Reasons to Believe: The Potential of Imaging in CNS Drug Development

  • Richard Hargreaves
  • Edward Bullmore
  • Lino R. Becerra
  • David Borsook


Despite major scientific and technological advances in drug discovery over the past 10–15 years, the success rate of compounds in clinical development has continued to decline. This trend is particularly pronounced for diseases of the central nervous system (CNS). Neuroimaging, while not new to the domain of drug development, has in recent years brought a wealth of new technological advances that may be highly useful in drug development. In the present chapter, we provide an overview of the challenges and opportunities that neuroimaging may provide in transformation and enhancement of CNS drug development from aspects of animal to human translation, CNS target engagement, and the use in defining a phenotype in clinical conditions affecting the CNS.


Positron Emission Tomography Positron Emission Tomography Imaging Target Engagement Central Nervous System Drug Central Nervous System Imaging 


  1. Borsook D, Becerra L, Hargreaves R (2006) A role for fMRI in optimizing CNS drug development. Nat Rev Drug Discov 5(5):411–424PubMedCrossRefGoogle Scholar
  2. Rudin M, Mueggler T, Allegrini PR, Baumann D, Rausch M (2003) Characterization of CNS disorders and evaluation of therapy using structural and functional MRI. Anal Bioanal Chem 377(6):973–981PubMedCrossRefGoogle Scholar
  3. Beckmann N, Laurent D, Tigani B, Panizzutti R, Rudin M (2004) Magnetic resonance imaging in drug discovery: lessons from disease areas. Drug Discov Today 9(1):35–42PubMedCrossRefGoogle Scholar
  4. Wise RG, Tracey I (2006) The role of fMRI in drug discovery. J Magn Reson Imaging 23(6):862–876PubMedCrossRefGoogle Scholar
  5. Matthews PM, Honey GD, Bullmore ET (2006) Applications of fMRI in translational medicine and clinical practice. Nat Rev Neurosci 7(9):732–744PubMedCrossRefGoogle Scholar
  6. Pohlmann A, Barjat H, Tilling LC, James MF (2007) Pharmacological fMRI – challenges in analysing drug-induced single-event BOLD responses. Conf Proc IEEE Eng Med Biol Soc. 2007:3411–3416PubMedGoogle Scholar
  7. Borsook D, Bleakman D, Hargreaves R, Upadhyay J, Schmidt KF, Becerra L (2008) A “BOLD” experiment in defining the utility of fMRI in drug development. Neuroimage 42(2):461–466PubMedCrossRefGoogle Scholar
  8. Prichard JW, Alger JR, Turner R (1999) Brain imaging: the NMR revolution. Interview by Clare Thompson. BMJ 319(7220):1302PubMedGoogle Scholar
  9. Gur RE (2002) Functional imaging is fulfilling some promises. Am J Psychiatry 159(5):693–694PubMedCrossRefGoogle Scholar
  10. Logothetis NK (2002) The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal. Philos Trans R Soc Lond B Biol Sci 357(1424):1003–1037PubMedCrossRefGoogle Scholar
  11. Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453(7197):869–878PubMedCrossRefGoogle Scholar
  12. Hyder F, Kida I, Behar KL, Kennan RP, Maciejewski PK, Rothman DL (2001) Quantitative functional imaging of the brain: Towards mapping neuronal activity by BOLD fMRI. NMR Biomed 14(7–8):413–431PubMedCrossRefGoogle Scholar
  13. Beckmann CF, DeLuca M, Devlin JT, Smith SM (2005) Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci 360(1457):1001–1013PubMedCrossRefGoogle Scholar
  14. Mori S, Zhang J (2006) Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron 51(5):527–539PubMedCrossRefGoogle Scholar
  15. Jissendi Tchofo P, Baleriaux D (2009) Brain (1)H-MR spectroscopy in clinical neuroimaging at 3T. J Neuroradiol 36:24–40PubMedCrossRefGoogle Scholar
  16. Uppoor RS, Mummaneni P, Cooper E, Pien HH, Sorensen AG, Collins J et al (2008) The use of imaging in the early development of neuropharmacological drugs: a survey of approved NDAs. Clin Pharmacol Ther 84(1):69–74PubMedCrossRefGoogle Scholar
  17. Wong DF, Tauscher J, Grunder G (2009) The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacology 34(1):187–203PubMedCrossRefGoogle Scholar
  18. Jack CR Jr, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K et al (2003) MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 60(2):253–260PubMedGoogle Scholar
  19. Jack CR Jr, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D et al (2008) The Alzheimer’s Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging 27(4):685–691PubMedCrossRefGoogle Scholar
  20. Cummings JL (2008) Optimizing phase II of drug development for disease-modifying compounds. Alzheimers Dement 4(1 Suppl 1):S15–S20PubMedCrossRefGoogle Scholar
  21. Bickle M (2008) High-content screening: a new primary screening tool? IDrugs 11(11):822–826PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Richard Hargreaves
    • 1
  • Edward Bullmore
  • Lino R. Becerra
  • David Borsook
  1. 1.Merck Research Laboratories, Neuroscience FranchiseWest PointUSA

Personalised recommendations