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microPET Experiences with Small Animal PET Imaging Simon R. Cherry, Ph.D. Crump Institute for Biological Imaging Dept. of Molecular and Medical Pharmacology UCLA School of Medicine, Los Angeles, California Supported by NCI grants CA 69370 CA 74036 and DOE contract FC03-87-ER60615

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micropet experiences with small animal pet imaging

microPETExperiences with Small Animal PET Imaging

Simon R. Cherry, Ph.D.

Crump Institute for Biological Imaging

Dept. of Molecular and Medical Pharmacology

UCLA School of Medicine, Los Angeles, California

Supported by NCI grants

CA 69370

CA 74036

and DOE contract

FC03-87-ER60615

outline
Outline
  • PET Basics
  • motivation for small animal PET
  • design & performance of a small animal PET scanner
  • applications for small animal PET
positron emission tomography

e+

e+

e+

e+

coincidence ?

e–

e+

Positron Emission Tomography

positron scatters in

tissue losing energy

nucleus

511 keV

yes

511 keV

annihilation

positron emitting radionuclides
Positron-Emitting Radionuclides

Isotope Halflife + fraction Max. Energy range(mm) production

C–11 20.4 mins 0.99 0.96 MeV 0.4 mm cyclotron

N–13 9.96 mins 1.00 1.20 MeV 0.7 mm cyclotron

O–15 123 secs 1.00 1.74 MeV 1.1 mm cyclotron

F–18 110 mins 0.97 0.63 MeV 0.3 mm cyclotron

Cu–62 9.74 mins 0.98 2.93 MeV 2.7 mm generator

Cu-64 12.7 hours 0.19 0.65 MeV 0.3 mm cyclotron

Ga–68 68.3 mins 0.88 1.83 MeV 1.2 mm generator

Br-76 16.1 hours 1.00 1.90 MeV 1.2 mm cyclotron

Rb–82 78 secs 0.96 3.15 MeV 2.8 mm generator

I–124 4.18 days 0.22 1.50 MeV 0.9 mm cyclotron

pet labeled probes for biological imaging
PET-labeled Probes for Biological Imaging

hemodynamic parameters (H215O, 15O-butanol, 11CO, 13NH3.....)

substrate metabolism(18F-FDG, 15O2, 11C-palmitic acid....)

protein synthesis (11C-leucine, 11C-methionine, 11C-tyrosine)

enzyme activity (11C-deprenyl, 18F-deoxyuracil...)

drugs (11C-cocaine, 13N-cisplatin, 18F-fluorouracil...)

receptor affinity (11C-raclopride, 11C-carfentanil, 11C-scopalamine)

neurotransmitter biochemistry (18F-fluorodopa, 11C-ephedrine...)

gene expression (18F-penciclovir, 18F-antisense oligonucleotides...)

.....................................

cyclotron

11C, 13N, 15O, 18F

PET can detect and image sub nanomolar levels

of these tracers in vivo

human whole body pet scanners
Human Whole-Body PET Scanners

18FDG - transaxial sections through brain

Siemens ECAT EXACT HR+

20,000 scintillator detectors

ring diameter ~ 80 cm

4 mm (64 µL) spatial resolution

(typically 6-12 mm in clinical practice)

time course of 18 f fdopa in the brain

0.0 mins

0.75 mins

1.25 mins

1.75 mins

2.25 mins

2.75 mins

4.5 mins

7.5 mins

10.5 mins

13.5 mins

20 mins

30 mins

40 mins

50 mins

60 mins

75 mins

95 mins

115 mins

Time Course of 18F-FDOPA in the Brain
tracer kinetic modeling

striatum

cerebellum

Tracer Kinetic Modeling

• Simplified model for FDOPA kinetics in striatum

• Rate constants K1, k2, k3 & k4 can be estimated using measured PET time activity curves and blood input function.

K1

k4

k3

FDA and its

metabolites

tissue

FDOPA

plasma

FDOPA

clearance of 18F

label to plasma

k2

FDOPA = [18F]fluoroDOPA

why small animal imaging
Why Small Animal Imaging?
  • in vivo  in vitro
  • non-destructive - repeat studies in the same animal
  • can efficiently survey whole animal
  • rapid in vivo screening?
  • provides bridge from animal studies to human studies
  • better decisions sooner!
in vivo small animal imaging
In Vivo Small Animal Imaging

Anatomic Physiologic Metabolic Molecular

optical imaging

x-ray CT

PET/SPECT

MRI

MR Spectroscopy

fMRI

ultrasound

which imaging technique
Which Imaging Technique?
  • what do you want to measure?
  • spatial resolution (µm or mm?)
  • temporal resolution (ms or mins?)
  • sensitivity (mM or nM?)
  • field of view (striatum or whole animal?)
  • what’s available
micropet
microPET
  • 30 detector modules
  • 1920 detector elements
  • ring diameter: 172 mm
  • axial field of view: 18 mm
  • spatial resolution: 1.8 mm (6 µL)
  • sensitivity: 200 cps/µCi (CFOV)
small animal pet scanner development
Small Animal PET Scanner Development
  • microPET (UCLA/Concorde Microsystems)
  • HIDAC (Oxford Positron Systems)
  • SHR-7700 (Hamamatsu, Japan)
  • Sherbrooke Animal PET (Sherbrooke, Canada)
  • RATPET (MRC Hammersmith)
  • TierPET (Jülich, Germany)
  • YAP-PET (Ferrara, Italy)
  • MAD-PET (Munich, Germany)
  • ANI-PET (Montreal, Canada)
micropet images
microPET images

baby monkey brain phantom (25 cc)

Siemens EXACT HR+

microPET

slide17

MicroPET images of rat myocardium (13NH3)

