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Principles of neuroreceptor pet imaging_Donald F. Smith
1. Principles of Molecular Brain Imaging
in Depressive Disorders
Donald F. Smith
Translational Neuropsychiatry Unit
Clinical Institute
Aarhus University
3. Principles of Molecular Brain Imaging
in Depressive Disorders
• The Challenges
• Principles of PET
• Principles of Molecular Neuroimaging
• Actions of Mirtazapine & Enantiomers
• [11C]Mirtazapine PET in Pig
• Requirements for Human PET
• Initial [11C]Mirtazapine PET in Humans
• Toward Evidence-based Neuropsychiatry
4. How might one go about
determining whether a particular
neurochemical and/or
neurophysiological process is causally
involved in affective disorders?
5. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of molecular neuroimaging
• Actions of mirtazapine & enantiomers
• [11C]Mirtazapine PET in pig
• Requirements for human PET
• Initial [11C]Mirtazapine PET in humans
• Toward Evidence-based Neuropsychiatry
7. N
H
HO CH2CH2NH2
1
O
O
O
NH
F
2
N N
NH
O2N
3
N N
NH
O2N
I
4
CH3
NHCH3
O
O
5
O
N
CH3H
6 N
SCH3
H
7
N
NOCH3
Br
CH3
8
O
NC
N
H3C CH3
F
9
N
H3C
I
CO2CH3
H
H
10
N
H
CO2CH3
CH3
H
H3C
11
OH
OCH3
N
CH3
CH3
12
H
N CH3
CH3
CF3
13
N
CF3
H3C
14
Structural drawings:
1 = Serotonin, 2 = Paroxetine, 3 = Nitroquipazine,
4 = 5-Iodo-6-nitro-quipazine, 5 = MDMA, 6 = Fluoxetine,
7 = McN5652, 8 = LY257327, 9 = Citalopram, 10 = -CIT,
11 = RTI-55, 12 = Venlafaxine, 13 = Fenfluramine, 14 = NS2381.
8.
9.
10.
11. Brief account of compartmental kinetic
models used for PET.
1. Reversible binding
(2- or 3-compartments)
a. with arterial input function (Logan)
b. with reference region (Lammertsma)
2. Irreversible binding (Gjedde-Patlak)
14. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of Molecular Neuroimaging
• Actions of Mirtazapine & Enantiomers
• [11C]Mirtazapine PET in Pig
• Requirements for Human PET
• Initial [11C]Mirtazapine PET in Humans
• Toward Evidence-based Neuropsychiatry
17. Receptor theory
First postulated by John Langley (1878)
– Established after his experiments using nicotine
and curare analogues on muscle contraction.
Isolated muscle fibers: pilocarpine (contraction) and
atropine (inhibition).
Two compounds competing for a third, but unknown
substrate.
Furthered by Paul Ehrlich (1854-1915)
– Demonstrated that stereoselectivity was
imperative in drug-receptor signaling.
18. Receptor occupancy
Activation of membrane receptors and
target cell responses are proportional to
the degree of receptor occupancy.
19. The amount of drug bound at any time is
solely determined by:
– the number of receptors
– the concentration of ligand added
– the affinity of the drug for its receptor.
Binding of drug to receptor is essentially the same
as binding of drug to enzyme as defined by the
Michelis-Menten equation.
24. Sequenced treatment alternatives to relieve depression
(STAR*D): rationale and design.
Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim
HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer
DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-
Wilson K, Lebowitz BD, Ritz L, Niederehe G; STAR*D Investigators Group.
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-
9086, USA. john.rush@utsouthwestern.edu
Control Clin Trials. 2004, Feb;25(1):119-42.
25. Treatment-Resistant Depression
25 – 30% of patients suffering from depression show ”treatment-
resistance”.
Some patients never respond satisfactorily to antidepressant
therapies, and many of them commit suicide.
Noone knows the neurobiological basis of treatment-resistant
depression.
Few molecular tools are currently available for assessing causes
and cures of treatment-resistant depression at neuroreceptors.
The long-term aim of this project is to discover molecular tools for
correctly diagnosing treatment-resistant depression and for
selecting the most appropriate therapeutic procedures.
26. A major goal of modern biological psychiatry
is discovering valid procedures for evaluating
neurochemical dysfunctions associated with
neuropsychiatric disorders such as
depression.
