Transcript The Role of Neuroimaging in Clinical Trials and Drug

The Role of Neuroimaging
in Clinical Trials and Drug
Discovery In Psychiatry
Joseph C. Masdeu, MD, PhD
Section on Integrative Neuroimaging
National Institutes of Health
Neuroimaging in Drug Discovery
and Development
 Preclinical models
 Early clinical experiments to demonstrate
'proof of biology'
 Linking target engagement (TE) to
 drug-induced biological changes expected to
give clinical benefit
 Clinical trials to demonstrate proof of
concept (PoC),
 Engaging a particular target is linked to
 a meaningful change in a clinical end point
 thus demonstrating a new avenue to treat a
condition in patients
The Glycine Transporter 1 and
Schizophrenia
 In schizophrenia NMDA function
is impaired

Lisman JE et al. Trends
Neurosci. 2008;31:234
 GlyT-1 regulates glycine levels
at NMDA sites
 Glycine is an essential coagonist of NMDA receptors
 GlyT-1 inhibitors enhance NMDA
function (preclinical studies)
 Selective GlyT-1 inhibitors are
being studied as drug candidates
for schizophrenia
Catafau A et al.
Neuroreceptor Meeting.
Pittsburgh 2008
[11C]GSK931145: A New PET Ligand
for Glycine Transporter 1
 Transporter
characteristics
 Autoradiography
 Physiology
 Pharmacology
[11C]GSK931145: A New PET Ligand
for Glycine Transporter 1
Pig
Primate
Human
[11C]GSK931145 distribution in a healthy volunteer
[11C]GSK931145: A New PET Ligand
for Glycine Transporter 1
 This new GlyT-1 PET ligand is
being applied to:
 Understand the role of GlyT-1 in
Neuropsychiatric disorders
 Drug development


 pharmacokinetics (PK)
 receptor occupancy (RO)
 pharmacodynamics (PD)
 dose estimations
New Drug Characteristics
Properties of Drug Candidate
Determined by Neuroimaging
 Whether it crosses the blood–brain barrier
 And, thus, it is delivered to the target
compartment (ie the brain)
 Whether it engages the appropriate target
 Receptor
 Transporter
 Enzyme
 in a dose/exposure-related manner
Uses of PET in Drug Development
 Two main approaches
 Radiolabel the new drug
 Estimate target occupancy
 By the new drug
Drug Candidate Biodistribution
Usual Radioisotopes:
and Kinetics
PET: [11C], [18F]
SPECT: [123I], [99mTc]
Ideally, a new lead drug
candidate should be isotopically radiolabeled
with a PET or SPECT radioisotope
 To determine brain distribution of the
compound
 Some of its washout characteristics
 Whether it is a substrate for BBB pumps
 More likely to induce multidrug resistance
 Also helpful in animal studies
Limitations to Radiolabeling
Candidate Drugs

Primary quantitative radiotracers label only a very small
number of potential drugs

Brain exposure for compounds that cross the BBB slowly
may be underestimated

Given the short acquisition times possible with these isotopes




90 min 11C
8 h for 18F
Higher brain concentrations after chronic dosing
True target engagement may be overestimated

Total regional brain activity is recorded, not distinguishing
between




binding to the test drug
brain-penetrated radiolabeled metabolites of the test drug
free tracer
tracer nonspecific binding
Instead of Radiolabeling Candidate
Drug: Label Drug Target
 Use existing PET/SPECT tracers
 E.g., to the serotonin transporter
 to determine the target occupancy of
the new drug
 in displacement studies
 More active drug
 Less labeled target available
Serotonin Trasporter Occupancy
After Rx with Paroxetine
 Studied with 123IADAM SPECT
Decrease in midbrain uptake
(71% serotonin transporter
occupancy)
Baseline
After 6-week
paroxetine
20 mg/day
Catafau AM et al. Psychopharmacology 2006;189:145
PET versus SPECT for the Study of
D2 Receptor Occupancy
 Comparing:


[123I]IBZM SPECT
[11C]Raclopride PET
 In the same subjects
 Occupancy values
measured by SPECT
were lower than those
measured with PET


