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Positron Emission Tomography: Tool to Facilitate Drug Development and to Study Pharmacokinetics

Positron Emission Tomography: Tool to Facilitate Drug Development and to Study Pharmacokinetics. Robert B. Innis, MD, PhD Molecular Imaging Branch National Institute Mental Health. Outline of Talk. PET has high sensitivity and specificity PET used in therapeutic drug development

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Positron Emission Tomography: Tool to Facilitate Drug Development and to Study Pharmacokinetics

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  1. Positron Emission Tomography: Tool to Facilitate Drug Development and to Study Pharmacokinetics Robert B. Innis, MD, PhD Molecular Imaging Branch National Institute Mental Health

  2. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling of plasma concentration and tissue uptake can measure receptor density • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  3. Positron Emission Tomography

  4. PET vs. MRI Radionuclide (11C): high sensitivityLigand (raclopride): high selectivityRadioligand [11C]raclopride: high sensitivity & selectivity

  5. Radioligand = Drug + Radioactivity • Drug administered at tracer doses • No pharm effects • Labels <1% receptors • Labeled subset reflects entire population • Radioligand disposed like all drugs • Metabolism & distribution • Radiation exposure

  6. NIH Rodent PET Camera18F bone uptake rat Developed By: Mike Green & Jurgen Seidel

  7. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy • Monitor gene or stem cell therapy

  8. Lazabemide blocks [11C]deprenyl binding to monoamine-oxidase-B (MAO-B) Selegilene is more potent and longer acting than lazabemide

  9. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy • Monitor gene or stem cell therapy

  10. Dopamine Transporter: Located on DA Terminals Removes DA from Synapse

  11. SPECT Imaging of Dopamine Transporter in Caudate and Putamen of Human Brain

  12. 123I-β-CIT Dopamine Transporter SPECT: Decreased in Parkinson’s Disease Parkinson Stage 1 Healthy

  13. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy • Monitor gene or stem cell therapy

  14. Serial Dopamine Transporter Imaging in a Parkinson Patient Institute for Neurodegenerative Disorders

  15. PET Imaging of Amyloid: Biomarker for Alzheimer’s Disease

  16. PET: Tool in TherapeuticDrug Development • Determine dose and dosing interval • Identify homogeneous group • Biomarker for drug efficacy • Monitor gene or stem cell therapy

  17. Gene Therapy Using Viral Vectors Viral vectors deliver gene that synthesizes dopamine (DA) Infuse virus into striatum (target cells) Target cells express the DA gene

  18. post pre pre post PET Dopamine Imaging in Hemi-Parkinson Monkey: Monitors gene for DA synthesis in right striatum Control Gene: Lac-Z DA Synthesis Gene: AADC

  19. PET Imaging to Monitor Embryonic Stem Cell Treatment of “Parkinson Disease” in Rats Normal Unilateral Lesion Embryonic Stem Cells PET & MRI

  20. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  21. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  22. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  23. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  24. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  25. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters & Affinity of Fluoxetine Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  26. Brain Uptake of [18F]Fluoxetine: Measures Density of Serotonin Transporters Patient Healthy Brain Drug AUC=32 AUC=16 Time Time

  27. Binding Potential (BP) BP equals uptake in brain relative to how much activity is delivered in arterial plasma Brain Drug AUC=16 Area Brain Curve BP = Area Plasma Curve 16 BP = = 8 2 Plasma Drug AUC=2 Time

  28. Binding Potential: Independent of Injected Dose* Double Plasma Input =>Double Brain Response *If ligand does not saturate receptors - i.e. if tracer doses used Brain Drug AUC=32 32 AUC=16 BP 1st Time = = 8 4 16 BP 2nd Time = = 8 2 Plasma Drug AUC=4 AUC=2 Time

  29. What’s So difficult? Limited, noisy data. Plasma Parent Activity AUC = ? Brain Activity AUC = ? Time

  30. Tissue uptake is proportional to density of receptors and the affinity of the drug Binding Potential

  31. K1 Plasma Brain k2

  32. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  33. “Peripheral” Benzodiazepine Receptor • Mitochondrial protein highly expressed in macrophages and activated microglia • Exists in periphery and brain • Multiple potential functions: steroid synthesis, nucleotide transport • Distinct from typical benzodiazepine GABAA receptor in brain • Marker for cellular inflammation

  34. [11C](R)-PK11195 [11C]PBR28 IC50 = 0.8 nM* ; cLogP = 5.3 IC50 = 0.6 nM* ; cLogP = 3.0 Old and New PBR PET Ligands New LigandAryloxyanilide StructureHigher specific receptor signalLower lipophilicity

  35. PBR Imaging in Cerebral Ischemia Cerebral ischemia (stroke) consists of a necrotic core surrounded by a penumbra with salvageable tissue. Penumbra accumulates a large number of activated microglia.

  36. (%SUV) C 300 A 200 100 0 (nCi/mg) 21 14 B 9 5 4 2 1 [11C]PBR28 PET summation image Cresyl violet staining Peri-ischemic area Contralateral Central ischemic region In vitro [3H]PK11195 autoradiography Radioactivity accumulates in the peri-ischemic area and correlates with PBR receptor autoradiography.

  37. %SUV 500 250 0 [11C]PBR28 Monkey Brain: Total Uptake Nonspecific Uptake: Preblocked with PK11195

  38. [11C]PBR01 Time-activity Curves Baseline scan Blocking scan Non-radiolabeled PBR01 1 mg/kg i.v. % standard uptake value (%SUV) 100 %SUV = Average of activity in the whole body High levels of specific binding

  39. Receptor Blockade Displaces from Lung & Kidney Drives More Radioligand to Brain Baseline Lungs Heart Kidneys Urinary bladder Brain Blocked PK11195 10 mg/kg Spleen Liver Gall bladder 2 min 115 min 25 min

  40. Brain Time Activity Curves 250 Front. ctx Thalamus 200 White matter Lines are unconstrained 2-compartment fits 150 Activity (%SUV) 100 50 0 0 20 40 60 80 100 120 Time (min) Imaging Peripheral Type Benzodiazepine Receptors Using [11C]PBR28 in Human PET average all frames

  41. [3H]PK 11195 Receptor Autoradiography: Human Carotid Artery with Plaque Total binding Non-specific binding Subject #1 Subject #2

  42. Outline of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

  43. [18F]FCWAY: Defluorination Bone uptake: human skull at 2 h

  44. Temp Ctx Skull [18F]FCWAY: Miconazole Baseline 15 mg/kg 30 mg/kg 60 mg/kg Miconazole Inhibits Defluorination & Bone Uptake [18F]Fluoride Skull Brain

  45. Disulfiram: Decreases Skull Activity &Increases Brain Uptake Baseline Disulfiram Images at 2 h in same subject. Disulfiram 500 mg PO prior night

  46. Disulfiram: Decreases skull uptake of fluoride & Increases brain uptake of [18F]FCWAY Skull Temporal Cortex

  47. Disulfiram: Decreases plasma fluoride &Increases plasma radiotracer [18F]FCWAY [18F]FCWAY (parent tracer) [18F]fluoride

  48. Summary of Talk • PET has high sensitivity and specificity • PET used in therapeutic drug development • Pharmacokinetic modeling: plasma concentration and tissue uptake • Study drug distribution: “peripheral” benzodiazepine receptor • Study drug metabolism: inhibit defluorination

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