Comparison of methodologies for the assessment of dopamine receptor binding in
subregions of the striatum
Functional Neuroimaging Lab School of Psychology
University of NewcastleSchizophrenia Research Institute
Darlinghurst, Australia
Sharna JamadarMentor: Julie Price
PET Modality Coordinator: Jonathan Carney
Project Aims• Become familiar with
the basics of PET radioligand methods– Compartmental
models– Logan graphical
method (arterial input function)
– Logan graphical method (cerebellum reference tissue)
• Become familiar with two types of dopamine radioligands– Raclopride– CFT– How do these differ?
Understand utility of PET radiotracer methods for the study of behaviour
PET Methodology• Compartmental models
– Model parameters determined by iterative non-linear least-squares fitting, used to obtain receptor binding measures, use arterial blood as model input
• Outcome measures:– Distribution volume (VT) the ratio of the concentration of radioligand in a region of tissue to
that in plasma (at equilibrium)– Distribution volume ratio (DVR) is related to receptor density x affinity, and equal to VT / VND
– Binding potential (BP) proportional to receptor density x affinity
1T
2T
VT = free + nonspecific + specific
VND = free + nonspecific(non-displaceable reference uptake)
PET Methodology• Logan Graphical Methods
– Linear alternative, use arterial blood as input (VT), possible to use reference-tissue (DVR)
– Transforms multiple time measurements of plasma and tissue uptake into a linear plot, the slope related to receptor binding measures
– Appropriate for radiotracers for which a constant relationship between blood and brain tissue radioactivity is established during the study (steady-state)
– Advantages• Simpler calculations (non-iterative)• Not reliant upon definition of underlying compartments
Radiotracers for Dopamine• [C-11]Raclopride
– D2/3 receptors– Benzamide that shows selective and moderate affinity
for D2 receptors and binds reversibly to postsynaptic D2 receptors
• [C-11]CFT 2-carbomethoxy-3-(4-[18F]-fluorophenyl)tropane – Dopamine transporter– Cocaine analogue that shows good selectivity for the
dopamine transporter over other transporters and shows little non-specific binding in the brain
– Dopamine transporter is present exclusively in dopamine-synthesising neurons, thus is an index of presynaptic dopaminergic function.
– (Almost) irreversible binding
Project
• N=4
• Assess compartmental modeling and graphical methods for [C-11]raclopride & [C-11]CFT
• Estimate binding potential: BP (VT/VND) – 1– Cerebellum used as reference tissue to estimate VND
• Free of dopamine receptors, good estimate of non-displaceable (i.e., free + non-specific) uptake
– Which method(s) are acceptable?• 1 tissue compartment model
• 2 tissue compartment model
• Logan (arterial)
• Logan (reference tissue)
Project
•Dorsal caudate (DCA)•Anteroventral striatum (AVS)
•accumbens, ventromedial caudate + anteroventral putamen
•Middle caudate (MCA)•Dorsal putamen (DPU)•Ventral putamen (VPU)
