Skip to main content

Advertisement

SpringerLink
Log in

Modeling of PET data in CNS drug discovery and development

  • Review Paper
  • Published:
Journal of Pharmacokinetics and Pharmacodynamics Aims and scope Submit manuscript

Abstract

Positron emission tomography (PET) is increasingly used in drug discovery and development for evaluation of CNS drug disposition and for studies of disease biomarkers to monitor drug effects on brain pathology. The quantitative analysis of PET data is based on kinetic modeling of radioactivity concentrations in plasma and brain tissue compartments. A number of quantitative methods of analysis have been developed that allow the determination of parameters describing drug pharmacokinetics and interaction with target binding sites in the brain. The optimal method of quantification depends on the properties of the radiolabeled drug or radioligand and the binding site studied. We here review the most frequently used methods for quantification of PET data in relation to CNS drug discovery and development. The utility of PET kinetic modeling in the development of novel CNS drugs is illustrated by examples from studies of the brain kinetic properties of radiolabeled drug molecules.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Fischman AJ, Alpert NM, Rubin RH (2002) Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action. Clin Pharmacokinet 41(8):581–602

    Article  PubMed  CAS  Google Scholar 

  2. Bergström M, Grahnen A, Långström B (2003) Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development. Eur J Clin Pharmacol 59(5–6):357–366

    Article  PubMed  Google Scholar 

  3. Lee CM, Farde L (2006) Using positron emission tomography to facilitate CNS drug development. Trends Pharmacol Sci 27(6):310–316

    Article  PubMed  CAS  Google Scholar 

  4. Baron JC, Roeda D, Munari C, Crouzel C, Chodkiewicz JP, Comar D (1983) Brain regional pharmacokinetics of 11C-labeled diphenylhydantoin: positron emission tomography in humans. Neurology 33(5):580–585

    Article  PubMed  CAS  Google Scholar 

  5. Bauer M, Langer O, Dal-Bianco P et al (2006) A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer’s disease. Clin Pharmacol Ther 80(3):216–227

    Article  PubMed  CAS  Google Scholar 

  6. Gulyás B, Halldin C, Sandell J et al (2002) PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Acta Neurol Scand 106(6):325–332

    Article  PubMed  Google Scholar 

  7. Gunn RN, Summerfield SG, Salinas CA et al (2012) Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs. J Cereb Blood Flow Metab 32(5):874–883

    Article  PubMed  CAS  Google Scholar 

  8. Hartvig P, Bergström K, Lindberg B et al (1984) Kinetics of 11C-labeled opiates in the brain of rhesus monkeys. J Pharmacol Exp Ther 230(1):250–255

    PubMed  CAS  Google Scholar 

  9. Ito H, Nyberg S, Halldin C, Lundkvist C, Farde L (1998) PET imaging of central 5-HT2A receptors with carbon-11-MDL 100,907. J Nucl Med 39(1):208–214

    PubMed  CAS  Google Scholar 

  10. Lundberg T, Lindström LH, Hartvig P et al (1989) Striatal and frontal cortex binding of 11-C-labelled clozapine visualized by positron emission tomography (PET) in drug-free schizophrenics and healthy volunteers. Psychopharmacology 99(1):8–12

    Article  PubMed  CAS  Google Scholar 

  11. Neu H, Hartvig P, Torstenson R et al (1997) Synthesis of [11C-methyl]-(−)-OSU6162, its regional brain distribution and some pharmacological effects of (−)-OSU6162 on the dopaminergic system studied in the rhesus monkey by positron emission tomography. Nucl Med Biol 24(6):507–511

    Article  PubMed  CAS  Google Scholar 

  12. Smith DF, Jensen PN, Gee AD et al (1997) PET neuroimaging with [11C]venlafaxine: serotonin uptake inhibition, biodistribution and binding in living pig brain. Eur Neuropsychopharmacol 7(3):195–200

    Article  PubMed  CAS  Google Scholar 

  13. Mochizuki H, Kimura Y, Ishii K et al (2004) Quantitative measurement of histamine H1 receptors in human brains by PET and [11C]doxepin. Nucl Med Biol 31(2):165–171

    Article  PubMed  CAS  Google Scholar 

  14. Kim JW, Lee JS, Kim SJ et al (2012) Compartmental modeling and simplified quantification of [11C]sertraline distribution in human brain. Arch Pharm Res 35(9):1591–1597

