Skip to main content

Dynamic In Vivo Imaging of Receptors in Small Animals Using Positron Emission Tomography

  • Protocol
  • First Online:
  • 5501 Accesses

Part of the book series: Methods in Molecular Biology ((MIMB,volume 897))

Abstract

Positron emission tomography (PET) is a functional imaging technique with the potential to image and quantify receptors in vivo with high sensitivity. PET has been used extensively to study major neurotransmitters such as dopamine, serotonin, and benzodiazepine in humans as well as proving to be a very powerful tool to accelerate development and assessment of existing and novel drugs. With the recent development of dedicated PET scanners for small animals, such as the microPET, it is now possible to perform functional imaging in small animals such as rodents at high resolution. This will allow the study of animal models of disease and longitudinal studies in these models to monitor disease progression or effect of treatment in the same animal. Furthermore, the complete pharmacokinetics of a drug as well as pharmacodynamic information can be obtained in a single animal. Thus, small animal imaging will significantly reduce the number of animals needed for this type of experiment as well as reducing the effect of inter-animal variation. Experimental protocols in small animal imaging potentially can be very labor intensive. In this chapter, we discuss methods and practical aspects related to this type of experiment using the microPET system.

This is a preview of subscription content, log in via an institution.

Buying options

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Fowler JS, Ding YS, Volkow ND (2003) Radiotracers for positron emission tomography imaging. Semin Nucl Med 33:14–27

    Article  PubMed  Google Scholar 

  2. Farde L (1996) The advantage of using positron emission tomography in drug research. Trends Neurosci 19:211–214

    Article  PubMed  CAS  Google Scholar 

  3. Fowler JS, Volkow ND, Wang GJ, Ding YS, Dewey SL (1999) PET and drug research and development. J Nucl Med 40:1154–1163

    PubMed  CAS  Google Scholar 

  4. Burns HD, Hamill TG, Eng WS, Francis B, Fioravanti C, Gibson RE (1999) Positron emission tomography neuroreceptor imaging as a tool in drug discovery, research and development. Curr Opin Chem Biol 3:388–394

    Article  PubMed  CAS  Google Scholar 

  5. Aboagye EO, Price PM, Jones T (2001) In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. Drug Discov Today 6:293–302

    Article  PubMed  CAS  Google Scholar 

  6. Eckelman WC (2002) Accelerating drug discovery and development through in vivo imaging. Nucl Med Biol 29:777–782

    Article  PubMed  Google Scholar 

  7. Passchier J, Gee A, Willemsen A, Vaalburg W, van Waarde A (2002) Measuring drug-related receptor occupancy with positron emission tomography. Methods 27:278–286

    Article  PubMed  CAS  Google Scholar 

  8. Lee C-M, Farde L (2006) Using positron emission tomography to facilitate CNS drug development. Trends Pharmacol Sci 27:310–316

    Article  PubMed  CAS  Google Scholar 

  9. Iwata R (2002) Reference book 2002 for PET radiopharmaceuticals. Available at: http://kakuyaku.cyric.tohoku.ac.jp/indexe.html

  10. Welch MJ, Redvanly CS (eds) (2003) Handbook of radiopharmaceuticals—radiochemistry and applications. Wiley, Chichester

    Google Scholar 

  11. Robb RA, Hanson DP, Karwoski RA, Larson AG, Workman EL, Stacy MC (1989) Analyze: a comprehensive, operator-interactive software package for multidimensional medical image display and analysis. Comput Med Imaging Graph 13:433–454

    Article  PubMed  CAS  Google Scholar 

  12. Logan J (2000) Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 27:661–670

    Article  PubMed  CAS  Google Scholar 

  13. Slifstein M, Laruelle M (2001) Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl Med Biol 28:595–608

    Article  PubMed  CAS  Google Scholar 

  14. Lammertsma AA (2002) Radioligand studies: imaging and quantitative analysis. Eur Neuropsychopharmacol 12:513–516

    Article  PubMed  CAS  Google Scholar 

  15. Innis RB, Cunningham VJ, Delforge J et al (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27:1533–1539

    Article  PubMed  CAS  Google Scholar 

  16. Zanzonico P (2004) Positron emission tomography: a review of basic principles, scanner design and performance, and current systems. Semin Nucl Med 34:87–111

