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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 - PowerPoint PPT Presentation
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Positron Emission Tomography: Tool to Facilitate Drug Development and
to Study Pharmacokinetics
Robert B. Innis, MD, PhDMolecular Imaging BranchNational Institute Mental Health
Outline of Talk
1. PET has high sensitivity and specificity
2. PET used in therapeutic drug development
3. Pharmacokinetic modeling of plasma concentration and tissue uptake can measure receptor density
4. Study drug distribution: “peripheral” benzodiazepine receptor
5. Study drug metabolism: inhibit defluorination
Positron Emission Tomography
PET vs. MRI
PET MRI
Spatial Resolution
2 – 6 mm << 1 mm
Sensitivity 10-12 M 10-4 M
Temporal Resolution
minutes <1 sec
Radionuclide (11C): high sensitivityLigand (raclopride): high selectivityRadioligand [11C]raclopride: high sensitivity
& selectivity
Radioligand = Drug + Radioactivity
1. Drug administered at tracer doses
a) No pharm effects
b) Labels <1% receptors
c) Labeled subset reflects entire population
2. Radioligand disposed like all drugs
a) Metabolism & distribution
3. Radiation exposure
NIH Rodent PET Camera18F bone uptake rat
Developed By: Mike Green & Jurgen Seidel
PET: Tool in TherapeuticDrug Development
• Determine dose and dosing interval
• Identify homogeneous group
• Biomarker for drug efficacy
• Monitor gene or stem cell therapy
Lazabemide blocks [11C]deprenyl binding to monoamine-oxidase-B (MAO-B)
Selegilene is more potent and longer acting than lazabemide
PET: Tool in TherapeuticDrug Development
• Determine dose and dosing interval
• Identify homogeneous group
• Biomarker for drug efficacy
• Monitor gene or stem cell therapy
Dopamine Transporter: Located on DA TerminalsRemoves DA from Synapse
SPECT Imaging of Dopamine Transporter in Caudate and Putamen of Human Brain
Healthy ParkinsonStage 1
123I-β-CIT Dopamine Transporter SPECT:Decreased in Parkinson’s Disease
PET: Tool in TherapeuticDrug Development
• Determine dose and dosing interval
• Identify homogeneous group
• Biomarker for drug efficacy
• Monitor gene or stem cell therapy
Serial Dopamine Transporter Imaging in a Parkinson Patient
Institute for Neurodegenerative Disorders
PET Imaging of Amyloid: Biomarker for Alzheimer’s Disease
PET: Tool in TherapeuticDrug Development
• Determine dose and dosing interval
• Identify homogeneous group
• Biomarker for drug efficacy
• Monitor gene or stem cell therapy
Viral vectors deliver genethat synthesizes dopamine (DA)
Infuse virus into striatum (target cells)
Target cells express the DA gene
Gene Therapy Using Viral Vectors
Control Gene:Lac-Z
postpreDA Synthesis Gene:
AADC
pre post
PET Dopamine Imaging in Hemi-Parkinson Monkey:
Monitors gene for DA synthesis in right striatum
Normal Unilateral Lesion
Embryonic Stem Cells PET & MRI
PET Imaging to Monitor Embryonic Stem Cell Treatment of “Parkinson Disease” in Rats
Outline of Talk
1. PET has high sensitivity and specificity
2. PET used in therapeutic drug development
3. Pharmacokinetic modeling: plasma concentration and tissue uptake
4. Study drug distribution: “peripheral” benzodiazepine receptor
5. Study drug metabolism: inhibit defluorination
AUC=32 AUC=16
Bra
in D
rug
TimeTime
Brain Uptake of [18F]Fluoxetine:Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
AUC=32 AUC=16
Bra
in D
rug
TimeTime
Brain Uptake of [18F]Fluoxetine:Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Inject Activity 20 mCi 10 mCi
Patient Healthy
AUC=32 AUC=16
Bra
in D
rug
TimeTime
Brain Uptake of [18F]Fluoxetine:Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Inject Activity 20 mCi 20 mCi
Patient Healthy
AUC=32 AUC=16
Bra
in D
rug
TimeTime
Brain Uptake of [18F]Fluoxetine:Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Inject Activity 20 mCi 20 mCi
Weight 50 kg 100 kg
Patient Healthy
AUC=32 AUC=16
Bra
in D
rug
TimeTime
Brain Uptake of [18F]Fluoxetine:Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Inject Activity 20 mCi 20 mCi
Weight 100 kg 100 kg
Patient Healthy
AUC=32 AUC=16
Bra
in D
rug
TimeTime
Brain Uptake of [18F]Fluoxetine:Measures Density of Serotonin Transporters
Patient Healthy
Inject Activity 40 mCi 20 mCi
Weight 100 kg 100 kg
Liver disease Yes No
Patient Healthy
Binding Potential (BP)
BP equals uptake in brain relative to how much activity is delivered in arterial plasma
AUC=2Pla
sma
Dru
g
Time
Bra
in D
rug
AUC=16
Area Brain Curve
Area Plasma CurveBP =
BP = 162
= 8
Bra
in D
rug
Time
Binding Potential: Independent of Injected Dose*
Double Plasma Input =>Double Brain Response
AUC=32
AUC=16 BP 1st Time = 324 = 8
BP 2nd Time = 162 = 8
Pla
sma
Dru
g
AUC=2
AUC=4
*If ligand does not saturate receptors - i.e. if tracer doses used
What’s So difficult?Limited, noisy data.
