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
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
2 – 6 mm << 1 mm
Resolution

Sensitivity 10-12 M 10-4 M

Temporal
minutes <1 sec
Resolution

Radionuclide (11C): high sensitivity

Ligand (raclopride): high selectivity
Radioligand [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 Camera
18
F bone uptake rat

Developed By: Mike Green & Jurgen Seidel

 PET: Tool in Therapeutic
Drug 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 Therapeutic
Drug Development

• Determine dose and dosing interval

• Identify homogeneous group
• Biomarker for drug efficacy
• Monitor gene or stem cell therapy
Dopamine Transporter: Located on DA Terminals
Removes DA from Synapse
SPECT Imaging of Dopamine Transporter
in Caudate and Putamen of Human Brain
 I-β-CIT Dopamine Transporter SPECT:
123

Decreased in Parkinson’s Disease

Healthy Parkinson
Stage 1
 PET: Tool in Therapeutic
Drug 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 Therapeutic
Drug Development

• Determine dose and dosing interval

• Identify homogeneous group
• Biomarker for drug efficacy
• Monitor gene or stem cell therapy
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

 PET Dopamine Imaging in
Hemi-Parkinson Monkey:
Monitors gene for DA synthesis in right striatum

pre post pre post

Control Gene: DA Synthesis Gene:
Lac-Z AADC
PET Imaging to Monitor Embryonic Stem Cell
Treatment of “Parkinson Disease” in Rats
Normal Unilateral Lesion

Embryonic Stem Cells PET & MRI

 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
 Brain Uptake of [18F]Fluoxetine:
Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Brain Drug

AUC=32 AUC=16

Time Time
 Brain Uptake of [18F]Fluoxetine:
Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Brain Drug

AUC=32 AUC=16

Time Time
Patient Healthy
Inject Activity 20 mCi 10 mCi
 Brain Uptake of [18F]Fluoxetine:
Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Brain Drug

AUC=32 AUC=16

Time Time
Patient Healthy
Inject Activity 20 mCi 20 mCi
 Brain Uptake of [18F]Fluoxetine:
Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Brain Drug

AUC=32 AUC=16

Time Time
Patient Healthy
Inject Activity 20 mCi 20 mCi
Weight 50 kg 100 kg
 Brain Uptake of [18F]Fluoxetine:
Measures Density of Serotonin Transporters &
Affinity of Fluoxetine
Patient Healthy
Brain Drug

AUC=32 AUC=16

Time Time
Patient Healthy
Inject Activity 20 mCi 20 mCi
Weight 100 kg 100 kg
 Brain Uptake of [18F]Fluoxetine:
Measures Density of Serotonin Transporters

Patient Healthy
Brain Drug

AUC=32 AUC=16

Time Time
Patient Healthy
Inject Activity 40 mCi 20 mCi
Weight 100 kg 100 kg
Liver disease Yes No
 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
Plasma Drug

BP = 16 = 8
2

AUC=2
Time
Binding Potential: Independent of Injected Dose*

Double
*If ligand doesPlasma Inputreceptors
not saturate =>Double Brain
- i.e. Response
if tracer doses used
Brain Drug

AUC=32

AUC=16 BP 1st Time = 32

4 =8
BP 2nd Time = 162 =8
Plasma Drug

AUC=4

AUC=2
Time
 What’s So difficult?
Limited, noisy data.
Plasma Parent
Activity

AUC = ?
Brain Activity

AUC = ?
Time
Tissue uptake is proportional to density of
receptors and the affinity of the drug

Binding Bmax 1
BP   Bmax   Bmax  affinity
Potential K K
D D

Bmax  receptor density

K D  dissociation binding constant
1
 binding affinity drug
KD
 K1
Plasma Brain
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 [11C]PBR28
IC50 = 0.8 nM* ; cLogP = 5.3 IC50 = 0.6 nM* ; cLogP = 3.0

New Ligand
Aryloxyanilide Structure
Higher specific receptor signal
Lower 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.
[11C]PBR28 PET summation image Cresyl violet staining
(%SUV)
A Peri-ischemic area C
300

Contralateral 200

100
Central ischemic region

In vitro [3H]PK11195 autoradiography

(nCi/mg)
B
21
14
Radioactivity accumulates
9
in the peri-ischemic area
5 and correlates with PBR
4 receptor autoradiography.
2
1
[11C]PBR28 Monkey Brain: Total Uptake

%SUV
500

250
Nonspecific Uptake: Preblocked with PK11195

0
 [11C]PBR01 Time-activity Curves
Baseline scan Blocking scan
500 1250 Frontal Cortex
Cerebellar
400 1000
Putamen
750 4th Ventricle
300

%SUV
%SUV

Parent in plasma
200 500

100 250

0 0
0 25 50 75 100 125 150 0 25 50 75 100 125
Time (min) Time (min)

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

 Receptor Blockade Displaces from Lung & Kidney
Drives More Radioligand to Brain

Baseline Lungs Heart

Kidneys

Urinary bladder

Brain
Blocked Spleen
PK11195 10 mg/kg
Liver
Gall bladder

2 min 25 min 115 min

 Imaging Peripheral Type Benzodiazepine Receptors
Using [11C]PBR28 in Human

Brain Time Activity Curves

250
Front. ctx

200 Thalamus
White matter

Activity (%SUV)
150

Lines are unconstrained

100 2-compartment fits

50

0
0 20 40 60 80 100 120
Time (min)

PET average all frames

 [3H]PK 11195 Receptor Autoradiography:
Human Carotid Artery with Plaque

Total binding Non-specific binding

Subject #1

Subject #2
 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
 Miconazole Inhibits Defluorination &
Bone Uptake
[18F]Fluoride
Skull

Brain

Skull Temp Ctx

[18F]FCWAY: Miconazole

Baseline 15 mg/kg 30 mg/kg 60 mg/kg

Disulfiram: Decreases Skull Activity &
Increases Brain Uptake

Baseline Disulfiram
Images at 2 h in same subject. Disulfiram 500 mg PO prior night
 Disulfiram: Decreases skull uptake of fluoride &
Increases brain uptake of [18F]FCWAY

Skull Temporal Cortex

Baseline 500
400
400 Disulfiram
Mean %SUV

Mean %SUV
300
300
200
Disulfiram 200 Baseline
100 100

0 0
0 25 50 75 100 125 0 25 50 75 100 125
Time (min) Time (min)
 Disulfiram: Decreases plasma fluoride &
Increases plasma radiotracer [18F]FCWAY

[18F]FCWAY
[18F]fluoride (parent tracer)
1600
2000
1400

Activity (Bq/mL)
1750
Activity (Bq/mL)

1200
1500
1000
1250
800 1000 Disulfiram
600 Baseline 750 Baseline
400 500
Disulfiram
200 250
0 0
0 25 50 75 100 125 0 25 50 75 100 125
Time (min) Time (min)
 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.