Small animal PET as non-invasive tool
for preclinical imaging
Marta Oteo Vives
marta.oteo@ciemat.es
Biomedical Applications of Radioisotopes
and Pharmacokinetic Unit
Small animal PET as non-invasive tool
for preclinical imaging
 Preclinical imaging
- Animal models
- Major challenge for small animal imaging
 Available imaging modalities
 Preclinical PET equipment design
 Small animal PET as a tool for quick and cheaper
translational research
 PET tracer development
 MicroPET imaging examples
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Why do we need preclinical imaging on living animals?
Non-invasive in vivo validation of the candidate drugs and probes
(observing multi-scale changes, from organ, tissue, cell, down to molecular
level induced by physiological, pathological or pharmacological effects) is
critical prior to perform human trials.
In vitro and ex vivo systems lack the interacting physiological factors
present in vivo, facilitating investigation of systemic aspects of
physiological processes and disease
What small animal models are commonly used?
Mouse is the most used, followed by rat
Mouse is the ideal model:
Prolific (fast breeding cycle)
Inexpensive to house
Reproductive and nervous system are like those of humans
Same diseases as humans
99% homology with human genome
Big advances in mouse genomics
Wide range of animal models of human disease
Rat is commonly used in Neuroscience (because of the bigger size of its brain)
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What is the major challenge for small animal imaging?
To visualize anatomical structures and monitor physiological activities
on such a small scale
High resolution imaging modalities are required
Sensitivity
Spatial resolution
Signal/Noise
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Available small animal imaging modalities
Optical imaging
PET imaging
Magnetic resonance imaging
SPECT imaging
Ultrasound imaging
CT imaging
Jürgen K.William et all (2008). Molecular imaging in drug developement. Nature Reviews
Multimodality systems provide functional and anatomical information
PET/CT, PET/MR, SPECT/CT, SPECT/MR
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Comparative spatial resolution of clinical and preclinical
imaging modalities and associated design refinements
Modality
Spatial resolution (mm)
Clinical-to-preclinical design refinement(s)
Clinical
Preclinical
MRI
~1
 0.1
Higher field-strength magnets, improved
gradient fields and coils
MRSI
~10
~2
Higher field-strength magnets, improved
gradient fields and coils
PET
~5
1-2
Reduced detector element size, smallerdiameter detector rings
SPECT
~10
0.5-2
Pinhole collimation (and resulting
magnification)
CT
1-2
 0.2
Higher X-ray flux, smaller focal spot, and
higher magnification
US
1-2
 0.1
Higher-frequency scan heads
Fabian Kiessling and Bernd J. Pichler. “Small Animal imaging” Basics and Practical Guide. ISBN: 978-3-642-12944-5
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Performance parameters and logistical features
of small-animal imaging modalities
Modality
Time
per
study,
min
No. of
animals
per
study
Spatial Intrinsic
resocontrast
lution,
mm
Probe or
contrast
agent
sensitivity
Dynamic
imaging
Radiation Equipment
dose,
cost,
cGy
$
MRI
Up to
~10
1
 0.1
M-mM
Yes
0
MRSI
Up to
~60 with
set-up
~2
Variable
M-mM
No
0
PET
5-60
1 or 2
1-2
None
Sub pM
Yes
10-100
600-800K
SPECT
30-90
1
0.5-2
None
Sub pM
No
10-100
600-800K
CT
10-15
1
 0.2
High among soft
tissues/ bone; none
among soft t.
mM
No
10-20
200-400K
US
Up to
~60 with
set-up
1
 0.1
Low; high between
cystic & solid
structures
?
