Molecular Imaging and Biology

, Volume 13, Issue 5, pp 812–818 | Cite as

Synthesis of 2′-Deoxy-2′-[18F]Fluoro-9-β-D-Arabinofuranosylguanine: a Novel Agent for Imaging T-Cell Activation with PET

  • Mohammad Namavari
  • Ya-Fang Chang
  • Brenda Kusler
  • Shahriar Yaghoubi
  • Beverly S. Mitchell
  • Sanjiv Sam Gambhir
Brief Article



9-(β-D-Arabinofuranosyl)guanine (AraG) is a guanosine analog that has a proven efficacy in the treatment of T-cell lymphoblastic disease. To test the possibility of using a radiofluorinated AraG as an imaging agent, we have synthesized 2′-deoxy-2′-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG) and investigated its uptake in T cells.


We have synthesized [18F]F-AraG via a direct fluorination of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl)-9-(3′,5′-di-O-trityl-2′-O-trifyl-β-D-ribofuranosyl)guanine with [18F]KF/K.2.2.2 in DMSO at 85°C for 45 min. [18F]F-AraG uptake in both a CCRF-CEM leukemia cell line (unactivated) and activated primary thymocytes was evaluated.


We have successfully prepared [18F]F-AraG in 7–10% radiochemical yield (decay corrected) with a specific activity of 0.8–1.3 Ci/μmol. Preliminary cell uptake experiments showed that both a CCRF-CEM leukemia cell line and activated primary thymocytes take up the [18F]F-AraG.


For the first time to the best of our knowledge, [18F]F-AraG has been successfully synthesized by direct fluorination of an appropriate precursor of a guanosine nucleoside. This approach maybe also useful for the synthesis of other important positron emission tomography (PET) probes such as [18F]FEAU, [18F]FMAU, and [18F]FBAU which are currently synthesized by multiple steps and involve lengthy purification. The cell uptake studies support future studies to investigate the use of [18F]F-AraG as a PET imaging agent of T cells.

Key words

Imaging T cells 9-(β-D-Arabinofuranosyl) guanine (AraG) Positron emission tomography (PET) 



This work was supported in part by NCI In Vivo Cellular Molecular Imaging Center grant P50 CA114747 (SSG). We also thank Dr. David Dick for the [18F] production, Dr. Frederick T. Chin for modification of a GE TRACERlab FX-FN synthetic module for radiosynthesis, and Dr. Jelena Levi for her review of the manuscript.

Conflict of interest disclosure

The authors declare that they have no conflict of interest.