    Article  PubMed  Google Scholar 

  17. Ingvar M, Eriksson L, Rogers GA, Stone-Elander S, Widen L (1991) Rapid feasibility studies of tracers for positron emission tomography: high-resolution PET in small animals with kinetic analysis. J Cereb Blood Flow Metab 11:926–931

    Article  PubMed  CAS  Google Scholar 

  18. Chatziioannou AF (2002) Molecular imaging of small animals with dedicated PET tomographs. Eur J Nucl Med Mol Imaging 29: 98–114

    Article  PubMed  Google Scholar 

  19. Lewis JS, Achilefu S, Garbow JR, Laforest R, Welch MJ (2002) Small animal imaging: current technology and perspectives for oncological imaging. Eur J Cancer 38:2173–2188

    Article  PubMed  Google Scholar 

  20. Rowland DJ, Cherry SR (2008) Small-animal preclinical nuclear medicine instrumentation and methodology. Semin Nucl Med 38: 209–222

    Article  PubMed  Google Scholar 

  21. Pichler BJ, Wehrl HF, Kolb A, Judenhofer MS (2008) Positron emission tomography/magnetic resonance imaging: the next generation of multimodality imaging? Semin Nucl Med 38:199–208

    Article  PubMed  Google Scholar 

  22. Strome EM, Doudet DJ (2007) Animal models of neurodegenerative disease: insights from in vivo imaging studies. Mol Imaging Biol 9:186–195

    Article  PubMed  Google Scholar 

  23. Waerzeggers Y, Monfared P, Viel T, Winkeler A, Jacobs AH (2010) Mouse models in neurological disorders: applications of non-invasive imaging. Biochim Biophys Acta 1802: 819–839

    Article  PubMed  CAS  Google Scholar 

  24. Takasawa M, Beech JS, Fryer TD, Hong YT, Hughes JL, Igase K, Jones PS, Smith R, Aigbirhio FI, Menon DK, Clark JC, Baron JC (2007) Imaging of brain hypoxia in permanent and temporary middle cerebral artery occlusion in the rat using 18F-Fluoromisonidazole and positron emission tomography: a pilot study. J Cereb Blood Flow Metab 27:679–689

    PubMed  Google Scholar 

  25. Schroeter M, Dennin MA, Walberer M, Backes H, Neumaier B, Fink GR, Graf R (2009) Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195 and [18F]FDG-PET study. J Cereb Blood Flow Metab 29:1216–1225

    Article  PubMed  CAS  Google Scholar 

  26. Souza F, Simpson N, Raffo A, Saxena C, Maffei A, Hardy M, Kilbourn M, Goland R, Leibel R, Mann JJ, Van Heertum R, Harris PE (2006) Longitudinal noninvasive PET-based beta cell mass estimates in a spontaneous diabetes rat model. J Clin Invest 116:1506–1513

    Article  PubMed  CAS  Google Scholar 

  27. Cao Q, Cai W, Li ZB, Chen K, He L, Li HC, Hui M, Chen X (2007) PET imaging of acute and chronic inflammation in living mice. Eur J Nucl Med Mol Imaging 34:1832–1842

    Article  PubMed  Google Scholar 

  28. Davies JR, Izquierdo-Garcia D, Rudd JH, Figg N, Richards HK, Bird JL, Aigbirhio FI, Davenport AP, Weissberg PL, Fryer TD, Warburton EA (2010) FDG-PET can distinguish inflamed from non-inflamed plaque in an animal model of atherosclerosis. Int J Cardiovasc Imaging 26:41–48

    Article  PubMed  Google Scholar 

  29. Dalley JW, Fryer TD, Brichard L, Robinson ES, Theobald DE, Laane K, Pena Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron JC, Everitt BJ, Robbins TW (2007) Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science 315:1267–1270

