Skip to main content

Imaging of CNS Systems: Importance for Drug Development

  • Chapter
  • First Online:
Imaging in CNS Drug Discovery and Development

Abstract

Despite major scientific and technological advances in drug discovery over the past 10–15 years, the success rate of compounds in clinical development has shown a continued decline. This trend is particularly pronounced for diseases of the central nervous system, including “neurologic” conditions such as Alzheimer’s disease and stroke, and “psychiatric” disorders such as schizophrenia and major depression. The discipline of Translational Medicine aims to impact on this process by identifying novel biomarkers to help validate and understand disease models and pathophysiology, drug targets, and the action of investigational compounds in vivo. In this regard, imaging technologies are particularly useful for biomarker development, because of the relative inaccessibility of the central nervous system to direct sampling and examination of cells or tissues. In the present chapter, we illustrate examples of how neuroimaging can provide information about aspects of drug discovery such as target engagement or disease pathophysiology and of how it can ultimately be used to drive improved decision making in early clinical development.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

Institutional subscriptions

References

  • Altar CA, Amakye D, Bounos D, Bloom J, Clack G, Dean R, Devanarayan V, Fu D, Furlong S, Hinman L, Girman C, Lathia C, Lesko L, Madani S, Mayne J, Meyer J, Raunig D, Sager P, Williams SA, Wong P, Zerba K (2008) A prototypical process for creating evidentiary standards for biomarkers and diagnostics. Clin Pharmacol Ther 83:368–371

    Article  PubMed  CAS  Google Scholar 

  • American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edition, 4th edn. American Psychiatric Press, Washington, DC

    Google Scholar 

  • Ametamey SM, Honer M (2007) Pharmacological prerequisites for PET ligands and practical issues in preclinical PET research. Ernst Schering Res Found Workshop 62:317–327

    Article  PubMed  CAS  Google Scholar 

  • Anderson IM, Del-Ben CM, McKie S, Richardson P, Williams SR, Elliott R, Deakin JF (2007) Citalopram modulation of neuronal responses to aversive face emotions: a functional MRI study. Neuroreport 18:1351–1355

    Article  PubMed  CAS  Google Scholar 

  • Araujo DM, Lapchak PA, Robitaille Y, Gauthier S, Quirion R (1988) Differential alteration of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer’s disease. J Neurochem 50:1914–1923

    Article  PubMed  CAS  Google Scholar 

  • Barch DM, Sheline YI, Csernansky JG, Snyder AZ (2003) Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol Psychiatry 53:376–384

    Article  PubMed  Google Scholar 

  • Baron JC, Moseley ME (2000) For how long is brain tissue salvageable? Imaging-based evidence. J Stroke Cerebrovasc Dis 9:15–20

    Article  PubMed  CAS  Google Scholar 

  • Best JD, Smith DW, Reilly MA, O’Donnell R, Lewis HD, Ellis S, Wilkie N, Rosahl TW, Laroque PA, Boussiquet-Leroux C, Churcher I, Atack JR, Harrison T, Shearman MS (2007) The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2, 5-difluorophenyl)cyclohexyl]-1, 1, 1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse. J Pharmacol Exp Ther 320:552–558

    Article  PubMed  CAS  Google Scholar 

  • Bowen DM, Allen SJ, Benton JS, Goodhardt MJ, Haan EA, Palmer AM, Sims NR, Smith CC, Spillane JA, Esiri MM, Neary D, Snowdon JS, Wilcock GK, Davison AN (1983) Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer’s disease. J Neurochem 41:266–272

    Article  PubMed  CAS  Google Scholar 

  • Bozeat S, Gregory CA, Ralph MA, Hodges JR (2000) Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer’s disease? J Neurol Neurosurg Psychiatry 69:178–186

    Article  PubMed  CAS  Google Scholar 

  • Bunney WE, Bunney BG (2000) Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia. Brain Res Brain Res Rev 31:138–146

    Article  PubMed  CAS  Google Scholar 

  • Butcher K, Parsons M, Allport L, Lee SB, Barber PA, Tress B, Donnan GA, Davis SM (2008) Rapid assessment of perfusion-diffusion mismatch. Stroke 39:75–81