First defined in Drevets et al. (1999) in baboon, used in humans Drevets et al. (2001)
CER 1 Tissue Compartment
[C-11]RAC
0.1
0.35
K1 = 0.116 Err = 0.0134 %Err = 11.5
k2 = 0.300 Err = 0.0307 %Err = 10.2
VT = 0.387 = VND SS=0.057
Receptor free region= free + unspecific binding
µC
i/mL
obs-
fit
Time (min)
CER 1 Tissue Compartment
CER2 Tissue Compartment
[C-11]RAC
0.1
0.35
0.35
0.1
K1 = 0.130 Err = 0.0221 %Err = 17.0
k2 = 0.383 Err = 0.612 %Err = 42.4
k3 = 0.036 Err = 0.130 %Err >100
k4 = 0.232 Err = 0.397 %Err > 100
VT = 0.39 SS=0.055
K1 = 0.116 Err = 0.0134 %Err = 11.5
k2 = 0.300 Err = 0.0307 %Err = 10.2
VT = 0.387 = VND SS=0.057
Receptor free region= free + unspecific binding
Similar VTSlightly lower SS in 2TBetter k estimation in 1T
µC
i/mL
obs-
fit
Time (min)
CER 1 Tissue Compartment
CER2 Tissue Compartment
[C-11]RAC
0.1
0.35
K1 = 0.116 Err = 0.0134 %Err = 11.5
k2 = 0.300 Err = 0.0307 %Err = 10.2
VT = 0.387 SS = 0.057
0.35
0.1
K1 = 0.130 Err = 0.0221 %Err = 17.0
k2 = 0.383 Err = 0.612 %Err = 42.4
k3 = 0.036 Err = 0.130 %Err >100
k4 = 0.232 Err = 0.397 %Err > 100
VT = 0.39 SS=0.055
DPU
K1 = 0.097 Err = 0.0040 %Err = 4.1
k2 = 0.055 Err = 0.0027 %Err = 4.9
VT = 1.77 SS = 0.087
0.5
0.14
Receptor-rich region= free + unspecific + specific binding
Differences in curve shapes= differences in clearance &specific binding
CER 1 Tissue Compartment
CER2 Tissue Compartment
[C-11]RAC
0.1
K1 = 0.116 Err = 0.0134 %Err = 11.5
k2 = 0.300 Err = 0.0307 %Err = 10.2
VT = 0.387 SS = 0.057
0.1
K1 = 0.130 Err = 0.0221 %Err = 17.0
k2 = 0.383 Err = 0.612 %Err = 42.4
k3 = 0.036 Err = 0.130 %Err >100
k4 = 0.232 Err = 0.397 %Err > 100
VT = 0.39 SS=0.055
DPU
K1 = 0.097 Err = 0.0040 %Err = 4.1
k2 = 0.055 Err = 0.0027 %Err = 4.9
VT = 1.77 SS = 0.087
0.5
0.14
DPU
0.5
0.14
K1 = 0.121 Err = 0.091 %Err = 15.6
k2 = 0.143 Err = 0.120 %Err = 84.1
k3 = 0.139 Err = 0.218 %Err >100
k4 = 0.123 Err = 0.051 %Err = 41.1
VT = 1.81 SS=0.072
Differences in curve shapes= differences in clearance &specific binding
Similar VTLower SS in 2TBetter k estimation in 1T
0.35
0.35
DPU CER 1 Tissue Compartment
DPU CER2 Tissue Compartment
[C-11]RAC
µC
i/mL
obs-
fit
Time (min)
DPU CER 1 Tissue Compartment
DPU CER2 Tissue Compartment
DPU CERLogan Arterial
DPULogan Cerebellum
[C-11]RAC
VT = 1.87 VT = 0.459
VT = 1.81 VT = 0.39 DVR = 4.02
DVR = 1.87/0.459 = 4.08
DVR=4.64
µC
i/mL
obs-
fit
Time (min)
Cp/ROI
RO
I/R
OI
CER 1 Tissue Compartment
[C-11]CFT
K1 = 0.347 Err = 0.009 %Err = 2.6
k2 = 0.042 Err = 0.001 %Err = 2.8
VT = 8.34 SS = 0.092
0.6
0.08
µC
i/mL
obs-
fit
Time (min)
CER 1 Tissue Compartment
[C-11]CFT
K1 = 0.347 Err = 0.009 %Err = 2.6
k2 = 0.042 Err = 0.001 %Err = 2.8
VT = 8.34 SS = 0.092
CER2 Tissue Compartment
0.6
0.08
0.6
0.14
K1 = 0.401 Err = 0.012 %Err = 3.1
k2 = 0.056 Err = 0.040 %Err = 8.0
k3 = 0.005 Err = 0.030 %Err = 69.2
k4 = 0.012 Err = 0.014 %Err > 100
VT = 10.36 SS=0.063
VT 1T < 2TLower SS in 2TBetter k estimation in 1T
µC
i/mL
obs-
fit
Time (min)
CER 1 Tissue Compartment
[C-11]CFT
K1 = 0.347 Err = 0.009 %Err = 2.6
k2 = 0.042 Err = 0.001 %Err = 2.8
