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Development, Characterisation and Application
of PET radiotracers
02 May 2018
Nisha Kuzhuppilly Ramakrishnan
Molecular Imaging Chemistry Laboratory
Wolfson Brain Imaging Centre
Department of Clinical Neurosciences
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Contents
• An introduction to PET
• Development of novel radiotracers
• Pharmacokinetic modelling of PET data
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Positron Emission Tomography (PET)
• An imaging modality where molecules tagged
with radioactivity are
• tracked within the body
• used to produce quantitative three-
dimensional images
• used to measure biological functions
• Radiotracer / PET probe: A molecule labelled
with a positron emitting nuclide (e.g., 18F, 11C, 15O, 64Cu, 68Ga)
Su et al., The British Journal of Psychiatry, 2016
• Radiotracers are biomarkers
• that interact specifically with receptors, enzymes, transporters, misfolded
proteins etc.
• to image physiological, biochemical and pharmacological functions at a
molecular level in vivo.
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Positron Emission Tomography (PET)
http://jens-maus.de/ftp/langner_mscthesis.pdf
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Radiotracer development
• Target identification (TSPO, MAO-B, RAGE etc for neuroinflammation)
• Lead identification: literature, modification of drugs for the target, computational
modelling based on the structure of the target
• High affinity for target; e.g., for clear image visualization
• High selectivity for target; e.g., to reduce visualizing off-target processes
• Low non-specific binding; e.g., to decrease background
• Appropriate lipophilicity; e.g., to cross blood-brain-barrier
• Known metabolism; e.g., glucose
• Chemical synthesis of precursors and standards
• Radiosynthesis
• Reproducible radiolabelling methods; e.g., robust and fast
• High specific (molar) activity
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Radiosynthesis
6
Radiopharmacology
Small Animal PETHotcells
Modules
Cyclotron
Radionuclides
Organic
chemistry laboratory
Novel small molecules
EvaluationRadiosynthesis
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Radiotracer evaluation
• Preclinical evaluation
• In vitro: in cells, human or animal tissues
• Ex vivo: e.g. biodistribution studies
• In vivo: scanning in healthy animals and animal models of disease
• Entry and distribution in tissue of interest
• Kinetics in the region of interest (ROI) and in blood
• Formation of metabolites, especially radiometabolites
• Quantification of specific binding to the target using pharmacokinetic modelling
• Regulatory approval
• Translation to the clinic
• Clinical use
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A pre-clinical study
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Development of PET probes: A lengthy process
10
PRECLINICAL
WORK
Radioligand
development
Small animal
PET
CLINICAL
WORK
First in man
PET studies
CLINICAL
APPLICATIONS
Routine
diagnosis and
monitoring
therapy
Translation from
laboratory animals
to humans
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Mathematics in PET
• Pharmacokinetics
• Pharmakon "drug" ; Kinetikos “movement”
• What the body does to the drug/tracer
• ADME:
• Absorption, Distribution, Metabolism,
Excretion
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PET Data for kinetic modelling
• Time Activity Curve (TAC) from Regions of Interest (ROIs)
• From dynamically reconstructed PET scan image
• Input function
• Arterial input TAC
• Requires Arterial canulation
• Corrections
• Radioactive metabolites
• Plasma protein binding
• Image derived input: Reference region TAC
• Region devoid of specific binding
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• Mathematical model is used to
describe observed data
• Model driven
• Compartmental models
• Data driven
• Graphical analysis
Modelling
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Assumptions
• Tracer assumption: The PET measurement does not influence the physiology/
molecular interactions
• Low mass of the tracer
• Steady state: The measurement is performed when the physiology/ molecular
interactions is in a steady state
• Blood sugar during FDG scan
• Drug concentration during receptor occupancy study
• Instantaneous mixing: Each compartment is homogeneous with respect to
tracer concentration
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Compartment models
• Kinetic compartments are not necessarily identical to
physical spaces
K1
CFk2
Brain
freePlasma
CP
k3
k4 CS
Brain
bound
Brain
Non-specific
k5 k6
CNS
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Compartment models
Single tissue compartment model (1-TCM)
◦ Cerebral blood flow
K1
CTk2
BrainPlasma
CP
CT = CF + CNS + CS
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What information do we get?
• Single tissue compartment model
• Volume of distribution VT
• Ratio of concentrations in tissue (CT) and plasma (CP)
K1
CTk2
BrainPlasma
CP
VT = K1/ k2
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Compartment models
• Two-tissue compartment model
• Reversible
• Irreversible
K1
CFk2
Brain
freePlasma
CP
k3
k4CS
Brain
boundK1
CFk2
Brain
freePlasma
CP
k3
k4CS
Brain
bound
K1
k2
ND =
F +
NS
Plasmak3
k4S
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What information do we get? : Receptor binding
K1
CFk2
Brain
freePlasma
CP
k3
k4CS
Brain
bound
• total Distribution Volume, VT = (K1/k2) * (1+k3/k4)
• Non-displaceable Distribution Volume, VND = K1/k2
• Non-displaceable Binding Potential, BPND = k3/k4
• Proportional to Bmax/Kd
• VT = VND (1+ BPND)
• Individual k values may be too variable
Receptor numbers & function
Flow & permeability
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Simplification: Linearisation
• Patlak plot: Irreversible
• Logan plot: Reversible
http://www.bic.mni.mcgill.ca/~rgunn/PK_Course_2003/PKM_Manual_Web.pdf
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Simplification: Reference tissue models
• Simplified Reference Tissue Model
• No displaceable component in the reference
region
• One tissue compartment kinetics in the target
and reference region
• Blood volume contribution to the tissues is
negligible
• Same VND in target and reference region
• Outcome measure BPND
Lammertsma and Hume, Neuroimage. 1996
Salinas et al., J Cereb Blood Flow Metab. 2015
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SRTM in a NIMROD study
• [18F]AV-1451 to image misfolded protein Tau in AD, PSP, and healthy controls
Passamonti et al., BRAIN, 2017
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Further information on PET kinetic modelling
• PET Pharmacokinetics course manuals: 2003 and 2007 versions
available online
• http://www.nrm2018.org/nrm-conference/pet-pharmacokinetics-course/
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Current challenges
• Lead selection: Computational models
• Making PET truly non-invasive: avoiding blood sampling in the absence
of reference regions
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Thank you!
WBIC - MICL WBIC - RPU
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NIMROD Neuroimaging of Inflammation in Memory and Other Disorders
Bevan-Jones et al., BMJ Open. 2017