the role of neuroimaging in clinical trials and drug discovery in psychiatry joseph c. masdeu, md,...
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The Role of Neuroimaging in Clinical Trials and Drug Discovery In Psychiatry
Joseph C. Masdeu, MD, PhDSection on Integrative NeuroimagingNational 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 co-
agonist 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
[11C]GSK931145 distribution in a healthy volunteer
Pig Primate Human
[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 CandidateDetermined 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 and Kinetics
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
Usual Radioisotopes:
PET: [11C], [18F]
SPECT: [123I], [99mTc]Ideally, a new lead drugcandidate should be isotopically radiolabeled with a PET or SPECT radioisotope
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 123I-ADAM SPECT
Decrease in midbrain uptake (71% serotonin transporter
occupancy)
After 6-week paroxetine 20 mg/day
Baseline
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
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 could develop into a pre-
biomarker for antidepressant effects
Harmer CJ et al. Biol Psychiatry 2006;59:816
Fearful
Happy
Left
Left Right
Right
Role of MRI in Drug DistributionProton (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)
19F-MRS has been used to determine concentrations of fluorinated antipsychotics fluphenazine and trifluoperazine (Durst et al, 1990) And antidepressants such as fluoxetine (Karson et al, 1993) Also contain a fluorine atom
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
Anterior Cingulate Gyrus
MR spectrum
Yoon SJ et al. Neuropsychopharmacology 2009 [Epub ahead of print]
Cytidine Effect Linked to Glutamate
Studied with MR spectroscopy
Sco
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am
ilton D
epre
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ati
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core
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
Useful to fortify Proof of Concept for D2 DA
antagonists establish a dose range to test for new, pure
D2 antagonists
Dopamine D2 receptor occupancy
efficacy to treat delusions, hallucinations
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 [11C]FLB 457 PET
Takahashi H et al. Biol Psychiatry 2006;59:919
D2 binding in a healthy control
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
Reduced D2 Receptor Binding: Greater Receptor Occupancy by Endogenous DA
Striatal dopamine (DA) production is increased in schizophrenia Measured with
[18F]fluoro-DOPA PET dopamine causes
down-regulation of the D2 receptors
stimulation of the D2 receptors Hallucinations Treated by D2
antagonists
Meyer-Lindenberg A et al. Nat Neurosci 2002;5:267
18FD
OPA
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Controls Patients
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
Yet, clinically used doses are 50–150 mg per day Therapeutic plasma concentrations range 175–450 ng/ml*
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
r
After 160mg for 40 days
Aprepitant Rx
Baseline
Summary ConclusionsNeuroimaging 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
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
Example: Hyperdopaminergic state associated with the positive symptoms of schizophrenia
Serotonin Trasporter Occupancy After Rx with Paroxetine
Relationship between Paroxetine plasma
concentrations Serotonin
transporter occupancy (%SERTocc) Measured by
means of 123I-ADAM 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 second-generation, '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;163:425Keefe RD et al. Arch Gen Psychiatry 2007;64:633
Target Identification and Therapeutic Rationale
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. **
Example: Hypodopaminergic state associated with the abuse of cocaine, alcohol, ecstasy…
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