VT = 8.34 SS = 0.092
CER2 Tissue Compartment
0.6
0.08
0.6
0.14
K1 = 0.401 Err = 0.012 %Err = 3.1
k2 = 0.056 Err = 0.040 %Err = 8.0
k3 = 0.005 Err = 0.030 %Err = 69.2
k4 = 0.012 Err = 0.014 %Err > 100
VT = 10.36 SS=0.063
DPU
1.0
0.06
K1 = 0.307 Err = 0.003 %Err = 1.0
k2 = 0.005 Err = 0.0002 %Err = 5.0
VT = 68.0 SS = 0.037
DPU
1.0
0.12
K1 = 0.275 Err = NA %Err < -8000
k2 < 0 Err = 0.002 %Err < -100
k3 = 0.051 Err = 0.021 %Err = 40.7
k4 < 0 Err = 0.069 %Err < -100
VT < 0 SS=0.194
Irreversible binding
CER 1 Tissue Compartment
[C-11]CFT
CER2 Tissue Compartment
0.6
0.08
0.6
0.14
DPU
1.0
0.06
DPU
1.0
0.12
VT = 68 VT = 8.34
µC
i/mL
obs-
fit
Time (min)
CER 1 Tissue Compartment
[C-11]CFT
CER2 Tissue Compartment
0.6
0.08
0.6
0.14
DPU
1.0
0.06
DPU
1.0
0.12
DPU CER
Logan Arterial
DPULogan Cerebellum
VT = 68VT = 8.34
VT = 65 VT = 8.84
DVR = 3.03
DVR = 65/8.84 = 7.45
DVR=8.14
Cp/ROI
RO
I/R
OI
Interim Summary• [C-11]Raclopride 2Tcomp better fit• [C-11]CFT 1Tcomp better fit • Conclusions consistent with known properties of the
radiotracers:– [C-11]Raclopride shows reversible binding during the PET study.
Thus k3 and k4 can be determined– [C-11]CFT shows irreversible binding in receptor-rich regions
during the PET study. Thus k4 cannot be accurately determined
RAC - DPU CFT - DPU
Comparison of binding potential between methods
Simplified methods are appropriate for raclopride
Comparison of binding potential between methods
Utility of PET radioligand methods for the study of behaviour
• Or, I’m a psychologist, why do I care?
Utility of PET radioligand methods for the study of behaviour
• Or, I’m a psychologist, why do I care?
Utility of PET radioligand methods for the study of
behaviour• Sequential motor learning
– [C-11]Raclopride BP in dorsal striatum decreases during finger sequence learning task
– Both implicit & implicit learning of complex motor sequences increase [C-11]raclopride displacement in the caudate & putamen
• Reward-related processes– Decreased striatal [C-11]raclopride BP during an active but not
passive reward task
• Cognition– Decreases in [C-11]raclopride BP when planning a set shift, during
spatial planning and spatial working memory
Variability in BP outcomes are related to behaviour
Utility of PET radioligand methods for the study of behaviour
• Variability in BP outcomes are related to behaviour
• Variability in BP outcomesare related to EEG synchrony
Acknowledgements• PET Facility
– Julie Price– Jonathan (Eoin) Carney– Carl Becker– Amy Wagner
• MNTP– Seong-Gi Kim– Bill Eddy– Tomika Cohen– Rebecca Clark
• Schizophrenia Research Institute, Australia
• University of Newcastle, Australia
Comparison of binding potential between methods
Comparison of binding potential between methods
Comparison of binding potential between methods
BP = K3/k4
BP=VTROI/VTCER-1 = K1/k2(1+k3/k4)-1
Interim Summary
• Logan– Susceptible to bias– Bias is worse in CFT
because of slower reference tissue clearance relative to plasma
– Bias not so bad in RAC because of similar clearance in reference tissue relative to plasma