    Article  PubMed  CAS  Google Scholar 

  30. Dalley JW, Fryer TD, Aigbirhio FI, Brichard L, Richards HK, Hong YT, Baron JC, Everitt BJ, Robbins TW (2009) Modelling human drug abuse and addiction with dedicated small animal positron emission tomography. Neuropharmacology 56:9–17

    Article  PubMed  CAS  Google Scholar 

  31. Chen X, Park R, Khankaldyyan V, Gonzales-Gomez I, Tohme M, Moats RA, Bading JR, Laug WE, Conti PS (2006) Longitudinal microPET imaging of brain tumor growth with F-18-labeled RGD peptide. Mol Imaging Biol 8:9–15

    Article  PubMed  CAS  Google Scholar 

  32. Chao KS (2007) 3′-Deoxy-3′-18F-fluorothymidine (FLT) positron emission tomography for early prediction of response to chemoradiotherapy–a clinical application model of esophageal cancer. Semin Oncol 34(Suppl 1):S31–S36

    Article  PubMed  CAS  Google Scholar 

  33. Jost SC, Wanebo JE, Song SK, Chicoine MR, Rich KM, Woolsey TA, Lewis JS, Mach RH, Xu J, Garbow JR (2007) In vivo imaging in a murine model of glioblastoma. Neurosurgery 60:360–370

    Article  PubMed  Google Scholar 

  34. Direcks WG, van Gelder M, Lammertsma AA, Molthoff CF (2008) A new rat model of human breast cancer for evaluating efficacy of new anti-cancer agents in vivo. Cancer Biol Ther 7:532–537

    Article  PubMed  CAS  Google Scholar 

  35. Nair-Gill ED, Shu CJ, Radu CG, Witte ON (2008) Non-invasive imaging of adaptive immunity using positron emission tomography. Immunol Rev 221:214–228

    Article  PubMed  CAS  Google Scholar 

  36. Maeda J, Ji B, Irie T, Tomiyama T, Maruyama M, Okauchi T, Staufenbiel M, Iwata N, Ono M, Saido TC, Suzuki K, Mori H, Higuchi M, Suhara T (2007) Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer’s disease enabled by positron emission tomography. J Neurosci 27:10957–10968

    Article  PubMed  CAS  Google Scholar 

  37. Zhang H, Zheng X, Yang X, Fang S, Shen G, Zhao C, Tian M (2008) 11C-NMSP/18F-FDG microPET to monitor neural stem cell transplantation in a rat model of traumatic brain injury. Eur J Nucl Med Mol Imaging 35:1699–1708

    Article  PubMed  Google Scholar 

  38. Jackson J, Chapon C, Jones W, Hirani E, Qassim A, Bhakoo K (2009) In vivo multimodal imaging of stem cell transplantation in a rodent model of Parkinson’s disease. J Neurosci Methods 183:141–148

    Article  PubMed  Google Scholar 

  39. Atack JR, Wong DF, Fryer TD, Ryan C, Sanabria S, Zhou Y, Dannals RF, Eng WS, Gibson RE, Burns HD, Vega JM, Vessy L, Scott-Stevens P, Beech JS, Baron JC, Sohal B, Schrag ML, Aigbirhio FI, McKernan RM, Hargreaves RJ (2010) Benzodiazepine binding site occupancy by the novel GABAA receptor subtype-selective drug 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans. J Pharmacol Exp Ther 332:17–25

    Article  PubMed  CAS  Google Scholar 

  40. Matsumura A, Mizokawa S, Tanaka M, Wada Y, Nozaki S, Nakamura F, Shiomi S, Ochi H, Watanabe Y (2003) Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: comparison between quantitative data obtained with microPET and ex vivo autoradiography. Neuroimage 20:2040–2050

    Article  PubMed  Google Scholar 

  41. Toyama H, Ichise M, Liow JS, Vines DC, Seneca NM, Modell KJ, Seidel J, Green MV, Innis RB (2004) Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 31:251–256