Short Axis

Vertical long Axis

Horizontal long Axis

Baseline

Occlusion

Reperfusion

Polar Map

T. Kudo, A.J. Annala and H. Schelbert

slide18

Comparison of Metabolic Images

FCx

Caud/Put

PCx

Thal

TCx

FDG

autoradiography

Bs

FDG

microPET

Amy Moore, David Hovda, Simon Cherry

UCLA Crump Institute for Biological Imaging & Division of Neurosurgery

slide19

Quantitative FDG-microPET

microPET

120

microPET

autoradiography

100

autoradiography

80

CMRGlc

(mol/100g/min)

60

40

20

Amy Moore, David Hovda, Simon Cherry

UCLA Crump Institute for Biological Imaging

& Division of Neurosurgery

0

Frontal

Cx

Caudate/

Putamen

Parietal

Cx

Thalamus

slide20

CMRGlc Following Traumatic Brain Injury

Baseline

2 days

post-injury

75

CMRGlc

5 days

post-injury

0

10 days

post-injury

Rat #383

Amy Moore, David Hovda, Sheri Osteen, Simon Cherry

UCLA Crump Institute for Biological Imaging & Division of Neurosurgery

slide21

Lesioned Striatum

Lesioned Striatum

Rat Striatal Dopamine System Imaged with microPET

[C-11]WIN 35,428

DA Transporter Binding

[C-11]Raclopride

DA D2 Receptor Binding

Control

Unilateral

6-Hydroxydopamine

Lesion

Dan Rubins, Goran Lacan, Simon Cherry, andWilliam Melega

mouse brain 11 c win 35 428
Mouse Brain:11C-WIN 35,428

Time Activity curve

30g mouse

transverse brain section

180µCi of 11C-WIN 35,428

(0.018µg)

slide23

C6

LS174T

Liver

MicroPET Tumor Imaging 64Cu-DOTA anti-CEA Minibody

  • Athymic mouse with LS174T (CEA+) and C6 (CEA-) xenografts
  • Injected with 70 µCi 64Cu-anti-CEA minibody (engineered antibody fragment, scFv-CH3 )
  • Scanned 12 hr post injection

Data courtesy of Anna Wu (UCLA and City of Hope)

pet in drug development
PET in Drug Development
  • direct radiolabeling of drug
    • biodistribution and pharmacokinetics
  • binding/competition studies
    • dosing and pharmacodynamics
  • indirect markers
    • pharmacodynamic effect on secondary marker (e.g. metabolism or blood flow)
positron emission tomography26
Positron Emission Tomography

Advantages:

vast range of biological processes can be measured quantitatively

sensitivity can be in nM to pM range

whole animal biodistribution and kinetics

Disadvantages:

relatively coarse spatial (~mm) and temporal (~mins) sampling

synthesis of radiolabeled compounds can be a bottleneck

little or no anatomical information

mr compatible pet system
MR Compatible PET System

Concept

Animal MR system

PET

Detectors

MR Receiver Coil

prototype mr compatible pet scanner
Prototype MR Compatible PET Scanner

56 mm ring diameter

72 2x2x25 mm LSO scintillators

PMT’s

optical fibers

experimental setup
Experimental Setup

Prototype MR compatible PET scanner

inside 1.5T clinical MR

simultaneous in vivo imaging
Simultaneous In Vivo Imaging

200 g Rat - 18F-FDG Brain Study

PET

MRI

1.3 mCi 18F-FDG

imaging time 30 mins

slice thickness ~ 2mm

TE=12 msec, TR=280 msec

continuous 75 secs

acquisitions during PET study

slice thickness 4 mm

slide31

microCT

microPET

Rapid In Vivo Drug and Genetic Screening with PET and CT

combined anatomical & molecular imaging

for use with 18F-labeled ligands or secondary markers such as 18F- FDG

throughput of >20 mice per hour

sophisticated bioinformatics to assist in analysis

conveyor belt

references
References

Chatziioannou AF, Cherry SR, Shao Y, Silverman RW, Meadors K, Farquhar TH, Pedarsani M, Phelps ME. Performance evaluation of microPET: A high resolution LSO PET scanner for animal imaging. J Nucl Med 40: 1164-1175 (1999).

Gambhir SS, Barrio JR, Herschman HR, Phelps ME. Assays for Non-Invasive Imaging of Reporter Gene Expression. Nuclear Medicine and Biology, 26: 481-490 (1999).

MacLaren DC, Gambhir SS, Satyamurthy N, Barrio JR, Sharfstein S, Toyokuni T, Wu L, Berk AJ, Cherry SR, Phelps ME, Herschman HR. Repetitive, Non-invasive Imaging of the Dopamine D2 Receptor as a Reporter Gene in Living Animals. Gene Therapy, 6:785-791 (1999).

Gambhir SS, Barrio JR, Phelps ME, Iyer M, Namavari M, Satyamurthy N, Wu L, Green LA, Bauer E, MacLaren DC, Nguyen K, Berk AJ, Cherry SR, Herschman HR. Imaging Adenoviral-Directed Reporter Gene Expression in Living Animals with Positron Emission Tomography. Proc Natl Acad Sci (USA), 96: 2333-2338 (1999).

acknowledgments
Acknowledgments

Imaging Sciences Lab:

Andrew Goertzen

Andrew Wang

Daniel Rubins

Arion Chatziioannou

Yiping Shao

Yuan-Chuan Tai

Robert Silverman

Randal Slates

Niraj Doshi

Collaborators:

Richard Leahy (USC)

Jinyi Qi (LBNL)

Concorde Microsystems Inc.

UCLA:

Sam Gambhir

Harvey Herschman

Michael Phelps

Amy Moore

David Hovda

Harley Kornblum

Heinrich Schelbert

William Melega

Takashi Kudo

Alexander Annala

Anna Wu