title: Synthesis and evaluation of (18)F-labeled ATP competitive inhibitors of topoisomerase II as probes for imaging topoisomerase II expression.
abstract: Type II topoisomerase (Topo-II) is an ATP-dependent enzyme that is essential in the transcription, replication, and chromosome segregation processes and, as such, represents an attractive target for cancer therapy. Numerous studies indicate that the response to treatment with Topo-II inhibitors is highly dependent on both the levels and the activity of the enzyme. Consequently, a non-invasive assay to measure tumoral Topo-II levels has the potential to differentiate responders from non-responders. With the ultimate goal of developing a radiofluorinated tracer for positron emission tomography (PET) imaging, we have designed, synthesized, and evaluated a set of fluorinated compounds based on the structure of the ATP-competitive Topo-II inhibitor QAP1. Compounds 18 and 19b showed inhibition of Topo-II in in vitro assays and exhibited moderate, Topo-II level dependent cytotoxicity in SK-BR-3 and MCF-7 cell lines. Based on these results, (18)F-labeled analogs of these two compounds were synthesized and evaluated as PET probes for imaging Topo-II overexpression in mice bearing SK-BR-3 xenografts. [(18)F]-18 and [(18)F]-19b were synthesized from their corresponding protected tosylated derivatives by fluorination and subsequent deprotection. Small animal PET imaging studies indicated that both compounds do not accumulate in tumors and exhibit poor pharmacokinetics, clearing from the blood pool very rapidly and getting metabolized over. The insights gained from the current study will surely aid in the design and construction of future generations of PET agents for the non-invasive delineation of Topo-II expression.
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Daumar
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Zeglis
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ramos
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Divilov
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Kuntal Kumar
authors.initials: KK
authors.lastname: Sevak
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pillarsn@mskcc.org.
authors.forename: NagaVaraKishore
authors.initials: N
authors.lastname: Pillarsetty
authors.affiliation: Department of Radiology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: lewisj2@mskcc.org.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005462:Fluorine Radioisotopes; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D057054:Molecular Imaging / Q000379:methods*; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D049268:Positron-Emission Tomography; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000032:analysis / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005462:Fluorine Radioisotopes; D059005:Topoisomerase II Inhibitors; D000255:Adenosine Triphosphate; D004250:DNA Topoisomerases, Type II
keywords: (18)F-labeling; Catalytic inhibitors; Cytotoxicity; PET imaging; Purine derivatives; Topoisomerase II