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Dual-Modality Optical/PET Imaging of PARP1 in Glioblastoma



The current study presents [18F]PARPi-FL as a bimodal fluorescent/positron emission tomography (PET) agent for PARP1 imaging.


[18F]PARPi-FL was obtained by 19F/18F isotopic exchange and PET experiments, biodistribution studies, surface fluorescence imaging, and autoradiography carried out in a U87 MG glioblastoma mouse model.


[18F]PARPi-FL showed high tumor uptake in vivo and ex vivo in small xenografts (< 2 mm) with both PET and optical imaging technologies. Uptake of [18F]PARPi-FL in blocked U87 MG tumors was reduced by 84 % (0.12 ± 0.02 %injected dose/gram (%ID/g)), showing high specificity of the binding. PET imaging showed accumulation in the tumor (1 h p.i.), which was confirmed by ex vivo phosphor autoradiography.


The fluorescent component of [18F]PARPi-FL enables cellular resolution optical imaging, while the radiolabeled component of [18F]PARPi-FL allows whole-body deep-tissue imaging of malignant growth.

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  1. 1.

    Pittet Mikael J, Weissleder R (2011) Intravital imaging. Cell 147:983–991

  2. 2.

    Neves AA, Brindle KM (2006) Assessing responses to cancer therapy using molecular imaging. Biochim Biophys Acta 1766:242–261

  3. 3.

    Torigian DA, Huang SS, Houseni M, Alavi A (2007) Functional imaging of cancer with emphasis on molecular techniques. CA Cancer J Clin 57:206–224

  4. 4.

    Weissleder R, Pittet MJ (2008) Imaging in the era of molecular oncology. Nature 452:580–589

  5. 5.

    Condeelis J, Weissleder R (2010) In vivo imaging in cancer. Cold Spring Harb Perspect Biol 2:a003848–a003848

  6. 6.

    Alford R, Ogawa M, Choyke PL, Kobayashi H (2009) Molecular probes for the in vivo imaging of cancer. Mol Biosyst 5:1279–1291

  7. 7.

    van Dam GM, Themelis G, Crane LMA et al (2011) Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med 17:1315–1319

  8. 8.

    Stummer W, Pichlmeier U, Meinel T et al (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401

  9. 9.

    Jennings LE, Long NJ (2009) 'Two is better than one'—probes for dual-modality molecular imaging. Chem Commun 24:3511–3524

  10. 10.

    Louie A (2010) Multimodality imaging probes: design and challenges. Chem Rev 110:3146–3195

  11. 11.

    Brand C, Abdel-Atti D, Zhang Y et al (2014) In vivo imaging of GLP-1R with a targeted bimodal PET/Fluorescence imaging agent. Bioconjug Chem 25:1323–1330

  12. 12.

    Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev 65:71–79

  13. 13.

    Pérez-Medina C, Abdel-Atti D, Zhang Y et al (2014) A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting. J Nucl Med 55:1706–1711

  14. 14.

    Sanai N, Berger MS (2008) Glioma extent of resection and its impact on patient outcome. Neurosurgery 62:753–764

  15. 15.

    Pouratian N, Asthagiri A, Jagannathan J et al (2007) Surgery insight: the role of surgery in the management of low-grade gliomas. Nat Clin Pract Neurol 3:628–639

  16. 16.

    Roberts DW, Valdés PA, Harris BT et al (2012) Glioblastoma multiforme treatment with clinical trials for surgical resection (aminolevulinic acid). Neurosurg Clin N Am 23:371–377

  17. 17.

    Ossovskaya V, Koo IC, Kaldjian EP et al (2010) Upregulation of poly (ADP-ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer 1:812–821

  18. 18.

    Bièche I, de Murcia G, Lidereau R (1996) Poly(ADP-ribose) polymerase gene expression status and genomic instability in human breast cancer. Clin Cancer Res 2:1163–1167

  19. 19.

    Rojo F, García-Parra J, Zazo S et al (2012) Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol 23:1156–1164

  20. 20.

    Alanazi M, Pathan AAK, Abduljaleel Z et al (2013) Association between PARP-1 V762A polymorphism and breast cancer susceptibility in Saudi population. PLoS One 3:e92360

  21. 21.

    Galia A, Calogero AE, Condorelli R et al (2012) PARP-1 protein expression in glioblastoma multiforme. Eur J Histochem : EJH 56:e9

  22. 22.

    Barton VN, Donson AM, Kleinschmidt-DeMasters BK et al (2009) PARP1 expression in pediatric central nervous system tumors. Pediatr Blood Cancer 53:1227–1230

  23. 23.

    Thurber GM, Yang KS, Reiner T et al (2013) Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat Commun 4:1504

  24. 24.

    Irwin CP, Portorreal Y, Brand C et al (2014) PARPi-FL—a fluorescent PARP1 inhibitor for glioblastoma imaging. Neoplasia 16:432–440

  25. 25.

    Reiner T, Lacy J, Keliher EJ et al (2012) Imaging therapeutic PARP inhibition in vivo through bioorthogonally developed companion imaging agents. Neoplasia 14:169–177

  26. 26.

    Liu S, Lin T-P, Li D et al (2013) Lewis acid-assisted isotopic 18F-19F exchange in BODIPY dyes: facile generation of positron emission tomography/fluorescence dual modality agents for tumor imaging. Theranostics 3:181–189

  27. 27.

    Li Z, Lin T-P, Liu S et al (2011) Rapid aqueous [18F]-labeling of a BODIPY dye for positron emission tomography/fluorescence dual modality imaging. Chem Commun 47:9324–9326

  28. 28.

