Synthesis and evaluation of a radioiodinated tracer with specificity for poly(ADP-ribose) polymerase-1 (PARP-1) in vivo

Zmuda, F., Malviya, G., Blair, A., Boyd, M., Chalmers, A. J. , Sutherland, A. and Pimlott, S. L. (2015) Synthesis and evaluation of a radioiodinated tracer with specificity for poly(ADP-ribose) polymerase-1 (PARP-1) in vivo. Journal of Medicinal Chemistry, 58(21), pp. 8683-8693. (doi:10.1021/acs.jmedchem.5b01324) (PMID:26469301)

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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 123I-labeled version of 5 was generated using solid state halogen exchange methodology. Ex vivo biodistribution studies of [123I]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 [123I]5 as a noninvasive PARP-1 SPECT imaging agent.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pimlott, Dr Sally and Sutherland, Dr Andrew and Chalmers, Professor Anthony and Malviya, Dr Gaurav and Boyd, Dr Marie
Authors: Zmuda, F., Malviya, G., Blair, A., Boyd, M., Chalmers, A. J., Sutherland, A., and Pimlott, S. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Copyright Holders:Copyright © 2015 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 58(21):8683-8693
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
584861EPSRC Doctoral Training Grant 2011-2015Mary Beth KneafseyEngineering & Physical Sciences Research Council (EPSRC)EP/J500434/1VICE PRINCIPAL RESEARCH & ENTERPRISE