12.4% (occipital cortex
as reference region)
13.8% (cerebellum as
reference region)
 But the correlation
between D2 occupancy
using either method
approximates 1.0
Catafau A et al. Neuroimage 2009, Epub ahead of print
PET: Better Anatomical Definition than
SPECT (D2 Receptor Occupancy Study)
Functional MRI (fMRI)
Arterial spin labeling (ASL)
 To study
 brain systems responses to external
stimuli
 the modification of these responses by
drug treatment
 In normal healthy volunteers
 In patients
 Complement neuroreceptor imaging
by revealing the neurocircuitry
involved in behavior and responses
Fearful
Left
Right
fMRI as Pre-Biomarker
 The SSRI
antidepressant
citalopram
 reduced amygdala
activation in response to
fearful faces in normal
volunteers
 The amygdala response
to fearful stimuli
Happy
Left
Right
 could develop into a prebiomarker for
antidepressant effects
Harmer CJ et al. Biol Psychiatry 2006;59:816
Role of MRI in Drug Distribution
Proton (1H) Spectroscopy (MRS)

Assessment of glutamate and GABA amino acids

Psychotropic drugs with GABAergic or glutamatergic mechanisms
of action



eg acamprosate, for the Rx of alcohol dependence
7Li-MRS
has been used to measure lithium concentrations in
patients' brains

and to relate it to plasma concentrations (Plenge et al, 1994)



fluphenazine and trifluoperazine (Durst et al, 1990)
And antidepressants such as fluoxetine (Karson et al, 1993)
Also contain a fluorine atom
19F-MRS
has been used to determine concentrations of
fluorinated antipsychotics



perphenazine, risperidone, most of the butyrophenone
antipsychotics,
the SSRIs fluvoxamine and paroxetine
several benzodiazepines and the benzodiazepine antagonist
flumazenil
Effect of Cytidine on Bipolar Depression
and on Brain Glutamate Levels
Region Studied
MR spectrum
Anterior Cingulate
Gyrus
Yoon SJ et al. Neuropsychopharmacology 2009 [Epub ahead of print]
Scores on the Hamilton Depression Rating Score
Cytidine Effect Linked to  Glutamate
Studied with
MR spectroscopy
Yoon SJ et al. Neuropsychopharmacology 2009 [Epub ahead of print]
Biomarker
 Characteristic that is
 objectively measured and evaluated
 as an indicator of
 normal biologic processes,
 pathogenic processes, or
 pharmacological responses to a therapeutic
intervention
Frank R, Hargreaves R. Nat Rev Drug Discov 2003;2: 566
Types of Biomarkers
 Type 0
 Tracks the natural course of the disease
 Type 1
 Examines the effects of intervention along with
the known mechanism of action of the drug
 But without strict relationship to clinical outcome
 Type 2
 Change in the biomarker is predictive of clinical
outcome
 At present, most imaging methods in
psychiatry do not meet the biomarker status
‘Emerging’ Biomarker or
‘Pre-biomarker’
 With dopamine D2 receptor PET imaging
 A link was found between
Dopamine D2 receptor occupancy
efficacy to treat delusions, hallucinations
 Useful to
 fortify Proof of Concept for D2 DA
antagonists
 establish a dose range to test for new, pure
D2 antagonists
Dopamine D2 Receptor Binding
 Measured with
 [11C]raclopride
 Most widely used
 [11C]FLB 457
 Better for cortical D2
 But still a [11C]
compound
 [18F]fallypride
 Better for cortex, [18F]
 But scanning time
about 4 hours
D2 binding in a
healthy control
[11C]FLB 457
PET
Takahashi H et al. Biol Psychiatry 2006;59:919
Dopamine D2 Receptor Binding in
Schizophrenia
 Decreased D2
receptor binding
in untreated
schizophrenia
 Thalamus
 Dorsomedial
nucleus
 Striatum
 Anterior cingulate
 Amygdala
 Temporal cortex
Patients < Controls
Buchsbaum MS et al. Schizophr
Res 2006;85:232
ACNP 2008, Phoenix Az
 Measured with
 [18F]fluoro-DOPA PET
  dopamine causes
 down-regulation of the
D2 receptors
  stimulation of the D2
receptors
 Hallucinations
 Treated by D2
antagonists
18FDOPA
 Striatal dopamine (DA)
production is increased
in schizophrenia
striatal Ki values
Reduced D2 Receptor Binding: Greater
Receptor Occupancy by Endogenous DA
Controls
Patients
Meyer-Lindenberg A et al. Nat Neurosci 2002;5:267
DA D2 Receptor Antagonists in
Schizophrenia
 Drug: Haloperidol
 D2 binding studied
with
[11C]raclopride
 Effective: <80%
occupancy
 >80% occupancy:
parkinsonism or
akathisia
Kapur S et al. Am J Psychiatry 2000;157: 514
PET* to Assess Drug Behavior
 Straightforward to assess:
 Neutral orthosteric site antagonists
 Haloperidol
 Considerable challenges in the assessment of target
engagement (TE) and linking TE to efficacy for:
 Agonists
 Partial agonists
 Aripiprazole
 Inverse agonists
 Allosteric modulators
 Many new therapeutic approaches to psychiatric
disorders use positive allosteric modulators
 As a means to fine-tune the primary excitatory
(Glu) and inhibitory (GABA) systems
*In combination with structural MRI
Partial Agonists: Occupancy Studies
of the Antipsychotic Aripiprazole
 Conventional wisdom:
 within a 'therapeutic window' of 65–80% striatal D2
receptor occupancy
 D2 DA antagonists have antipsychotic efficacy
 with minimal EPS side effects
 But for aripiprazole, occupancies closer to 90 or 95%
were needed for the therapeutic range of the drug
 Because the likely mechanism of action of aripiprazole
is partial agonist at D2 receptors
 The original 'therapeutic window' of 65–80% receptor
occupancy is valid for D2 DA antagonists only
Antidepressants and dosing
 SSRIs have been shown to occupy
80% or more of the serotonin
transporter (SERT)
 at clinically used doses
 Within this class of drugs, this seems to
be independent of the specific SSRI
Meyer JH, et al. Am J Psychiatry 2001;158:1843
Antidepressant Dosing and PET:
The Clomipramine Paradox