    Article  PubMed  Google Scholar 

  • Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R, Goldberg TE, Weinberger DR (2000) Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 10:1078–1092

    Article  PubMed  CAS  Google Scholar 

  • Chen CH, Ridler K, Suckling J, Williams S, Fu CH, Merlo-Pich E, Bullmore E (2007) Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment. Biol Psychiatry 62:407–414

    Article  PubMed  CAS  Google Scholar 

  • Cocho D, Belvis R, Marti-Fabregas J, Molina-Porcel L, Diaz-Manera J, Aleu A, Pagonabarraga J, Garcia-Bargo D, Mauri A, Marti-Vilalta JL (2005) Reasons for exclusion from thrombolytic therapy following acute ischemic stroke. Neurology 64:719–720

    PubMed  CAS  Google Scholar 

  • Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    Article  PubMed  CAS  Google Scholar 

  • Davis KL, Hsieh JY, Levy MI, Horvath TB, Davis BM, Mohs RC (1982) Cerebrospinal fluid acetylcholine, choline, and senile dementia of the Alzheimer’s type. Psychopharmacol Bull 18:193–195

    PubMed  CAS  Google Scholar 

  • Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Desmond PM (2008) Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 7:299–309

    Article  PubMed  Google Scholar 

  • de Leon MJ, DeSanti S, Zinkowski R, Mehta PD, Pratico D, Segal S, Rusinek H, Li J, Tsui W, Saint Louis LA, Clark CM, Tarshish C, Li Y, Lair L, Javier E, Rich K, Lesbre P, Mosconi L, Reisberg B, Sadowski M, DeBernadis JF, Kerkman DJ, Hampel H, Wahlund LO, Davies P (2006) Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol Aging 27:394–401

    Article  PubMed  Google Scholar 

  • Del-Ben CM, Deakin JF, McKie S, Delvai NA, Williams SR, Elliott R, Dolan M, Anderson IM (2005) The effect of citalopram pretreatment on neuronal responses to neuropsychological tasks in normal volunteers: an FMRI study. Neuropsychopharmacology 30:1724–1734

    Article  PubMed  CAS  Google Scholar 

  • Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME (1992) A functional anatomical study of unipolar depression. J Neurosci 12:3628–3641

    PubMed  CAS  Google Scholar 

  • Feuerstein GZ (2007) The role of translational medicine and biomarkers research in drug discovery and development. Am Drug Discov 2:23–28

    Google Scholar 

  • Feuerstein GZ, Gill D, Dormer C, Ruffolo RR Jr, Rutkowski JL, Walsh FS, Hurko O (2008) Translational medicine perspectives in drug discovery and development part II: target compound interaction the vastly neglected biomarkers contributing to early clinical development failure. Am Drug Discov 3:48–54

    Google Scholar 

  • Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M (2005) Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 64:1563–1572

    Article  PubMed  CAS  Google Scholar 

  • Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, Mayberg H (2004) Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 61:34–41

    Article  PubMed  Google Scholar 

  • Goodwin GM (1997) Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. J Psychopharmacol 11:115–122

    Article  PubMed  CAS  Google Scholar 

  • Hurwitz TA, Clark C, Murphy E, Klonoff H, Martin WR, Pate BD (1990) Regional cerebral glucose metabolism in major depressive disorder. Can J Psychiatry 35:684–688

    PubMed  CAS  Google Scholar 

  • Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, Buck T, Walter D, Demont E, Howes C, Naylor A, Jeffrey P, Gonzalez MI, Dingwall C, Michel A, Redshaw S, Davis JB (2007) Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo. J Neurochem 100:802–809

    Article  PubMed  CAS  Google Scholar 

  • Jack CR Jr, Petersen RC, Xu Y, O’Brien PC, Smith GE, Ivnik RJ, Tangalos EG, Kokmen E (1998) Rate of medial temporal lobe atrophy in typical aging and Alzheimer’s disease. Neurology 51:993–999