Yes
0
200K
Optical: bioluminescence
~5
Up to 5
~10
None
nM
Yes
0
200-400K
Optical:
fluorescence
~5
1
<5
Variable
nM
No
0
100-200K
1
<5
None
pM
No
0
200-300K
NIR:
~10
fluorescence
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High
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~ 1M
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Clinical PET equipments
To
Preclinical PET equipments
spatial resolution and
sensitvity:
 To improve detector instrumentation and overall system design:
• novel detector geometry ( ring diameter / detector size)
• new scintillators
• reconstruction methods: iterative algorithms

Low positron range

Radiotracer specific activity
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Characteristics of preclinical PET Scanners
Inveon
Siemens
Mosaic
HP
Philips
ClearPET Argus
Raytest
Sedecal
Detector
material
LSO
LYSO
LYSO/
LuYAP
LYSO1/
Crystal
dimension, mm
1.51x
1.51x10
2x2x10
2x2x10
1.45x1.45x 1.8x 1.8x7 1.12x
71/82
1.12x13
40x40x10
Ring diameter,
mm
161
197
135225
118
50+
181
111
Axial FOV
127
119
110
48
94
94,8
40
Energy window, 350-625 385keV
665
250650
560700
150650
250750
350650
Peak detection
efficiency, %
6.72
2.83
3.03
4.32
14
7.7
2
Transaxial
FWHM
resolution
@5mm, mm
1.64
2.34
2.02
1.66
1.4
~1.6
1.55
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Genisys4
Sofie bio
sciences
NanoPet/C Albira
T Mediso
Bruker
BGO
LYSO
GSO2
LYSO
monolithic
Claudia Kuntner and David Stout. Frontiers in Physics. February 2014 | Volume 2 | Article 12
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Identification of
the target molecule
Preclinical PET imaging
Find a probe that
binds specifcally
to the target
Probes or labeled drugs
evaluation and
characterization in vivo
(pharmacodynamics and
pharmacokinetics)
Radioactive labeling
of the probe
In vitro tests (binding
affinity, stability etc.)
Translational research
In vivo experiments
- quicker translation to clinical practice
- better scientific foundation
- more rapid elimination of ineffective
compounds
- reduced number of experimental animals
Clinical PET imaging
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Main goal in radiotracer development
Specific
probes
Peptides
- fast blood clearance
- rapid tissue penetration
- Low antigenicity
mAb: Immuno-PET Labeling strategies:
high specificity
low blood clearance
high tissue penetration
immunogenic
 Direct (halogens)
 Indirect (metals)
: using chelators
Positron
Emitter
(PET)
Half life
18F
1.83h
124I
100.3h
68Ga
1.13h
64Cu
12.7h
76Br
16.2h
86Y
14.7h
89Zr
78.4h
mAb
-Diagnosis
peptide
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-Treatment
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“THERANOSTICS”
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68Ga
Applications
68Ge/68Ga
generator
GMP compliant
Eckert & Ziegler
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Immuno-PET
 Combines the high resolution and sensitivity of a PET camera with the unique
ability of a mAbs to selectively bind specific antigens.
 Application in diagnostic as well as in prognostic and therapeutic oncology
Radioisotopes more suitable for ImmunoPET:
• 124I (103 h) – For Ab that do not became internalized (not residualizing)
• 89Zr (78,4 h) – For Ab that became internalized (residualizing)
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Melanoma overexpressing MC1R (a-MSH receptor)
MC1R (melanocortin -1 receptor)
a-MSH (a-melanocyte-stimulating hormone)
B
A
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C
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PET detection of pulmonary NETs overexpressing
SSTR using SST analogs.
Lung Cancer transgenic mouse model
Developed at Molecular Oncology Unit (CIEMAT)
18F-FDG
68Ga-DOTATATE
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Detection of NETs (Meningioma) overexpressing
SSTR using SST analogs
Mouse model s.c. implanted
with CH157-MN
(Meningioma cell line)
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Detection of NETs (Pheochromocytoma)
overexpressing SSTR using SST analogs
Mouse model s.c.
implanted with PC-12
(Pheochromocytoma rat cell line)
68Ga-DOTATATE
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Immuno-PET
•
•
•
•
Nude mice
Implanted (s.c) with the glioblastoma cell line U87-MG
Two weeks later: 1-2 mg mAb/Kg (50-150 µCi)
PET performed at different times post-administration
89Zr-DFO-anti-MMP14
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Immuno-PET
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Concluding remark
PET molecular imaging allows for the non-invasive
assessment of biological and biochemical processes
in living subjects, contributing to improve our
understanding of disease and drug activity during
preclinical and clinical drug development.
Cracow PET Symposium
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Biomedical Applications of Radioisotopes
and Pharmacokinetic Unit (CIEMAT)
Cracow PET Symposium
23/09/2014
marta.oteo@ciemat.es
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