Pla
sma
Par
ent
A
ctiv
ity
Bra
in A
ctiv
ity
Time
AUC = ?
AUC = ?
Tissue uptake is proportional to density of receptors and the affinity of the drug
BindingPotential
affinity1
maxD
maxD
max BK
BK
BBP
drugaffinitybinding1
constant bindingon dissociati
densityreceptor
D
D
max
K
K
B
Plasma Brain
K1
k2
Outline of Talk
1. PET has high sensitivity and specificity
2. PET used in therapeutic drug development
3. Pharmacokinetic modeling: plasma concentration and tissue uptake
4. Study drug distribution: “peripheral” benzodiazepine receptor
5. Study drug metabolism: inhibit defluorination
“Peripheral” Benzodiazepine Receptor
1. Mitochondrial protein highly expressed in macrophages and activated microglia
2. Exists in periphery and brain
3. Multiple potential functions: steroid synthesis, nucleotide transport
4. Distinct from typical benzodiazepine GABAA receptor in brain
5. Marker for cellular inflammation
Old and New PBR PET Ligands
[11C](R)-PK11195
IC50 = 0.8 nM* ; cLogP = 5.3
[11C]PBR28
IC50 = 0.6 nM* ; cLogP = 3.0
New LigandAryloxyanilide StructureHigher specific receptor signalLower lipophilicity
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.
21
9
5
1
2
4
14
(nCi/mg)B
CA(%SUV)
0
300
100
200
[11C]PBR28 PET summation image
In vitro [3H]PK11195 autoradiography
Cresyl violet staining
Contralateral
Peri-ischemic area
Central ischemic region
Radioactivity accumulates in the peri-ischemic area and correlates with PBR receptor autoradiography.
500
250
%SUV
0
[11C]PBR28 Monkey Brain: Total Uptake
Nonspecific Uptake: Preblocked with PK11195
[11C]PBR01 Time-activity Curves
0 25 50 75 100 125 1500
100
200
300
400
500
Time (min)
%SU
V
0 25 50 75 100 1250
250
500
750
1000
1250 Frontal Cortex
Cerebel larPutamen
4th Ventricle
Parent in plasma
Time (min)%
SUV
Non-radiolabeled PBR01 1 mg/kg i.v.
Baseline scan Blocking scan
% standard uptake value (%SUV)100 %SUV = Average of activity in the whole body
High levels of specific binding
2 min 25 min 115 min
Brain
Lungs
Kidneys
Heart
LiverGall bladder
Urinary bladder
Spleen
Baseline
BlockedPK11195 10 mg/kg
Receptor Blockade Displaces from Lung & KidneyDrives More Radioligand to Brain
Brain Time Activity Curves
0 20 40 60 80 100 1200
50
100
150
200
250Front. ctx
Thalamus
White matter
Time (min)
Act
ivit
y (%
SU
V)
Lines are unconstrained2-compartment fits
Imaging Peripheral Type Benzodiazepine ReceptorsUsing [11C]PBR28 in Human
PET average all frames
Subject #1
Subject #2
Total binding Non-specific binding
[3H]PK 11195 Receptor Autoradiography:Human Carotid Artery with Plaque
Outline of Talk
1. PET has high sensitivity and specificity
2. PET used in therapeutic drug development
3. Pharmacokinetic modeling: plasma concentration and tissue uptake
4. Study drug distribution: “peripheral” benzodiazepine receptor
5. Study drug metabolism: inhibit defluorination
[18F]FCWAY: Defluorination Bone uptake: human skull at 2 h
[18F]Fluoride
Brain
Skull
Miconazole Inhibits Defluorination & Bone Uptake
Temp CtxSkull
[18F]FCWAY: Miconazole
Baseline 15 mg/kg 30 mg/kg 60 mg/kg
Disulfiram: Decreases Skull Activity &Increases Brain Uptake
Baseline DisulfiramImages at 2 h in same subject. Disulfiram 500 mg PO prior night
Disulfiram: Decreases skull uptake of fluoride &Increases brain uptake of [18F]FCWAY
0 25 50 75 100 1250
100
200
300
400
500
Baseline
Disulfiram
Time (min)
Me
an
%
SU
V
0 25 50 75 100 1250
100
200
300
400Baseline
Disulfiram
Time (min)
Me
an
%
SU
V
Skull Temporal Cortex
0 25 50 75 100 1250
250
500
750
1000
1250
1500
1750
2000
Baseline
Disulfiram
Time (min)
Ac
tiv
ity
(B
q/m
L)
Disulfiram: Decreases plasma fluoride &Increases plasma radiotracer [18F]FCWAY
[18F]fluoride[18F]FCWAY
(parent tracer)
0 25 50 75 100 1250
200
400
600
800
1000
1200
1400
1600
Baseline
Disulfiram
Time (min)
Ac
tiv
ity
(B
q/m
L)
Summary of Talk
1. PET has high sensitivity and specificity
2. PET used in therapeutic drug development
3. Pharmacokinetic modeling: plasma concentration and tissue uptake
4. Study drug distribution: “peripheral” benzodiazepine receptor
5. Study drug metabolism: inhibit defluorination
Self-Assessment Quiz: True or False?
• Positron emission tomography (PET) studies involve the injection of a radioactively labeled drug that emits a particle called a positron.
• PET shows the location of radioactivity in a cross section (or tomograph) of the body.
• PET can be used to quantify the density of specific proteins in the body.
• Compartmental modeling of PET data typically uses measurements over time of 1) PET images of the target tissue and 2) concentrations of unchanged parent radioligand in plasma.
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