    Article  PubMed  CAS  Google Scholar 

  15. Hiraoka K, Okamura N, Funaki Y et al (2009) Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-11C-methoxy]donepezil. NeuroImage 46(3):616–623

    Article  PubMed  Google Scholar 

  16. Farde L, Ehrin E, Eriksson L et al (1985) Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 82(11):3863–3867

    Article  PubMed  CAS  Google Scholar 

  17. Farde L, von Bahr C (1990) Distribution of remoxipride to the human brain and central D2-dopamine receptor binding examined in vivo by PET. Acta Psychiatr Scand Suppl 358:67–71

    Article  PubMed  CAS  Google Scholar 

  18. Christian BT, Livni E, Babich JW et al (1996) Evaluation of cerebral pharmacokinetics of the novel antidepressant drug, BMS-181101, by positron emission tomography. J Pharmacol Exp Ther 279(1):325–331

    PubMed  CAS  Google Scholar 

  19. Kågedal M, Cselényi Z, Nyberg S et al (2012) Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers. NeuroImage 61(4):849–856

    Article  PubMed  Google Scholar 

  20. European Medicines Agency (2004) Position Paper on non-clinical safety studies to support clinical trials with a single microdose. Position paper CPMP/SWP/2599

  21. Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (2006) Guidance for industry, investigators, and reviewers, exploratory IND studies

  22. Farde L, Heminway S, Lee CM, McCarthy D, Nordgren I, Nyberg S (2007) Using positron emission tomography (PET) micro-dosing to improve CNS drug development. Regul Rapp 4:2–8

    Google Scholar 

  23. Reiman EM, Jagust WJ (2012) Brain imaging in the study of Alzheimer’s disease. NeuroImage 61(2):505–516

    Article  PubMed  Google Scholar 

  24. Varrone A, Halldin C (2012) New developments of dopaminergic imaging in Parkinson’s disease. Q J Nucl Med Mol Imaging 56(1):68–82

    PubMed  CAS  Google Scholar 

  25. Booij J, Berendse HW (2011) Monitoring therapeutic effects in Parkinson’s disease by serial imaging of the nigrostriatal dopaminergic pathway. J Neurol Sci 310(1–2):40–43

    Article  PubMed  Google Scholar 

  26. Varrone A, Halldin C (2010) Molecular imaging of the dopamine transporter. J Nucl Med 51(9):1331–1334

    Article  PubMed  CAS  Google Scholar 

  27. Carson RE, Channing MA, Blasberg RG et al (1993) Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography. J Cereb Blood Flow Metab 13(1):24–42

    Article  PubMed  CAS  Google Scholar 

  28. Carson RE (2003) Tracer kinetic modeling in PET. In: Bailey DL, Townsend DW, Valk PE, Maisey MN (eds) Positron emission tomography: basic science and clinical practice, 1st edn. Springer, London

    Google Scholar 

  29. 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(5):595–608

    Article  PubMed  CAS  Google Scholar 

  30. Gunn RN, Gunn SR, Cunningham VJ (2001) Positron emission tomography compartmental models. J Cereb Blood Flow Metab 21(6):635–652

    Article  PubMed  CAS  Google Scholar 

  31. Ichise M, Meyer JH, Yonekura Y (2001) An introduction to PET and SPECT neuroreceptor quantification models. J Nucl Med 42(5):755–763

    PubMed  CAS  Google Scholar 

  32. Farde L, Eriksson L, Blomquist G, Halldin C (1989) Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET—a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 9(5):696–708

    Article  PubMed  CAS  Google Scholar 

  33. Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15(3):217–227

    Article  PubMed  CAS  Google Scholar 

  34. Leenders KL, Perani D, Lammertsma AA et al (1990) Cerebral blood flow, blood volume and oxygen utilization. Normal values and effect of age. Brain 113:27–47

    Article  PubMed  Google Scholar 

  35. Roland PE, Eriksson L, Stone-Elander S, Widen L (1987) Does mental activity change the oxidative metabolism of the brain? J Neurosci 7(8):2373–2389

    PubMed  CAS  Google Scholar 

  36. 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(9):1533–1539

    Article  PubMed  CAS  Google Scholar 

  37. Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE (1991) Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 11(5):735–744

    Article  PubMed  CAS  Google Scholar 

  38. Varnäs K, Nyberg S, Halldin C et al (2011) Quantitative analysis of [11C]AZ10419369 binding to 5-HT1B receptors in human brain. J Cereb Blood Flow Metab 31:113–123