27. Neuropsychosocial Model
Sense of Danger
Corticostriato- thalamic Pathway
Symptoms of Depression
5-HT
Sleep Disorders Cognitive
Disorders
Eating Disorders
ACh NAGABA
Unconditioned
Responses
Conditioned
Responses
Emotional Memory
Amygdalothalamo-
cortical Pathway
Visceral
Limbic Pathway
5-HTACh
Corticothalamic
Pathway
Cortico-
cortico Pathway
Cortical
Limbic
Pathway
28.
29. Antidepressants (clinical and preclinical) that have been tested
as PET radioligands
• Paroxetine
• Citalopram
• Fluoxetine
• Venlafaxine
• Clomipramine
• Nefopam
• Mianserin
• NS2381 & NS2456
• McN5652
• Mirtazapine
31. = NA neuron
= 5-HT neuron
= α2-autoreceptor
= α2-heteroceptor
NA
NA
NA
NA
NA
NA
NA
NA
5-HT
5-HT
Noradrenaline (NA) exerts a tonic, inhibitory action on serotonin (5-HT) release
via α2-heteroceptors, so antagonism of α2-heteroceptors enhances 5-HT release.
NA binding at α2-autoreceptors reduces NA release, so antagonism of
α2-autoreceptors enhances NA release.
33. • Mirtazapine’s antidepressant
actions are related primarily to
effects at noradrenergic
receptors.
• Mirtazapine has shown promise
for alleviating depression in
treatment-resistant cases.
34. Fig. 2. Differences in the remission rate of mirtazapine and SSRIs from Montgomery et al. (2002). Data
represent a meta-analysis of three clinical studies of mirtazapine versus fluoxetine, paroxetine and citalopram.
A remission was defined as a score of 7 points or less on the HAMD-17, or 12 points or less on the MADRS. The
sample represented is an intent-to-treat sample; dropouts were handled by a last-observation carried forward
procedure.
35. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of molecular neuroimaging
• Actions of Mirtazapine & Enantiomers
• [11C]Mirtazapine PET in pig
• Requirements for human PET
• Initial [11C]Mirtazapine PET in humans
• Toward Evidence-based Neuropsychiatry
36.
37. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of molecular neuroimaging
• Actions of mirtazapine & enantiomers
• [11C]Mirtazapine PET in Pig
• Requirements for human PET
• Initial [11C]Mirtazapine PET in humans
• Toward Evidence-based Neuropsychiatry
40. Metabolite analysis carried out by HPLC for plasma samples of pig blood
after intravenous injection of [N-methyl-11C]mirtazapine.
UV detector
Radiodetector
Product + Cold
Reference - UV
Product + Cold
Reference -
Radiodetector
41. Resolution of enantiomers:
Enantiomer B
Enantiomer A
Daicel Chiralcel OD-H column 250 x 4,6 mm, n-hexane:ethanol (95:5),
0,1% diethylamine, flow 0.5 ml/min, 232 nm
Enantiomer B
Ca. 20 µg of each enantiomer resolved per injection
47. Tomograph: Siemens ECAT HR
Animal model: Pig* (35 - 45 kg)
Anaesthesia: Midazolam/ketamine HCl, followed by
isoflurane in O2/N2O
Data acquisition over 90 minutes in 2 D mode
Arterial blood samples for metabolite correction
ROI either using a neuroanatomical atlas of the pig
brain or by co-registration to a statistical MR atlas of
porcine brain.
PET Procedure
* Animal studies were performed in accordance with Danish Animal
Experimentation Act on a licence granted by the Danish Ministry of Justice
48. Time course of radioactivity derived from [N-methyl-11C]mirtazapine in selected regions of the
living porcine brain under baseline conditions.
Frontal cortex (squares), Thalamus (triangles), Basal ganglia (filled circles), Cerebellum
(triangles), Olfactory bulb (unfilled circles).
