2. Academic Validation
  3. Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo

Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo

  • J Med Chem. 2015 Nov 12;58(21):8683-93. doi: 10.1021/acs.jmedchem.5b01324.
Filip Zmuda 1 2,  Gaurav Malviya 3,  Adele Blair 1,  Marie Boyd 4,  Anthony J Chalmers 2,  Andrew Sutherland 1,  Sally L Pimlott 5
Affiliations

Affiliations

  • 1 WestCHEM, School of Chemistry, University of Glasgow , The Joseph Black Building, Glasgow G12 8QQ, U.K.
  • 2 Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow , Glasgow G61 1QH, U.K.
  • 3 Nuclear Imaging, Cancer Research UK Beatson Institute , Glasgow G61 1BD, U.K.
  • 4 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , John Arbuthnott Building, Glasgow, G4 0RE, U.K.
  • 5 West of Scotland PET Centre, Greater Glasgow and Clyde NHS Trust, Glasgow G12 0YN, U.K.
PMID: 26469301 DOI: 10.1021/acs.jmedchem.5b01324
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.

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