    Article  PubMed  Google Scholar 

  39. Parsey RV, Slifstein M, Hwang DR et al (2000) Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tissue input functions. J Cereb Blood Flow Metab 20(7):1111–1133

    Article  PubMed  CAS  Google Scholar 

  40. Logan J, Fowler JS, Volkow ND et al (1990) Graphical analysis of reversible radioligand binding from time–activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10(5):740–747

    Article  PubMed  CAS  Google Scholar 

  41. Slifstein M, Laruelle M (2000) Effects of statistical noise on graphic analysis of PET neuroreceptor studies. J Nucl Med 41(12):2083–2088

    PubMed  CAS  Google Scholar 

  42. Ichise M, Toyama H, Innis RB, Carson RE (2002) Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab 22(10):1271–1281

    Article  PubMed  Google Scholar 

  43. Wong DF, Gjedde A, Wagner HN Jr (1986) Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands. J Cereb Blood Flow Metab 6(2):137–146

    Article  PubMed  CAS  Google Scholar 

  44. Lammertsma AA, Bench CJ, Price GW et al (1991) Measurement of cerebral monoamine oxidase B activity using l-[11C]deprenyl and dynamic positron emission tomography. J Cereb Blood Flow Metab 11(4):545–556

    Article  PubMed  CAS  Google Scholar 

  45. Logan J, Fowler JS, Volkow ND, Wang GJ, MacGregor RR, Shea C (2000) Reproducibility of repeated measures of deuterium substituted [11C]l-deprenyl ([11C]l-deprenyl-D2) binding in the human brain. Nucl Med Biol 27(1):43–49

    Article  PubMed  CAS  Google Scholar 

  46. Rusjan PM, Wilson AA, Mizrahi R et al (2013) Mapping human brain fatty acid amide hydrolase activity with PET. J Cereb Blood Flow Metab 33(3):407–414

    Article  PubMed  CAS  Google Scholar 

  47. Hirvonen J, Kailajarvi M, Haltia T et al (2009) Assessment of MAO-B occupancy in the brain with PET and [11C]-l-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther 85(5):506–512

    Article  PubMed  CAS  Google Scholar 

  48. Fowler JS, Logan J, Volkow ND, Wang GJ (2005) Translational neuroimaging: positron emission tomography studies of monoamine oxidase. Mol Imaging Biol 7(6):377–387

    Article  PubMed  Google Scholar 

  49. Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 231(4735):258–261

    Article  PubMed  CAS  Google Scholar 

  50. Lammertsma AA, Bench CJ, Hume SP et al (1996) Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 16(1):42–52

    Article  PubMed  CAS  Google Scholar 

  51. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4(3 Pt 1):153–158

    Article  PubMed  CAS  Google Scholar 

  52. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL (1996) Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16(5):834–840

    Article  PubMed  CAS  Google Scholar 

  53. Ichise M, Liow JS, Lu JQ et al (2003) Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J Cereb Blood Flow Metab 23(9):1096–1112

    Article  PubMed  Google Scholar 

  54. Cselényi Z, Olsson H, Halldin C, Gulyás B, Farde L (2006) A comparison of recent parametric neuroreceptor mapping approaches based on measurements with the high affinity PET radioligands [11C]FLB 457 and [11C]WAY 100635. NeuroImage 32(4):1690–1708

    Article  PubMed  Google Scholar 

  55. Ikoma Y, Watabe H, Shidahara M, Naganawa M, Kimura Y (2008) PET kinetic analysis: error consideration of quantitative analysis in dynamic studies. Ann Nucl Med 22(1):1–11

    Article  PubMed  Google Scholar 

  56. Lappin G, Garner RC (2003) Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2(3):233–240

    Article  PubMed  CAS  Google Scholar 

  57. Wagner CC, Langer O (2011) Approaches using molecular imaging technology—use of PET in clinical microdose studies. Adv Drug Deliv Rev 63(7):539–546

    Article  PubMed  CAS  Google Scholar 

  58. Renkin EM (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 197:1205–1210

    PubMed  CAS  Google Scholar 

  59. Crone C (1963) The permeability of capillaries in various organs as determined by use of the ‘Indicator Diffusion’ method. Acta Physiol Scand 58:292–305

