title: Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo.
abstract: Interest in nuclear imaging of poly(ADP-ribose) polymerase-1 (PARP-1) has grown in recent years due to the ability of PARP-1 to act as a biomarker for glioblastoma and increased clinical use of PARP-1 inhibitors. This study reports the identification of a lead iodinated analog 5 of the clinical PARP-1 inhibitor olaparib as a potential single-photon emission computed tomography (SPECT) imaging agent. Compound 5 was shown to be a potent PARP-1 inhibitor in cell-free and cellular assays, and it exhibited mouse plasma stability but approximately 3-fold greater intrinsic clearance when compared to olaparib. An (123)I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [(123)I]5 in mice bearing subcutaneous glioblastoma xenografts revealed that the tracer had the ability to be retained in tumor tissue and bind to PARP-1 with specificity. These findings support further investigations of [(123)I]5 as a noninvasive PARP-1 SPECT imaging agent.
authors.affiliation: WestCHEM, School of Chemistry, University of Glasgow , The Joseph Black Building, Glasgow G12 8QQ, U.K.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow , Glasgow G61 1QH, U.K.
authors.forename: Filip
authors.initials: F
authors.lastname: Zmuda
authors.affiliation: Nuclear Imaging, Cancer Research UK Beatson Institute , Glasgow G61 1BD, U.K.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Malviya
authors.affiliation: WestCHEM, School of Chemistry, University of Glasgow , The Joseph Black Building, Glasgow G12 8QQ, U.K.
authors.forename: Adele
authors.initials: A
authors.lastname: Blair
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , John Arbuthnott Building, Glasgow, G4 0RE, U.K.
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow , Glasgow G61 1QH, U.K.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Chalmers
authors.affiliation: WestCHEM, School of Chemistry, University of Glasgow , The Joseph Black Building, Glasgow G12 8QQ, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sutherland
authors.affiliation: West of Scotland PET Centre, Greater Glasgow and Clyde NHS Trust, Glasgow G12 0YN, U.K.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Pimlott
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000175:diagnosis* / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D010793:Phthalazines / Q000737:chemistry* / Q000493:pharmacokinetics; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D004791:Enzyme Inhibitors; D007457:Iodine Radioisotopes; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib