title: Fluorinated quinazolinones as potential radiotracers for imaging kinesin spindle protein expression.
abstract: Anti-mitotic anti-cancer drugs offer a potential platform for developing new radiotracers for imaging proliferation markers associated with the mitosis-phase of the cell-cycle. One interesting target is kinesin spindle protein (KSP)-an ATP-dependent motor protein that plays a vital role in bipolar spindle formation. In this work we synthesised a range of new fluorinated-quinazolinone compounds based on the structure of the clinical candidate KSP inhibitor, ispinesib, and investigated their properties in vitro as potential anti-mitotic agents targeting KSP expression. Anti-proliferation (MTT and BrdU) assays combined with additional studies including fluorescence-assisted cell sorting (FACS) analysis of cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Additional studies using confocal fluorescence microscopy showed that these compounds induce M-phase arrest via monoaster spindle formation. Structural studies revealed that compound 20-(R) is the most potent fluorinated-quinazolinone inhibitor of KSP and represents a suitable lead candidate for further studies on designing (18)F-radiolabelled agents for positron-emission tomography (PET).
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Department of Radiology, Harvard Medical School, 55 Fruit St., White 427, Boston, MA 02114, USA. holland.jason@mgh.harvard.edu
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jones
authors.forename: Susan
authors.initials: S
authors.lastname: Cohrs
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054879:Halogenation; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D052999:Quinazolinones; D019275:Radiopharmaceuticals; D016547:Kinesins