The tricyclic antidepressant (TCA) clomipramine


occupies 80% of the SERT


at doses as low as 10 mg
at a plasma concentration of 1.42 ng/ml

Therapeutic plasma concentrations range 175–450 ng/ml*
Yet, clinically used doses are 50–150 mg per day

Is blockade of the SERT and the norepinephrine transporter (NET)
the therapeutic principle of clomipramine (and of the TCAs in
general)?

Or do TCAs behave completely different from SSRIs, due to their
broad pharmacological actions at many different molecular targets?

How valid are the studies upon which therapeutic doses and plasma
concentrations have been determined for clinical use of the TCAs
over decades?
*Baumann P et al. Pharmacopsychiatry 2004;37:243
Dosing and PET
 A radiotracer/pre-biomarker that has
been demonstrated to predict the
biological effects of a certain class of
compounds
 might lose its validity for a drug
 with a slight modification of its mechanism
of action
 even if it binds to the same target molecule
Imaging and Dose Finding for
Clinical Trials: Rejecting New Drugs
 If a dose that demonstrated adequate
target engagement in humans
 With a high degree of confidence
 does not have efficacy in the clinical
trial
 Proof of concept can be rejected, and
a drug target can be abandoned more
quickly
Rejecting a Disease Mechanism:
Role of PET
 Aprepitant blocked
the neurokinin 1
receptor

Visualized with
[18F]SPA-RQ PET
 But did not improve
depression

No better than
placebo on the
Hamilton
Depression Scale
Aprepitant
Rx
Baseline
After 160mg
for 40 days
r
Summary Conclusions
Neuroimaging in Drug Development*
 Justification/rationale for a specific neurotransmitter
receptor system as a target for therapeutic intervention
 E.g., dopamine, serotonin, etc
 Radiolabeling the potential therapeutic compound of
interest to examine biodistribution and BBB penetration
 Rational therapeutic dosing
 to test efficacy efficiently in the target patient population
 Mechanism of pharmacological action
 how does the efficacious action might occur
 during therapeutic doses
 in the target patient populations
*Especially as pertains to neurotransmitter and neuroreceptor imaging
Thank you!
Thank you!
Imaging to Determine Level of
Target Engagement (TE)
 With isotopically labeled drug candidates to
estimate total brain exposure
 generally using either C-11 or F-18 tracers
 Functional studies such as measurement of
test drug effects on regional cerebral blood
flow
 (PET/SPECT or MRI)
 A direct measure of TE employing a PET
radioligand that can be used for measuring
occupancy
 E.g., DA D2/D3 receptor occupancy studies with
[11C]raclopride.
Imaging to Determine Level of
Target Engagement (TE)
 It is challenging to determine what
level of TE is needed for a novel
mechanism for a class of compounds
 It is typically guided by efficacy
studies in appropriate preclinical
models
Target Identification and
Therapeutic Rationale
Example: Hyperdopaminergic state associated
with the positive symptoms of schizophrenia
 Studies of presynaptic DA neuron function
measuring dopa decarboxylase with
[18F]fluorodopa
 Studies demonstrating elevations in
amphetamine-induced intrasynaptic DA release
 DA occupancy of D2/3 receptors by endogenous DA
 Studies showing elevation of D2 receptor
density or binding potential
Serotonin Trasporter Occupancy
After Rx with Paroxetine
 Relationship
between
 Paroxetine plasma
concentrations
 Serotonin
transporter
occupancy
(%SERTocc)
 Measured by
means of 123IADAM SPECT
Paroxetine plasma levels (ng/mL)
Catafau AM et al. Psychopharmacology 2006;189:145
Dopamine antagonists
(antipsychotics)

