesh_terms: D000818:Animals; D001967:Bromine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D002478:Cells, Cultured; D018432:Drug Resistance, Multiple; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D012016:Reference Values; D013045:Species Specificity
chemical_list: D001967:Bromine Radioisotopes; D005462:Fluorine Radioisotopes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D017239:Paclitaxel