0
20
40
60
80
100
0 10 20 30 40 50 60
Radioactivity(MBq/cc)
57. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of molecular neuroimaging
• Actions of mirtazapine & enantiomers
• [11C]Mirtazapine PET in pig
• Requirements for Human PET
• Initial [11C]Mirtazapine PET in humans
• Toward Evidence-based Neuropsychiatry
58. Steps for using a
New Radiopharmaceutical for
Human Research in Denmark
1. Animal pharmacokinetic and pharmaco-
dynamic evidence
2. Animal Whole-Body Dosimetry
3. Ethical Committee Application
4. Good Clinical Practice Approval
5. Human Whole-Body Dosimetry
6. Lægemiddelstyrelsen Approval
7. Ethical Committee Approval
8. Good Clinical Practice Monitoring
9. Recruitment of volunteers
10. Screening of volunteers
11. Scheduling of MRI and PET
12. Completion of Case Report Forms
13. Data Register Rule and Regulations
14. Reporting to Lægemiddelstyrelsen
15. Reporting to Good Clinical Practice Unit
62. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of molecular neuroimaging
• Actions of mirtazapine & enantiomers
• [11C]Mirtazapine PET in pig
• Requirements for human PET
• Initial [11C]Mirtazapine PET in Humans
• Toward Evidence-based Neuropsychiatry
63.
64. 0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60
Time (min)
C-11Mirtazapine(%unmetabolised)
Figure 1. Percentage of [11C]-derived radioactivity corresponding
to unmetabolised [N-methyl-11C]mirtazapine in the bloodstream of
five humans at times after intravenous injection of the
radioligand (dose of 175 – 413 MBq, specific activity of 13 – 67
GBq/mol). An exponential function was used for curve-fitting.
65. 0
2
4
6
8
10
12
0 10 20 30 40 50 60
Time (min)
Radioactivity(kBq/cc)
Cerebellum
Amygdala
Frontal cortex
Thalamus
Striatum
Hippocampus
Figure 2. Time-course of radioactivity derived from
[N-methyl-11C]mirtazapine in selected regions of
human brain.
66. 12
9
6
3
1
Figure 3. Parametric map of
Ve’-values (Volume of
distribution) of [N-methyl-
11C]mirtazapine in the brain of
a healthy volunteer.
The brain image is shown in
Talairach coordinates (Talairach
and Tournoux, 1988). The planes
shown are transaxial (upper),
coronal (lower left) and
sagittal (lower right). The ‘ +
’ mark in each image shows the
location and orientation of the
planes of corresponding images.
The color bar presents the scale
of Ve’-values.
67. Table 1. Kinetic parameters of [N-methyl-11C]mirtazapine in
human brain regions (means ± s.d. of five subjects).
Region Hemisphere K1 k2’’ Ve’
_____________________________________________________
Cerebellum Both 0.44 ± 0.07 0.067 ± 0.016 6.7 ± 1.3
Hippocampus Right 0.40 ± 0.05 0.034 ± 0.006 11.8 ± 0.9
Left 0.41 ± 0.07 0.034 ± 0.006 11.9 ± 0.8
Frontal cortex Right 0.37 ± 0.07 0.040 ± 0.007 9.5 ± 1.0
Left 0.38 ± 0.06 0.041 ± 0.006 9.3 ± 1.1
Temporal cortex Right 0.35 ± 0.05 0.032 ± 0.007 10.9 ± 1.4
Left 0.36 ± 0.06 0.034 ± 0.007 10.8 ± 1.5
_________________________________________________
68. Properties of [11C]Mirtazapine as
PET Radiotracer
• Synthesized readily and obtained pure
• Enters brain readily
• Metabolized relatively slowly
• Good target-to-noise ratio
• Binds reversibly and competitively to certain cerebral sites
• Low binding in cerebellum (O.K. as reference region)
• Only antidepressant suitable for PET
69. The Golden Opportunity
Relating TDM to Neuroreceptor Occupancy
Therapeutic Drug Monitoring is used for determining whether
the patient takes her medicine.
There is often an inadequate therapeutic effect despite
measureable amounts of antidepressant in plasma.
Little is known concerning whether plasma levels of
antidepressants reflect drug actions at central sites.
Combining TDM and PET neuroimaging could perhaps identify
treatment-resistant patients with abnormal neuroreceptors.
70. Principles of Molecular Neuroimaging
in Depression Research.
• The Challenges
• Principles of PET
• Principles of Molecular Neuroimaging
• Actions of Mirtazapine & Enantiomers
• [11C]Mirtazapine PET in Pig
• Requirements for Human PET
• Initial [11C]Mirtazapine PET in Humans
• Toward Evidence-based Neuropsychiatry
71. The project aims to develop methods, based on
neuroimaging, that can contribute to a reliable, evidence-based
selection of the most effective type of therapy for each patient
suffering from treatment-resistant depression.