It has been known for more than 30 years that these compounds
exert their effects on the positive symptoms of schizophrenia by
antagonizing DA D2 receptors (Seeman et al, 1976). It was later
discovered with PET that clinically effective doses of typical
neuroleptics occupy D2-like DA receptors in the human striatum in
the range between 65 and 90% (Farde et al, 1992). The
suggestion of a 'therapeutic window' between 60 and 80% striatal
D2 RO for sufficient treatment response and a 'ceiling' of around
80% occupancy, above which extrapyramidal side effects (EPS) are
likely, was later confirmed by several other researchers (eg Kapur
et al, 2000). Although clozapine and quetiapine seem to be
exceptions, this rule also applies for most of the secondgeneration, 'atypical' antipsychotics (Nyberg et al, 1999). When
their doses are raised above a certain threshold, striatal (and
potentially extrastriatal) D2 DA occupancy increases to levels that
are associated with a higher incidence of EPS. As described above
the relationship between doses of antipsychotic drugs and their
(striatal) D2-like DA RO has almost approached the status of a
biomarker,
Dopamine antagonists
(antipsychotics)
 But long-term functional outcome in
schizophrenia is determined by
 improvement in cognitive function
 rather than control of positive symptoms (Bowie
et al, 2006)
 And the available antipsychotics have
limited activity against cognitive symptoms
(Keefe et al, 2007)
 Thus, D2/D3 receptor occupancy is an
incomplete marker of disease control or
progression
Bowie CR et al. Am J Psychiatry 2006;163:425
Keefe RD et al. Arch Gen Psychiatry 2007;64:633
Target Identification and
Therapeutic Rationale
Example: Hypodopaminergic state associated
with the abuse of cocaine, alcohol, ecstasy…
 Furthermore, other evidences from
studies in, as well as methamphetamine
and ecstasy users, have demonstrated
reductions of DA and some serotonin
chemical markers supporting a concept
of reduced DA function. **
Single vs Multiple Dosing of the
Candidate Drug
 In many cases single-dose studies very
accurately predict receptor occupancies
achieved with multiple dosing
 But this might not be the situation for
certain drugs
 E.g., ziprasidone
 Single-dose occupancy studies should be
supplemented by subchronic studies
 to avoid an incorrect dose selection for large
efficacy trials
Single vs Multiple Dosing of
Ziprasidone
 For occupancy studies, ziprasidone was given to
healthy volunteers in single oral doses of 40-60 mg
 Causing a striatal D2 occupancy of 67%-85%
 It was concluded from these studies that effective
antipsychotic ziprasidone doses should be around
40 mg
 But phase II clinical efficacy studies demonstrated
40 mg to be not better than placebo
 Ziprasidone has potent antipsychotic efficacy at
120–160 mg
 PET studies in patients after subchronic treatment
demonstrated that the striatal D2 occupancy was
markedly lower than was predicted by the early
single-dose studies
Single vs Multiple Dosing of
Ziprasidone
Vernaleken I et al. J Clin Psychopharmacol 2008;28:608
Striatal vs Extrastriatal brain
Occupancy
 The selection of the correct brain region for
determination of receptor occupancy
 Is an increasingly crucial issue
 Conventional belief of a 'therapeutic window' in the
range of 60–80% striatal D2 occupancy
 is true for most antipsychotics
 But, low-affinity D2 antagonists
 such as clozapine or quetiapine
 occupy striatal D2 receptors (<50%)
 to a lesser extent than cortical D2 receptors (>50%)
(Gründer et al, 2006; Kessler et al, 2006).
 A likely basis for their beneficial extrapyramidal side
effect profile
Mechanism of Action of Candidate
Therapeutic Drugs
 PET imaging can provide actual empirical
evidence for a drug candidate's effect or
potential effect
 E.g., potential use of DA transporter (DAT)
inhibitors in the treatment of stimulant
abuse
 In nonhuman primates, the preadministration of
the DAT inhibitor, GBR12909, blocked the
amphetamine-induced DA release substantially
 Before the amphetamine challenge, there was
an increase of basal intrasynaptic DA, which
could be useful in reducing, for example, cocaine
craving