    Article  PubMed  CAS  Google Scholar 

  60. Wagner CC, Simpson M, Zeitlinger M et al (2011) A combined accelerator mass spectrometry–positron emission tomography human microdose study with 14C- and 11C-labelled verapamil. Clin Pharmacokinet 50(2):111–120

    Article  PubMed  CAS  Google Scholar 

  61. Bankstahl JP, Kuntner C, Abrahim A et al (2008) Tariquidar-induced P-glycoprotein inhibition at the rat blood–brain barrier studied with (R)-11C-verapamil and PET. J Nucl Med 49(8):1328–1335

    Article  PubMed  CAS  Google Scholar 

  62. Kreisl WC, Liow JS, Kimura N et al (2010) P-glycoprotein function at the blood–brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J Nucl Med 51(4):559–566

    Article  PubMed  CAS  Google Scholar 

  63. Muzi M, Mankoff DA, Link JM et al (2009) Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans. J Nucl Med 50(8):1267–1275

    Article  PubMed  CAS  Google Scholar 

  64. Hammarlund-Udenaes M, Fridén M, Syvänen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25(8):1737–1750

    Article  PubMed  CAS  Google Scholar 

  65. Liu X, Vilenski O, Kwan J, Apparsundaram S, Weikert R (2009) Unbound brain concentration determines receptor occupancy: a correlation of drug concentration and brain serotonin and dopamine reuptake transporter occupancy for eighteen compounds in rats. Drug Metab Dispos 37(7):1548–1556

    Article  PubMed  CAS  Google Scholar 

  66. Laruelle M, Slifstein M, Huang Y (2003) Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. Mol Imaging Biol 5(6):363–375

    Article  PubMed  Google Scholar 

  67. Summerfield SG, Lucas AJ, Porter RA et al (2008) Toward an improved prediction of human in vivo brain penetration. Xenobiotica 38(12):1518–1535

    Article  PubMed  CAS  Google Scholar 

  68. Maurer TS, Debartolo DB, Tess DA, Scott DO (2005) Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice. Drug Metab Dispos 33(1):175–181

    Article  PubMed  CAS  Google Scholar 

  69. Fridén M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2007) In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos 35(9):1711–1719

    Article  PubMed  Google Scholar 

  70. Smith DA, Di L, Kerns EH (2010) The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov 9(12):929–939

    Article  PubMed  CAS  Google Scholar 

  71. Raboisson P, Breitholtz-Emanuelsson A, Dahllöf H et al (2012) Discovery and characterization of AZD9272 and AZD6538—two novel mGluR5 negative allosteric modulators selected for clinical development. Bioorg Med Chem Lett 22(22):6974–6979

    Article  PubMed  CAS  Google Scholar 

  72. Fowler JS, MacGregor RR, Wolf AP et al (1987) Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 235(4787):481–485

    Article  PubMed  CAS  Google Scholar 

  73. Fowler JS, Volkow ND, Logan J et al (1993) Monoamine oxidase B (MAO B) inhibitor therapy in Parkinson’s disease: the degree and reversibility of human brain MAO B inhibition by Ro 19 6327. Neurology 43(10):1984–1992

    Article  PubMed  CAS  Google Scholar 

  74. Lappin G, Kuhnz W, Jochemsen R et al (2006) Use of microdosing to predict pharmacokinetics at the therapeutic dose: experience with 5 drugs. Clin Pharmacol Ther 80(3):203–215

    Article  PubMed  CAS  Google Scholar 

  75. Lappin G, Garner RC (2008) The utility of microdosing over the past 5 years. Expert Opin Drug Metab Toxicol 4(12):1499–1506

    Article  PubMed  CAS  Google Scholar 

  76. Lappin G, Shishikura Y, Jochemsen R et al (2010) Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability. Eur J Pharm Sci 40(2):125–131

    Article  PubMed  CAS  Google Scholar 

  77. Farde L, Wiesel FA, Stone-Elander S et al (1990) D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride. Arch Gen Psychiatry 47(3):213–219

    Article  PubMed  CAS  Google Scholar 

  78. Pike VW (2009) PET radiotracers: crossing the blood–brain barrier and surviving metabolism. Trends Pharmacol Sci 30(8):431–440

    Article  PubMed  CAS  Google Scholar 

  79. Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN (2010) Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab 30(1):46–50

    Article  PubMed  Google Scholar 

  80. Karlsson P, Farde L, Halldin C, Sedvall G, Ynddal L, Sloth-Nielsen M (1995) Oral administration of NNC 756—a placebo controlled PET study of D1-dopamine receptor occupancy and pharmacodynamics in man. Psychopharmacology (Berl) 119(1):1–8