PET Neuroimaging with [11C]Mirtazapine for
Evidence-based Psychiatry
72. Experimental Null Hypotheses
• No reliable relationship between daily dose of mirtazapine
and binding potential of radioactive PET tracer.
• No reliable difference in receptor binding between (+)- og (-)-
(11C)mirtazapin in brain regions.
73. • Klinisk ansvarlig
• Prof. Raben Rosenberg, Center for Psykiatrisk Grundforskning, Psykiatrisk Hospital, 8240
Risskov, DK (raben@dadlnet.dk)
• Andre akademiske medarbejdere
• Poul Videbech, Overlæge, Psykiatrisk Hospital, 8240 Risskov, DK
• Dirk Bender, Chef Radiokemiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK
• Steen Jakobsen, Radiokemiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK
• Katalin Marthi, Kemiker, Hungarian Academy of Sciences, H-1111 Budapest, Hungary
• Søren B. Hansen, Ledende Sektionsfysiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK
• Ole L. Munk, Fysiker, Aarhus Sygehus, 8000 Aarhus C, DK
• Paul Cumming, Neurofarmakolog, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK
• Luciano Minuzzi, MD, PhD stud., PET Center, Aarhus Sygehus, 8000 Aarhus C, DK
• Pompiliu Sorin Aburel, Radiokemiker, PET Center, Aarhus Sygehus, 8000 Aarhus C, DK
• Håkan Hall, Assoc. Prof. Afd. Clinical Neuroscience, Karolinska Hospital, Stockholm, SE
Project participants:
74.
75. Study Design
• Double-blind
• Placebo-controlled
• Randomized
• 5 healthy males given each enantiomers
• Blinded curve-fitting and kinetic analysis to
estimate binding potentials
77. Organ (R)-[11C]Mirtazapine (S)-[11C]Mirtazapine
Adrenals 3.41 x 10-3 3.31 x 10-3
Brain 6.40 x 10-3 7.98 x 10-3
Breasts 2.16 x 10-3 2.14 x 10-3
Gallbladder Wall 5.61 x 10-3 1.13 x 10-2
LLI Wall 2.26 x 10-3 2.22 x 10-3
Small Intestine 2.53 x 10-3 2.46 x 10-3
Stomach Wall 2.64 x 10-3 2.56 x 10-3
ULI Wall 2.65 x 10-3 2.58 x 10-3
Heart Wall 9.96 x 10-3 9.06 x 10-3
Kidneys 2.80 x 10-3 2.69 x 10-3
Liver 1.67 x 10-2 1.52 x 10-2
Lungs 1.30 x 10-2 1.57 x 10-2
Muscle 2.20 x 10-3 2.15 x 10-3
Ovaries 2.38 x 10-3 2.33 x 10-3
Pancreas 3.30 x 10-3 3.21 x 10-3
Red Marrow 2.16 x 10-3 2.13 x 10-3
Osteogenic Cells 3.14 x 10-3 3.07 x 10-3
Skin 1.75 x 10-3 1.71 x 10-3
Spleen 2.43 x 10-3 2.38 x 10-3
Testes 1.90 x 10-3 1.85 x 10-3
Thymus 2.57 x 10-3 2.54 x 10-3
Thyroid 2.17 x 10-3 2.15 x 10-3
Urinary Bladder Wall 3.92 x 10-3 5.92 x 10-3
Uterus 2.41 x 10-3 2.41 x 10-3
Total Body 2.89 x 10-3 2.87 x 10-3
Effective Dose (mSv/MBq) 4.33 x 10-3 4.65 x 10-3
78. 0
1
2
3
4
5
6
7
0 15 30 45 60 75 90
Time (min)
SUV
Average standard uptake values (SUV) of [11C]mirtazapine enantiomers in plasma,
frontal cortex, and cerebellum studied by positron emission tomography in four healthy
males.
Cerebellum
Frontal cortex
Metabolite-corrected plasma
(R)-Mirtazapine
(R)-Mirtazapine
(S)-Mirtazapine
(S)-Mirtazapine
84. Properties of [11C]Mirtazapine as PET
Radiotracer
• Synthesized readily and obtained pure
• Enters brain readily
• Metabolized relatively slowly
• Good target-to-noise ratio
• Binds reversibly and competitively to certain cerebral sites
• Low binding in cerebellum (O.K. as reference region)
• Only antidepressant suitable for PET
85. •
From Yasuno et al., Neuroimage, 16: 577-586, 2002
Volume-of-Interest (VOI) Templates shown on axial slices
86. 0
2
4
6
8
10
12
0 10 20 30 40 50 60
Time (min)
Radioactivity(kBq/cc)
Cerebellum
Amygdala
Frontal cortex
Thalamus
Striatum
Hippocampus
Time-course of radioactivity derived from
[N-methyl-11C]mirtazapine in selected regions
of human brain.