    PubMed  Google Scholar 

  • Jack CR Jr, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K, Xu Y, Shiung M, O’Brien PC, Cha R, Knopman D, Petersen RC (2003) MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 60:253–260

    PubMed  Google Scholar 

  • Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG (1981) Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 54:773–782

    Article  PubMed  CAS  Google Scholar 

  • Kakuda W, Lansberg MG, Thijs VN, Kemp SM, Bammer R, Wechsler LR, Moseley ME, Parks MP, Albers GW (2008) Optimal definition for PWI/DWI mismatch in acute ischemic stroke patients. J Cereb Blood Flow Metab 28(5):887–891

    Article  PubMed  Google Scholar 

  • Kane I, Carpenter T, Chappell F, Rivers C, Armitage P, Sandercock P, Wardlaw J (2007) Comparison of 10 different magnetic resonance perfusion imaging processing methods in acute ischemic stroke: effect on lesion size, proportion of patients with diffusion/perfusion mismatch, clinical scores, and radiologic outcomes. Stroke 38:3158–3164

    Article  PubMed  Google Scholar 

  • Kidwell CS, Alger JR, Saver JL (2003) Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 34:2729–2735

    Article  PubMed  Google Scholar 

  • King JA, Garelick TS, Brevard ME, Chen W, Messenger TL, Duong TQ, Ferris CF (2005) Procedure for minimizing stress for fMRI studies in conscious rats. J Neurosci Methods 148:154–160

    Article  PubMed  Google Scholar 

  • Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319

    Article  PubMed  CAS  Google Scholar 

  • Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, Abrahamson EE, Debnath ML, Holt DP, Huang GF, Shao L, DeKosky ST, Price JC, Mathis CA (2005) Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 25:10598–10606

    Article  PubMed  CAS  Google Scholar 

  • Konarski JZ, McIntyre RS, Kennedy SH, Rafi-Tari S, Soczynska JK, Ketter TA (2008) Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disorders 10:1–37

    Article  PubMed  Google Scholar 

  • Kuhl DE, Koeppe RA, Snyder SE, Minoshima S, Frey KA, Kilbourn MR (2006) Imaging butyrylcholinesterase activity in Alzheimer’s disease. Ann Neurol 60:746

    Article  PubMed  Google Scholar 

  • Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT (2000) Differential limbic–cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 48:30–42

    Article  PubMed  CAS  Google Scholar 

  • Manoach DS, Gollub RL, Benson ES, Searl MM, Goff DC, Halpern E, Saper CB, Rauch SL (2000) Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 48:99–109

    Article  PubMed  CAS  Google Scholar 

  • Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA (2000) Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry 48:830–843

    Article  PubMed  CAS  Google Scholar 

  • Mega MS, Chen SS, Thompson PM, Woods RP, Karaca TJ, Tiwari A, Vinters HV, Small GW, Toga AW (1997) Mapping histology to metabolism: coregistration of stained whole-brain sections to premortem PET in Alzheimer’s disease. Neuroimage 5:147–153

    Article  PubMed  CAS  Google Scholar 

  • Molina V, Gispert JD, Reig S, Sanz J, Pascau J, Santos A, Desco M, Palomo T (2005) Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement. Psychopharmacology (Berl) 178:17–26

    Article  CAS  Google Scholar 

  • Mosconi L, Tsui WH, De Santi S, Li J, Rusinek H, Convit A, Li Y, Boppana M, de Leon MJ (2005) Reduced hippocampal metabolism in MCI and AD: automated FDG-PET image analysis. Neurology 64:1860–1867

    Article  PubMed  CAS  Google Scholar 

  • Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack C, Jagust W, Trojanowski JQ, Toga AW, Beckett L (2005) The Alzheimer’s disease neuroimaging initiative. Neuroimaging Clin N Am 15:869–877 xi-xii

    Article  PubMed  Google Scholar 

  • Nabavi DG, Cenic A, Henderson S, Gelb AW, Lee TY (2001) Perfusion mapping using computed tomography allows accurate prediction of cerebral infarction in experimental brain ischemia. Stroke 32:175–183

    PubMed  CAS  Google Scholar 

  • Pangalos MN, Schechter LE, Hurko O (2007) Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 6:521–532