    Hendricks JA, Keliher EJ, Wan D et al (2012) Synthesis of [18F]BODIPY: bifunctional reporter for hybrid optical/positron emission tomography imaging. Angew Chem 51:4603–4606

  29. 29.

    Keliher EJ, Klubnick JA, Reiner T et al (2014) Efficient acid-catalyzed 18F/19F fluoride exchange of BODIPY dyes. ChemMedChem 9:1368–1373

  30. 30.

    Menear KA, Adcock C, Boulter R et al (2008) 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem 51:6581–6591

  31. 31.

    Zhou D, Chu W, Xu J et al (2014) Synthesis, [18F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography. Bioorg Med Chem 22:1700–1707

  32. 32.

    Keliher EJ, Reiner T, Turetsky A et al (2011) High-yielding, two-step 18F labeling strategy for 18F-PARP1 inhibitors. ChemMedChem 6:424–427

  33. 33.

    Sonnenblick A, de Azambuja E, Azim HA, Piccart M (2014) An update on PARP inhibitors-moving to the adjuvant setting. Nat Rev Clin Oncol 12:27–41

  34. 34.

    Li M, Yu X (2014) The role of poly(ADP-ribosyl)ation in DNA damage response and cancer chemotherapy. Oncogene 1:8

  35. 35.

    Ledermann J, Harter P, Gourley C et al (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852–861

  36. 36.

    Sandhu SK, Schelman WR, Wilding G, et al The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 14:882-892

  37. 37.

    Murai J, Huang S-YN, Renaud A et al (2014) Stereospecific PARP trapping by BMN 673 and comparison with Olaparib and Rucaparib. Mol Cancer Ther 13:433–443

  38. 38.

    Miller CR, Perry A (2007) Glioblastoma. Arch Pathol Lab Med 131:397–406

  39. 39.

    Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

  40. 40.

    Liu Z, Radtke MA, Wong MQ et al (2014) Dual mode fluorescent 18F-PET tracers: efficient modular synthesis of rhodamine-[cRGD]2-[18F]-organotrifluoroborate, rapid, and high yielding one-step 18F-labeling at high specific activity, and correlated in vivoPET imaging and ex vivo fluorescence. Bioconjug Chem 25:1951–1962

  41. 41.

    Murai J, Huang SN, Das BB et al (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 72:5588–5599

  42. 42.

    Chen Y, Zhang L, Hao Q (2013) Olaparib: a promising PARP inhibitor in ovarian cancer therapy. Arch Gynecol Obstet 288:367–374

  43. 43.

    Liu S, Li D, Zhang Z et al (2014) Efficient synthesis of fluorescent-PET probes based on [18F]BODIPY dye. Chem Commun 50:7371–7373

  44. 44.

    Hecht M, Fischer T, Dietrich P et al (2013) Fluorinated boron-dipyrromethene (BODIPY) dyes: bright and versatile probes for surface analysis. Chem Open 2:25–38

  45. 45.

    Lakshmi V, Chatterjee T, Ravikanth M (2014) Lewis acid assisted decomplexation of F-BODIPYs to dipyrrins. Eur J Org Chem 2014:2105–2110

  46. 46.

    Thurber GM, Reiner T, Yang KS et al (2014) Effect of small-molecule modification on single-cell pharmacokinetics of PARP inhibitors. Mol Cancer Ther 13:986–995

  47. 47.

    Kharasch ED, Thummel KE (1993) Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane and methroxyflurane. Anesthesiology 79:795

  48. 48.

    Ryu YH, Liow JS, Zoghbi S et al (2007) Disulfiram inhibits defluorination of (18)F-FCWAY, reduces bone radioactivity, and enhances visualization of radioligand binding to serotonin 5-HT1A receptors in human brain. J Nucl Med 48:1154

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The authors thank Drs. Ralph Weissleder (Harvard Medical School), NagaVaraKishore Pillarsetty (MSKCC), and Jason S. Lewis (MSKCC) for helpful discussions. They also thank Beatriz Salinas-Rodriguez for technical assistance, Valerie Longo for assisting with animal experiments, and David Gregory for critical reading of the manuscript. Support was provided by the Animal Imaging Core Facility, the Radiochemistry and Molecular Imaging Probe Core, as well as the Molecular Cytology Core at Memorial Sloan Kettering Cancer Center (P30 CA008748). This work was made possible by a financial contribution from American Italian Cancer Foundation (AICF) and the Clinical and Translational Science Center (CTSC) at Weill Cornell Medical College (NIH/NCATS Grant TL1TR000459). Finally, the authors thank the National Science Foundation Integrative Graduate Education and Research Traineeship (IGERT 0965983 at Hunter College), the NIH (K25EB016673 for T.R.), the Brain Tumor Center of Memorial Sloan Kettering Cancer Center (for T.R.), and the Radiology Development Fund (for T.R.) for their generous funding.

Conflict of Interest

The authors report no conflicts of interest.

Authors’ Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Author information

Correspondence to Thomas Reiner.

Additional information

Giuseppe Carlucci and Brandon Carney contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.


Detailed experimental procedures, characterization data, two tables and seven figures provide additional documentation of the studies described in this manuscript. (PDF 1.68 mb)

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Carlucci, G., Carney, B., Brand, C. et al. Dual-Modality Optical/PET Imaging of PARP1 in Glioblastoma. Mol Imaging Biol 17, 848–855 (2015).

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Key words

  • PARP1
  • Glioblastoma
  • PET
  • Fluorescence
  • Multimodality
  • Imaging
  • U87 MG