Abstract
Monitoring immune function with molecular imaging could have a considerable impact on the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron emission tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [18F]FAC (1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine) by differential screening as a new PET probe for the deoxyribonucleotide salvage pathway. [18F]FAC enabled visualization of lymphoid organs and was sensitive to localized immune activation in a mouse model of antitumor immunity. [18F]FAC microPET also detected early changes in lymphoid mass in systemic autoimmunity and allowed evaluation of immunosuppressive therapy. These data support the use of [18F]FAC PET for immune monitoring and suggest a wide range of clinical applications in immune disorders and in certain types of cancer.
Similar content being viewed by others
References
Phelps, M.E. Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc. Natl. Acad. Sci. USA 97, 9226–9233 (2000).
Koehne, G. et al. Serial in vivo imaging of the targeted migration of human HSV-TK–transduced antigen-specific lymphocytes. Nat. Biotechnol. 21, 405–413 (2003).
Dubey, P. et al. Quantitative imaging of the T cell antitumor response by positron-emission tomography. Proc. Natl. Acad. Sci. USA 100, 1232–1237 (2003).
Su, H., Forbes, A., Gambhir, S.S. & Braun, J. Quantitation of cell number by a positron emission tomography reporter gene strategy. Mol. Imaging Biol. 6, 139–148 (2004).
Shu, C.J. et al. Visualization of a primary anti-tumor immune response by positron emission tomography. Proc. Natl. Acad. Sci. USA 102, 17412–17417 (2005).
Su, H., Chang, D.S., Gambhir, S.S. & Braun, J. Monitoring the antitumor response of naive and memory CD8 T cells in Rag1−/− mice by positron emission tomography. J. Immunol. 176, 4459–4467 (2006).
Radu, C.G., Shu, C.J., Shelly, S.M., Phelps, M.E. & Witte, O.N. Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 104, 1937–1942 (2007).
Van Rompay, A.R., Johansson, M. & Karlsson, A. Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases. Pharmacol. Ther. 100, 119–139 (2003).
Griffith, D.A. & Jarvis, S.M. Nucleoside and nucleobase transport systems of mammalian cells. Biochim. Biophys. Acta 1286, 153–181 (1996).
Pankiewicz, K.W. Fluorinated nucleosides. Carbohydr. Res. 327, 87–105 (2000).
Gray, J.H., Owen, R.P. & Giacomini, K.M. The concentrative nucleoside transporter family, SLC28. Pflugers Arch. 447, 728–734 (2004).
Baldwin, S.A. et al. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch. 447, 735–743 (2004).
Eriksson, S., Munch-Petersen, B., Johansson, K. & Eklund, H. Structure and function of cellular deoxyribonucleoside kinases. Cell. Mol. Life Sci. 59, 1327–1346 (2002).
Nakano, Y. et al. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. Br. J. Cancer 96, 457–463 (2007).
van der Wilt, C.L. et al. The role of deoxycytidine kinase in gemcitabine cytotoxicity. Adv. Exp. Med. Biol. 486, 287–290 (2000).
Shipley, L.A. et al. Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs. Drug Metab. Dispos. 20, 849–855 (1992).
Shields, A.F. et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat. Med. 4, 1334–1336 (1998).
Sun, H. et al. Imaging DNA synthesis in vivo with 18F-FMAU and PET. J. Nucl. Med. 46, 292–296 (2005).
Fefer, A., McCoy, J.L., Perk, K. & Glynn, J.P. Immunologic, virologic and pathologic studies of regression of autochthonous Moloney sarcoma virus–induced tumors in mice. Cancer Res. 28, 1577–1585 (1968).
Schepers, K. et al. Differential kinetics of antigen-specific CD4+ and CD8+ T cell responses in the regression of retrovirus-induced sarcomas. J. Immunol. 169, 3191–3199 (2002).
Morse, H.C. III et al. Abnormalities induced by the mutant gene Ipr: expansion of a unique lymphocyte subset. J. Immunol. 129, 2612–2615 (1982).
Kelley, V.E. & Roths, J.B. Interaction of mutant lpr gene with background strain influences renal disease. Clin. Immunol. Immunopathol. 37, 220–229 (1985).
McKay, L.I. & Cidlowski, J.A. Molecular control of immune/inflammatory responses: interactions between nuclear factor-κB and steroid receptor-signaling pathways. Endocr. Rev. 20, 435–459 (1999).
Overwijk, W.W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).
Le, L.Q. et al. Mice lacking the orphan G protein–coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 14, 561–571 (2001).
Hamacher, K., Coenen, H.H. & Stocklin, G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J. Nucl. Med. 27, 235–238 (1986).