  1. 1.
    Barrio JR, Namavari M, Phelps ME, Satyamurthy N (1996) Elemental fluorine to 8-fluoropurines in one step. J Am Chem Soc 118:10408–10411CrossRefGoogle Scholar
  2. 2.
    Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps T, Cottam HB (1992) Oral antilymphocyte activity and induction of apoptosis by 2-chloro-2′-arabinofluoro-2′-deoxyadenosine. Pro Natl Acad Sci USA 89:2970–2974CrossRefGoogle Scholar
  3. 3.
    Takahashi T, Kanazawa J, Akinaga S, Tamoaki T, Okabe M (1999) Cancer antitumor activity of 2-chloro-9-(2-deoxy-2-fluoro-beta-d-arbionfuranosyl)adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Chemother Pharmacol 43:233–240CrossRefGoogle Scholar
  4. 4.
    Kim CG, yang DJ, Kim EE, Cherif A, Kuang LR, Li C, Tansey W, Liu CW, Li SC, Wallace S, Podolof DA (1996) Assesment of tumor cell proliferation using [18F]fluorodeoxyadenosine and [18F]fluorouracile. J Pharm Sci 85:339–344PubMedCrossRefGoogle Scholar
  5. 5.
    Marquez VE, Tseng CK-H, Mitsuya H, Aoki S, Kelly JA, H-jr F, Roth JS, Broder S, Johns DG, Driscoll JS (1990) Acid stable 2′-fluoro purine dideoxynuceosides as active agents against HIV. J Med Chem 33:978–985PubMedCrossRefGoogle Scholar
  6. 6.
    Barchi JJ, Marquez VE, Driscoll JS, H-jr F, Mitsuya H, Shirasaka T, Aoki S, Kelly JA (1991) Potential anti-AIDS drugs. Lipophilic, adenosine deaminase-activated prodrugs. J Med Chem 34:1647–1655PubMedCrossRefGoogle Scholar
  7. 7.
    Masood R, Ahluwalia GS, Cooney DA, Fridland A, Marquez VE, Driscoll JS, Hao Z, Mitauya H, Pemo CF, Broder S, Johns DG (1990) 2′-Flouro-2′, 3′-dideoxyarabinosyladenine: a metaboloically stable analogues of antiviral agent 2′, 3′- dideoxyarabinosyladenine. Mol Pharmacol 37:590–596PubMedGoogle Scholar
  8. 8.
    Hitchcock MJ, Woods K, DeBoeck H, Ho HT (1990) Biochemical pharmacology of 2-flouro-2′, 3′-dideoxyarabinofuranosyladenine, an inhibitor of HIV with improved metabolic and chemical stability over 2′, 3′-dideoxyadenosine. Antiviral Chem Chemother 1:319–327Google Scholar
  9. 9.
    Silverman RB (1988) In mechanism-based enzyme inactivation: chemistry and enzymology, vol 1. CRC, Boca Raton, p 59Google Scholar
  10. 10.
    Mitchell BS, Kelly WN (1980) Purinogenic immunodeficiency diseases: clinical features and molecular mechanisums. Ann Intern Med 92:826–831PubMedGoogle Scholar
  11. 11.
    Shewach DS, Mitchell BS (1989) Differential metabolism of 9-bta-d-arabinofuranosylguanine in human leukemic cells. Cancer Res 49:6498–6502PubMedGoogle Scholar
  12. 12.
    Leanza L, Ferraro P, Bianchi V (2008) Metabolic interrelations within guanine deoxynucleotide pools for mitochondrial and nuclear DNA maintenance. J Biol Chem 283:16437–16445PubMedCrossRefGoogle Scholar
  13. 13.
    Kurtzberg J, Ernst TJ, keating MJ, Gandhi V, Hodge JP, Kisor DF, Lager JJ, Stephens C, Levin J, Kerenitsky T, Elion G, Mitchell BS (2005) Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23:3396–3403PubMedCrossRefGoogle Scholar
  14. 14.
    Curbo S, Karlsson A (2006) Nelarabine: a new purine analog in the treatment of hemtologic malignancies. Rev Recent Clin Trials 1:185–192PubMedCrossRefGoogle Scholar
  15. 15.
    Radu CG, Shu CJ, Nair-Gill E, Shelly MS, Barrio JR, Satyamurthy N, Phelps ME, Witte ON (2008) Molecular imaging of lymphoid organs and immuneactivation by positron emission tomography with a new [18F]labeled 2′-deoxycytidine analog. Nat Med 14:783–788PubMedCrossRefGoogle Scholar
  16. 16.
    Lyer M, Barrio JR, Namavari M, Bauer E, Satyamurthy N, Nguyen K, Toyokuni T, Phelps ME, Herschman HR, Gambhir SS (2001) 8-[18F]Fluoropenciclovir: an improved reporter probe for imaging HSV1-tk reporter gene expression in vivo using PET. J Nucl Med 42:96–105Google Scholar
  17. 17.
    Namavari M, Barrio JR, Toyokuni T, Gambhir SS, Cherry SR, Herschman HR, Phelps ME, Satyamurthy N (2000) Synthesis of 8-[18F]fluoroguanine derivatives: in vivo probes for imaging gene expression with PET. Nucl Med Biol 27:157–162PubMedCrossRefGoogle Scholar
  18. 18.
    Barrio JR, Namavari M, Phelps ME, Satyamurthy N (1996) Regioselective fluorination of substituted guanines with dilute F2: a facile entry to 8- fluoroguanine derivatives. J Org Chem 61:6084–6085PubMedCrossRefGoogle Scholar
  19. 19.
    Alauddin MM, Fissekis JD, Conti PS (2003) Synthesis of [18F]labeled adenosine analogues as potential PET imaging agents. J Label Compd Radiopharm 46:805–814CrossRefGoogle Scholar
  20. 20.
    Pankieweiz KW, Krzeminiski J, Watanabe KA (1992) Synthesis of 2′-β-fluoro- and 3′-α-fluoro-substituted guanine nucleosides: effects of sugar conformational shifts on nucleophilic displacement of the 2′-hydroxy and 3′-hydroxy group with DAST. J Org Chem 57:7315–7321CrossRefGoogle Scholar
  21. 21.
    Chatila T, Silverman L, Miller R, Geha R (1989) Mechanism of T cell activation by the calcium ionophore ionomycin. J Immunol 143:1283–1289PubMedGoogle Scholar
  22. 22.
    Reichman U, Watanabe KA, Fox JJ (1975) A practical synthesis of 2-deoxy-2-fluoro-d-arabinofuranose derivatives. Carbohydr Res 42:233–240PubMedCrossRefGoogle Scholar
  23. 23.
    Tann CH, Brodfuehrer PR, Brundige SP, C-Jr S, Howell HG (1985) Fluorocarbohydrate in synthesis. An efficient synthesis of 1-(2-Deoxy-2-fluoro-β-d-arabinofuranosl)-5-iodouracil (β-FIAU) and 1-(2-Deoxy-2-fluoro-β-d-arabinofuranosl)thymine (β-FMAU). J Org Chem 50:3644–3647CrossRefGoogle Scholar
  24. 24.
    Chu CK, Matulic-Aamic J, Huang JT, Chou TC, Bruchenal JH, Fox JJ, Watanabe KA (1989) Synthesis of 9-(-2-Deoxy-2-fluoro-b-d-arabinofuranosy)-9-H-purines and their biological activites. Chem Pharm Bull 37:336–339Google Scholar
  25. 25.
    Alauddin MM, Conti PS, Fissekis JD (2003) General synthesis of 2′-deoxy-2′-[18F]fluoro-1-β-d-arabinofuranosyluracil and its 5-substituted nucleosides. J Label Radiopharm 46:285–289CrossRefGoogle Scholar
  26. 26.
    Cooper TM (2007) Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manage 3(6):1135–1141Google Scholar

Copyright information

© Academy of Molecular Imaging and Society for Molecular Imaging 2010

Authors and Affiliations

  • Mohammad Namavari
    • 1
    • 2
    • 3
  • Ya-Fang Chang
    • 1
    • 2
    • 3
  • Brenda Kusler
    • 4
    • 5
  • Shahriar Yaghoubi
    • 1
    • 2
    • 3
  • Beverly S. Mitchell
    • 4
    • 5
  • Sanjiv Sam Gambhir
    • 1
    • 2
    • 3
  1. 1.Molecular Imaging Program at Stanford (MIPS)Stanford UniversityStanfordUSA
  2. 2.Department of Radiology, Bio-X ProgramStanford UniversityStanfordUSA
  3. 3.Department of Bioengineering, Bio-X ProgramStanford UniversityStanfordUSA
  4. 4.Division of Oncology, Stanford Cancer CenterStanford UniversityStanfordUSA
  5. 5.Division of Hematology, Stanford Cancer CenterStanford UniversityStanfordUSA

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