87. Region K1 k2 Vd Binding Potential
Cerebellum 0.44 0.067 6.7
Hippocampus 0.40 0.034 11.9 1.20
Amygdala 0.32 0.028 11.6 1.09
Frontal Cortex 0.37 0.041 9.4 1.48
Thalamus 0.52 0.055 9.4 0.46
Striatum 0.48 0.050 9.6 0.77
The distribution volume (Vd) and binding potential
of rac-[N-methyl-11C]mirtazapine human brain
regions.
88.
89.
90.
91.
92. Experimental Design
• Baseline PET scans of 18 healthy, drug-free males and females
from previous study using [11C]mirtazapine to determine
receptor occupancy.
• PET scans using [11C]mirtazapine in drug-free men and women
with treatment-resistant depression.
• Brief description of recruitment procedure.
93. Table 1. Clinical characteristics of currently drug-free subjects with
treatment-resistant depression.
I.D.
Age Sex HDR BDI BAI Antidepressant
drug treatments
AMP 43 F 25 37 23 2
KJ 41 M 30 38 16 2
IK 56 F 19 21 21 9 + ECT
PA 54 F 25 26 12 4
SLM 36 F 21 33 32 3
KVS 43 M 20 23 12 6
KA 43 F 24 28 16 7
MLN 31 F 29 27 5 4
KR 34 F 29 27 18 3
JL 45 F 31 16 19 4
JM 44 M 32 37 24 5
VMH 52 M 34 30 23 9
EPS 52 F 21 21 10 3
AMGH 35 F 23 17 9 4
BEKT 41 F 28 38 14 6
HDR = 17-item Hamilton Depression Rating Scale
BDI = 21-item Beck Self-Rating Depression Inventory
BAS = 14-item Beck Self-Rating Anxiety Inventory
Antidepressant drug treatments had last at least 4 weeks.
94. Relationship between the amount of mirtazapine injected as a
bolus (µg) (natural logarithmic scale) and the binding potential
(BPND) of [11C]mirtazapine in frontal cortex of drug-free subjects
with treatment-resistant depression and in healthy controls.
95. Regional binding potential of [11C]mirtazapine in drug-
free, healthy subjects (unfilled bars) and in drug-free
subjects with treatment-resistant depression (filled bars).
97. Main finding
The relationship between BPND of [11C]mirtazapine in brain
regions differed significantly between drug-free, TRD subjects
and healthy controls (group x region interaction: p < 0.001).
Inspection of the data shows that BPND values of
[11C]mirtazapine were higher in cortical regions of healthy
subjects than of TRD subjects, whereas no marked differences
were found between the two groups for [11C]mirtazapine BPND
values in hippocampus, thalamus and putamen.
98. Main findings
• The binding potential of [11C]mirtazapine depends heavily on the
injected dose of mirtazapine at levels as low as 2 µg.
• Analysis of covariance is required to control for the strong inverse
relationship between binding potential and injected dose of
mirtazapine.
• Regional binding potentials of [11C]mirtazapine differ
between drug-free subjects with treatment-resistant depression and
healthy subjects.
• Treatment-resistant depression is a heterogeneous disorder that can be
studied by PET.
99. Treatment-resistant depression is a heterogeneous disorder
that can be studied by PET.
PET neuroimaging may eventually aid in the diagnosis of
depression and in selection of the most appropriate
antidepressant treatment.
Main conclusions
100. Here’s a View of the Future in Pharmacodynamics!
This slide shows the Treatment Evaluation Team (TET)
of Aarhus University Hospital.
The TET consists of specialists in pharmacodynamics, genetics, neuropsychiatry,
neuroimaging, bioanalysis and biopsychology. They work at the newly constructed,
high-tech Skejby Translational Neuropsychiatry Unit. They are evaluating the
digital molecular profiles of a treatment-resistant depressed person in order to
select the most appropriate, individualized, evidence-based therapy.