    Article  PubMed  CAS  Google Scholar 

  • Pimlott SL (2005) Radiotracer development in psychiatry. Nucl Med Commun 26:183–188

    Article  PubMed  Google Scholar 

  • Raje S, Patat AA, Parks V, Schechter L, Plotka A, Paul J, Langstrom B (2008) A positron emission tomography study to assess binding of lecozotan, a novel 5-hydroxytryptamine-1A silent antagonist, to brain 5-HT1A receptors in healthy young and elderly subjects, and in patients with Alzheimer’s disease. Clin Pharmacol Ther 83:86–96

    Article  PubMed  CAS  Google Scholar 

  • Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O’Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL (2007) Imaging beta-amyloid burden in aging and dementia. Neurology 68:1718–1725

    Article  PubMed  CAS  Google Scholar 

  • Salgado-Pineda P, Junque C, Vendrell P, Baeza I, Bargallo N, Falcon C, Bernardo M (2004) Decreased cerebral activation during CPT performance: structural and functional deficits in schizophrenic patients. Neuroimage 21:840–847

    Article  PubMed  Google Scholar 

  • Schechter LE, Smith DL, Rosenzweig-Lipson S, Sukoff SJ, Dawson LA, Marquis K, Jones D, Piesla M, Andree T, Nawoschik S, Harder JA, Womack MD, Buccafusco J, Terry AV, Hoebel B, Rada P, Kelly M, Abou-Gharbia M, Barrett JE, Childers W (2005) Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. J Pharmacol Exp Ther 314:1274–1289

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (2006) Targeting the dopamine D2 receptor in schizophrenia. Expert Opin Ther Targets 10:515–531

    Article  PubMed  CAS  Google Scholar 

  • Shinotoh H, Aotsuka A, Fukushi K, Nagatsuka S, Tanaka N, Ota T, Tanada S, Irie T (2001) Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET. Neurology 56:408–410

    PubMed  CAS  Google Scholar 

  • Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, Lavretsky H, Burggren AC, Cole GM, Vinters HV, Thompson PM, Huang SC, Satyamurthy N, Phelps ME, Barrio JR (2006) PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 355:2652–2663

    Article  PubMed  CAS  Google Scholar 

  • Solomon B (2007) Antibody-mediated immunotherapy for Alzheimer’s disease. Curr Opin Investig Drugs 8:519–524

    PubMed  CAS  Google Scholar 

  • Takasawa M, Jones PS, Guadagno JV, Christensen S, Fryer TD, Harding S, Gillard JH, Williams GB, Aigbirhio FI, Warburton EA, Ostergaard L, Baron JC (2008) How reliable is perfusion MR in acute stroke? Validation and determination of the penumbra threshold against quantitative PET. Stroke 39:870–877

    Article  PubMed  Google Scholar 

  • Tauscher J, Kapur S (2001) Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies. CNS Drugs 15:671–678

    Article  PubMed  CAS  Google Scholar 

  • Wardlaw JM (2001) Radiology of stroke. J Neurol Neurosurg Psychiatry 70(Suppl 1):I7–I11

    Article  PubMed  Google Scholar 

  • Wardlaw JM, West TM, Sandercock PA, Lewis SC, Mielke O (2003) Visible infarction on computed tomography is an independent predictor of poor functional outcome after stroke, and not of haemorrhagic transformation. J Neurol Neurosurg Psychiatry 74:452–458

    Article  PubMed  CAS  Google Scholar 

  • Weinberger DR, Berman KF (1996) Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 351:1495–1503

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Jack CR Jr, O’Brien PC, Kokmen E, Smith GE, Ivnik RJ, Boeve BF, Tangalos RG, Petersen RC (2000) Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD. Neurology 54:1760–1767

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Menelas N. Pangalos .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Wan, H.I. et al. (2010). Imaging of CNS Systems: Importance for Drug Development. In: Borsook, D., Beccera, L., Bullmore, E., Hargreaves, R. (eds) Imaging in CNS Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0134-7_2

Download citation

Publish with us

Policies and ethics