    Article  CAS  Google Scholar 

  81. Varnäs K, Nyberg S, Karlsson P et al (2011) Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369. Psychopharmacology (Berl) 213(2–3):533–545

    Article  Google Scholar 

  82. Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45(1):71–76

    Article  PubMed  CAS  Google Scholar 

  83. Nordström AL, Farde L, Wiesel FA et al (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 33(4):227–235

    Article  PubMed  Google Scholar 

  84. Nord M, Farde L (2011) Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther 17(2):97–103

    Article  PubMed  Google Scholar 

  85. Fujita M, Woods SW, Verhoeff NP et al (1999) Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 368(2–3):161–172

    Article  PubMed  CAS  Google Scholar 

  86. Greenwald MK, Johanson CE, Moody DE et al (2003) Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology 28(11):2000–2009

    Article  PubMed  CAS  Google Scholar 

  87. Kent JM, Coplan JD, Lombardo I et al (2002) Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with [11C]McN 5652. Psychopharmacology (Berl) 164(4):341–348

    Article  CAS  Google Scholar 

  88. Melichar JK, Hume SP, Williams TM et al (2005) Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies. J Pharmacol Exp Ther 312(1):309–315

    Article  PubMed  CAS  Google Scholar 

  89. Meyer JH, Wilson AA, Sagrati S et al (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161(5):826–835

    Article  PubMed  Google Scholar 

  90. Suhara T, Takano A, Sudo Y et al (2003) High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Arch Gen Psychiatry 60(4):386–391

    Article  PubMed  CAS  Google Scholar 

  91. Grimwood S, Hartig PR (2009) Target site occupancy: emerging generalizations from clinical and preclinical studies. Pharmacol Ther 122(3):281–301

    Article  PubMed  CAS  Google Scholar 

  92. Saijo T, Maeda J, Okauchi T et al (2009) Utility of small-animal positron emission tomographic imaging of rats for preclinical development of drugs acting on the serotonin transporter. Int J Neuropsychopharmacol 12(8):1021–1032

    Article  PubMed  CAS  Google Scholar 

  93. Takano A, Suhara T, Ichimiya T, Yasuno F, Suzuki K (2006) Time course of in vivo 5-HTT transporter occupancy by fluvoxamine. J Clin Psychopharmacol 26(2):188–191

    Article  PubMed  CAS  Google Scholar 

  94. Atack JR, Wong DF, Fryer TD et al (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(1):17–25

    Article  PubMed  CAS  Google Scholar 

  95. Atack JR, Wafford KA, Tye SJ et al (2006) TPA023 [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], an agonist selective for α2- and α3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316(1):410–422

    Article  PubMed  CAS  Google Scholar 

  96. Farde L, Andree B, Ginovart N, Halldin C, Thorberg S (2000) PET-determination of robalzotan (NAD-299) induced 5-HT1A receptor occupancy in the monkey brain. Neuropsychopharmacology 22(4):422–429

    Article  PubMed  CAS  Google Scholar 

  97. Andrée B, Hedman A, Thorberg SO, Nilsson D, Halldin C, Farde L (2003) Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain. Psychopharmacology (Berl) 167(1):37–45

    Google Scholar 

  98. Mathis CA, Bacskai BJ, Kajdasz ST et al (2002) A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 12(3):295–298

    Article  PubMed  CAS  Google Scholar 

  99. Klunk WE, Engler H, Nordberg A et al (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55(3):306–319

    Article  PubMed  CAS  Google Scholar 

  100. Rinne JO, Brooks DJ, Rossor MN et al (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol 9(4):363–372

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge Martin Schain for the very helpful comments and discussions related to the contents reviewed in this article.

Author information

Authors and Affiliations

  1. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Katarina Varnäs, Andrea Varrone & Lars Farde

  2. AstraZeneca Translational Science Center at Karolinska Institutet, Stockholm, Sweden

    Lars Farde

Authors
  1. Katarina Varnäs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Varrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lars Farde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katarina Varnäs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Varnäs, K., Varrone, A. & Farde, L. Modeling of PET data in CNS drug discovery and development. J Pharmacokinet Pharmacodyn 40, 267–279 (2013). https://doi.org/10.1007/s10928-013-9320-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10928-013-9320-6

Keywords

Search

Navigation