    Article  PubMed  CAS  Google Scholar 

  42. Croteau E, Benard F, Cadorette J, Gauthier ME, Aliaga A, Bentourkia M, Lecomte R (2003) Quantitative gated PET for the assessment of left ventricular function in small animals. J Nucl Med 44:1655–1661

    PubMed  Google Scholar 

  43. Zhang M-R, Maeda J, Ogawa M, Noguchi J, Ito T, Yoshida Y, Okauchi T, Obayashi S, Suhara T, Suzuki K (2004) Development of a new radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. J Med Chem 47:2228–2235

    Article  PubMed  CAS  Google Scholar 

  44. Shimoji K, Ravasi L, Schmidt K, Soto-Montenegro ML, Esaki T, Seidel J, Jagoda E, Sokoloff L, Green MV, Eckelman WC (2004) Measurement of cerebral glucose metabolic rates in the anesthetized rat by dynamic scanning with 18F-FDG, the ATLAS small animal PET scanner, and arterial blood sampling. J Nucl Med 45:665–672

    PubMed  CAS  Google Scholar 

  45. Fryer TD, Beech JS, Hughes JL, Cleij M, Aigbirhio FI, Barret O, Harris NG, Carpenter TA, Menon DK, Clark JC, Baron JC (2003) Imaging benzodiazepine receptors in control and stroked rat brains using [11C]flumazenil and microPET. Mol Imaging Biol 5:107–108

    Google Scholar 

  46. Lapointe D, Cadorette J, Rodrigue S, Rouleau D, Lecomte R (1998) A microvolumetric blood counter/sampler for metabolic PET studies in small animals. IEEE Trans Nucl Sci 45:2195–2199

    Article  Google Scholar 

  47. Zimmer L, Hassoun W, Pain F, Bonnefoi F, Laniece P, Mastrippolito R, Pinot L, Pujol JF, Leviel V (2002) SIC, an intracerebral beta(+)-range-sensitive probe for radiopharmacology investigations in small laboratory animals: binding studies with 11C-raclopride. J Nucl Med 43:227–233

    PubMed  CAS  Google Scholar 

  48. Huang SC, Wu HM, Shoghi-Jadid K, Stout DB, Chatziioannou A, Schelbert HR, Barrio JR (2004) Investigation of a new input function validation approach for dynamic mouse microPET studies. Mol Imaging Biol 6:34–46

    Article  PubMed  Google Scholar 

  49. Tai YC, Chatziioannou A, Siegel S, Young J, Newport D, Goble RN, Nutt RE, Cherry SR (2001) Performance evaluation of the microPET P4: a PET system dedicated to animal imaging. Phys Med Biol 46:1845–1862

    Article  PubMed  CAS  Google Scholar 

  50. Kinahan PE, Rogers JG (1989) Analytic 3D image-reconstruction using all detected events. IEEE Trans Nucl Sci 36:964–968

    Article  CAS  Google Scholar 

  51. Johnström P, Fryer TD, Richards HK, Harris NG, Barret O, Clark JC, Pickard JD, Davenport AP (2005) Positron emission tomography using 18F-labelled endothelin-1 reveals prevention of binding to cardiac receptors owing to tissue-specific clearance by ETB receptors in vivo. Br J Pharmacol 144:115–122

    Article  PubMed  Google Scholar 

  52. Hawkes RC, Fryer TD, Siegel S, Ansorge RE, Carpenter TA (2010) Preliminary evaluation of a combined microPET-MR system. Technol Cancer Res Treat 9:53–60

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Supported by grants from the British Heart Foundation (RG10/007/28300) and the Medical Research Council.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter Johnström .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Johnström, P., Fryer, T.D., Bird, J.L., Richards, H.K., Davenport, A.P. (2012). Dynamic In Vivo Imaging of Receptors in Small Animals Using Positron Emission Tomography. In: Davenport, A. (eds) Receptor Binding Techniques. Methods in Molecular Biology, vol 897. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-909-9_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-909-9_11

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-908-2

  • Online ISBN: 978-1-61779-909-9

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics