Small animal PET as non-invasive tool for preclinical imaging Marta Oteo Vives [email protected] Biomedical Applications of Radioisotopes and Pharmacokinetic

Small animal PET as non-invasive tool for preclinical

imaging

Marta Oteo [email protected]

Biomedical Applications of Radioisotopesand Pharmacokinetic Unit

Small animal PET as non-invasive tool for preclinical

imagingPreclinical 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

Cracow PET Symposium 23/09/2014 2(C) Marta Oteo, CIEMAT, Madrid

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 humansSame diseases as humans99% homology with human genomeBig advances in mouse genomicsWide range of animal models of human disease

Rat is commonly used in Neuroscience (because of the bigger size of its brain)


Spatial resolution Sensitivity

Signal/Noise

What is the major challenge for small animal imaging?

To visualize anatomical structures and monitor physiological activitieson such a small scale

High resolution imaging modalities are required


Available small animal imaging modalities

Multimodality systems provide functional and anatomical information

PET/CT, PET/MR, SPECT/CT, SPECT/MR

Jürgen K.William et all (2008). Molecular imaging in drug developement. Nature Reviews

CT imaging

SPECT imaging

PET imaging

Ultrasound imaging

Magnetic resonance imaging

Optical imaging


Cracow PET Symposium 23/09/2014 (C) Marta Oteo, CIEMAT, Madrid 6

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, smaller-diameter 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-f requency scan heads

Comparative spatial resolution of clinical and preclinical imaging modalities and associated design

refinements

Fabian Kiessling and Bernd J. Pichler. “Small Animal imaging” Basics and Practical Guide. ISBN: 978-3-642-12944-5

Performance parameters and logistical features of small-animal imaging modalities

Modality Time per study, min

No. of animals per study

Spatial reso-lution, mm

I ntrinsic contrast

Probe or contrast agent sensitivity

Dynamic imaging

Radiation dose, cGy

Equipment cost, $

MRI

MRSI

Up to ~60 with set-up

Up to ~10 1

0.1 ~2

High Variable

M-mM M-mM

Yes No

0 0

~ 1M

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 sof t tissues/ bone; none among sof t 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: bio-luminescence

~5 Up to 5 ~10 None nM Yes 0 200-400K

Optical: fluorescence

~5 1 < 5 Variable nM No 0 100-200K

NI R: fluorescence

~10 1 < 5 None pM No 0 200-300K


Clinical PET equipments Preclinical PET equipments

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

To spatial resolution and sensitvity:


Characteristics of preclinical PET Scanners

I nveon Siemens

Mosaic HP Philips

ClearPET Raytest

Argus Sedecal

Genisys4 Sofie bio sciences

NanoPet/ CT Mediso

Albira Bruker

Detector material

LSO LYSO LYSO/ LuYAP

LYSO1/

GSO2

BGO LYSO LYSO monolithic

Crystal dimension, mm

1.51x 1.51x10

2x2x10 2x2x10 1.45x1.45x71/ 82

1.8x 1.8x7 1.12x 1.12x13

40x40x10

Ring diameter, mm

161 197 135- 225

118 50+ 181 111

Axial FOV 127 119 110 48 94 94,8 40

Energy window, keV

350-625 385- 665

250- 650

560- 700

150- 650

250- 750

350- 650

Peak detection effi ciency, %

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


Claudia Kuntner and David Stout. Frontiers in Physics. February 2014 | Volume 2 | Article 12

Preclinical PET imaging

Clinical PET imaging

Translational research

Probes or labeled drugs evaluation and

characterization in vivo(pharmacodynamics

and pharmacokinetics)

- quicker translation to clinical practice- better scientific foundation- more rapid elimination of ineffective

compounds- reduced number of experimental

animals

Identification of the target molecule

Find a probe that binds specifcally

to the target

Radioactive labeling of the probe

In vitro tests (binding affinity, stability etc.)

In vivo experiments


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

Labeling strategies:Direct (halogens)Indirect (metals) : using chelators

Main goal in radiotracer development

Specific probes

Peptides

mAb: Immuno-PET

- fast blood clearance- rapid tissue penetration- Low antigenicity

- high specificity - low blood clearance- high tissue penetration- immunogenic

-Diagnosis

-Treatment “THERANOSTICS”

mAb

peptide


Cracow PET Symposium 23/09/2014 (C) Marta Oteo, CIEMAT, Madrid 12

68Ga Applications

68Ge/68Ga generator GMP compliant

Eckert & Ziegler

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)

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

Immuno-PET


Melanoma overexpressing MC1R (-MSH receptor)

A CB


MC1R (melanocortin -1 receptor)-MSH (-melanocyte-stimulating hormone)

PET detection of pulmonary NETs overexpressing SSTR using SST analogs.

Lung Cancer transgenic mouse modelDeveloped at Molecular Oncology Unit (CIEMAT)

18F-FDG

68Ga-DOTATATE


Detection of NETs (Meningioma) overexpressing SSTR using SST analogs

Mouse model s.c. implanted with CH157-MN (Meningioma cell line)


Detection of NETs (Pheochromocytoma) overexpressing SSTR using SST analogs

Mouse model s.c. implanted with PC-12 (Pheochromocytoma rat cell line)

68Ga-DOTATATE


Immuno-PET

89Zr-DFO-anti-MMP14

• 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


Immuno-PET


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.


[email protected] PET Symposium 23/09/2014 21(C) Marta Oteo, CIEMAT, Madrid

Biomedical Applications of Radioisotopesand Pharmacokinetic Unit (CIEMAT)

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Small animal PET as non-invasive tool for preclinical imaging Marta Oteo Vives [email protected] Biomedical Applications of Radioisotopes and Pharmacokinetic