Mangner, T.J., Klecker, R.W., Anderson, L. & Shields, A.F. Synthesis of 2′-deoxy-2′-[18F]fluoro-β-D-arabinofuranosyl nucleosides, [18F]FAU, [18F]FMAU, [18F]FBAU and [18F]FIAU, as potential PET agents for imaging cellular proliferation. Synthesis of [18F]labelled FAU, FMAU, FBAU, FIAU. Nucl. Med. Biol. 30, 215–224 (2003).
Qi, J., Leahy, R.M., Cherry, S.R., Chatziioannou, A. & Farquhar, T.H. High-resolution 3D Bayesian image reconstruction using the microPET small-animal scanner. Phys. Med. Biol. 43, 1001–1013 (1998).
Chow, P.L., Stout, D.B., Komisopoulou, E. & Chatziioannou, A.F. A method of image registration for small animal, multi-modality imaging. Phys. Med. Biol. 51, 379–390 (2006).
Loening, A.M. & Gambhir, S.S. AMIDE: a free software tool for multimodality medical image analysis. Mol. Imaging 2, 131–137 (2003).
Acknowledgements
We are grateful to D. Stout, W. Ladno and J. Edwards for microPET imaging and to the chemists and cyclotron group for production of PET probes. We thank G. Toy, M. Riedinger, S. Quan, D. Chen, J. Wengrod, D. Goldstein and A. Tran for outstanding technical assistance. We thank J. Lee for the analysis of the microarray data, H. Su for imaging of the U87 tumors, J. Liu and C. Shen for help with biochemical analyses, J. McLaughlin (UCLA) for providing leukemic animal models for imaging studies, and J. Czernin, H. Herschman and A. Ribas for insightful discussions. We also thank B. Anderson for help with preparing the manuscript. O.N.W. is an investigator of the Howard Hughes Medical Institute. C.G.R. was supported by In Vivo Cellular and Molecular Imaging Centers Developmental Project Award, grant NIH P50 CA86306 from the National Cancer Institute at the US National Institutes of Health, by US National Cancer Institute grant 5U54 CA119347 and by Juvenile Diabetes Research Foundation Award 17-2006-870. C.G.R. acknowledges unrestricted support from Merck Research Laboratories. C.J.S. was supported by a Fred Eiserling and Judith Lengyel Graduate Doctorate Fellowship. E.N.-G. was supported by the US National Institutes of Health T32 GM08042 UCLA Medical Scientist Training Program. This research was supported in part by US Department of Energy Contract DE-FG02-06ER64249 (M.E.P.), by US National Cancer Institute grant R24CA92865 and by funds from the Samuel Waxman Cancer Research Foundation and the W.M. Keck Foundation.
Author information
Authors and Affiliations
Contributions
C.G.R., C.J.S., E.N.-G., N.S., J.R.B., M.E.P. and O.N.W. designed research; C.G.R., C.J.S., E.N.-G., N.S. and S.M.S. performed research; C.G.R., C.J.S., E.N.-G., N.S., S.M.S. and O.N.W. analyzed data; C.G.R., C.J.S. and O.N.W. wrote the paper.
Corresponding authors
Ethics declarations
Competing interests
Portions of the work covered in this manuscript have been disclosed to the University of California, Los Angeles Office of Intellectual Property Administration and included in patent applications to the US Patent Office.
Supplementary information
Supplementary Text and Figures
Supplementary Figs. 1–8 and Supplementary Methods (PDF 2372 kb)
Supplementary Movie 1
[18F]FAC biodistribution during the first 3 min after injection. (MOV 1899 kb)
Supplementary Movie 2
[18F]FAC biodistribution 3–10 min after injection. (MOV 2195 kb)
Supplementary Movie 3
[18F]FAC biodistribution 10–30 min after injection. (MOV 2290 kb)
Supplementary Movie 4
[18F]FAC biodistribution 30–60 min after injection. (MOV 2008 kb)
Rights and permissions
About this article
Cite this article
Radu, C., Shu, C., Nair-Gill, E. et al. Molecular imaging of lymphoid organs and immune activation by positron emission tomography with a new [18F]-labeled 2′-deoxycytidine analog. Nat Med 14, 783–788 (2008). https://doi.org/10.1038/nm1724
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1724
- Springer Nature America, Inc.
This article is cited by
-
Non-invasive biomarkers for monitoring the immunotherapeutic response to cancer
Journal of Translational Medicine (2020)
-
Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14–16, 2018; Vienna, Austria
Molecular Imaging and Biology (2020)
-
Plasma metabolites reveal distinct profiles associating with different metabolic risk factors in monozygotic twin pairs
International Journal of Obesity (2019)
-
Anti PD-1 treatment increases [18F]FDG uptake by cancer cells in a mouse B16F10 melanoma model
EJNMMI Research (2018)
-
Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression
Nature Communications (2017)