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PET in Radiation Oncology:

Advances in Chemistry,

Biology, and Physics

Cancer Biology ProgramMolecular Imaging Program @ Stanford Bio-X

Stanford University School of Medicine, Department of Radiation Oncology

Edward “Ted” Graves, Ph.D. (egraves@stanford.edu)

Imaging in Radiation Oncology

Imaging in Radiation Oncology

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Positron Emission Tomography

• Positron emitters and radiochemistry

• Imaging technology

• Imaging targets and radiotracers

• Quantitation

Positron Emitters

Isotope Half life

(hours)

Decay Maximum

b+ energy

(keV)

Mean

b+ energy

(keV)

11C 0.34 b+ (99.8%) 960 386

13N 0.17 b+ (99.8%) 1198 492

15O 0.03 b+ (99.9%) 1732 735

18F 1.83 b+ (96.7%) 634 250

64Cu 12.70 b+ (17.4%)

b– (39.0%)

EC (43.6%)

653 278

68Ga 1.13 b+ (88.9%)

EC (11.1%)

1899 836

89Zr 78.40 b+ (22.7%)

EC (76.2%)

902 396

124I 100.20 b+ (22.7%)

EC (77.3%)

2138 819

P. McQuade et al., Cur Med Chem, 2005

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

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PET Radiochemistry

11C, 18F, 124I

64Cu, 89Zr 68Ga

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Organic synthesis/

Radiolabeling

O

OAc

TsO

OAcAcO

AcOH2C

O

OH

18F

OHHO

HOH2C

K222, K18F

Hydrolysis:

Chelation/

Conjugation :R R

64Cu 64Cu

PET/CT HardwareRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

Current clinical PET performance: Spatial resolution ~5 mm

Sensitivity <pM

TOF PETRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

Early PET scanners utilized

coincidence detector timing to

localize events along a line-of-

response, however these

detectors were abandoned due

to poor sensitivity.

Philips introduced the Gemini TF

in 2006 taking advantage of

detector improvements to revisit

time-of-flight PET.

TOF resolution 300-500 ps

(9-15 cm)

S. Vandenberghe et al., EJNMMI Phys, 2016

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DOI PET

Dx

q

Increasing PET detector thickness is a

standard approach to improving

sensitivity. However, this comes with an

increase in parallax error.

DOI detectors are capable of measuring

the location of interaction of a 511 keV

photon within a scintillation crystal.

M. Ito, Biomed Eng Letters, 2011

M.F. Bieniosek et al., Phys Med Bio, 2017

M.S. Lee, Phys Med Bio, 2017

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Imaging Targets

Immune Cells

Tumor Cells

Cells

Proteins

Nucleic Acids

Molecules

Perfusion

Metabolism

Proliferation

Processes

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

FDG PET signal is dependent on:

• Vascular delivery

• Cell number

• GLUT expression

• Hexokinase expression

• Excretion pathways

Glucose-6-phosphatase

Slow!!!

Hexokinase

O

OHOH

HO

–PO4–OH2C

18F

Pyruvate

Phosphohexose

isomerase

OH

HO

–PO4–OH2C O CH2OH

18F

O

OH

18F

OHHO

HOH2C

GLUT

FluorodeoxyglucoseRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

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2-nitroimidazole uptake is dependent on:

• Vascular delivery

• Cell number

• Reductase expression

• Oxygen

• Excretion pathways

N N

NO2

R

N N

NHOH

R

N N

NH2

R

One Electron

Reductases

O2

Hypoxia PETRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

FD

GF

DG

FM

ISO

Pre

-txP

re-tx

Po

st-tx

D. Rischin et al., J Clin Onc, 2006

Hypoxia PET and PrognosisRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

Hypoxia PET and RT Response

0

0.5

1

1.5

2

2.5

3

3.5

4

0 10 20 30 40 50 60

No

rmal

ised

Po

st-R

T V

olu

me

Days Post Treatment

4 x 10Gy

0

0.5

1

1.5

2

2.5

3

3.5

4

0 10 20 30 40 50 60

No

rmal

ised

Po

st-R

T V

olu

me

Days Post Treatment

4 x 5Gy

R.S. Ali et al., PLoS One, 2015

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 30 35 40

No

rmal

ised

Po

st-R

T V

olu

me

Days Post Treatment

1 x 40Gy

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 30 35

No

rmal

ised

Po

st-R

T V

olu

me

Days Post Treatment

1 x 10Gy

p < 0.05

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

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Hypoxia PET and RT Response

Y. Qian et al., Int J Radiat Oncol Biol Phys, 2018

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Radiotracer Design

Small molecules• Require organic synthesis/radiolabeling

• Short blood half life/clearance time

• Can use short-lived positron emitters

• Unsuitable for conjugation to large labels such as chelators

Biologics and Nanoparticles• Typically expensive to manufacture

• Long blood half life/clearance time

• Require long-lived positron emitter

• Suitable for non-specific labeling, chelators

O

OH

18F

OHHO

HOH2C

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Quantitation

• Maximum intensity

• Minimum intensity

• Mean intensity

• Median intensity

• Integrated intensity

• 75th percentile

• 90th percentile

• Standard deviation

• Variance

• Skew

• Kurtosis

• ROI volume

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

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Variability in PET

F. Habte et al., Am J Nuc Med Mol Im, 2006

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Variability in PET

R. Jeraj et al., J Nuc Med, 2015

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Image SegmentationRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

Q. Black et al., Int J Rad Onc Biol Phys, 2004

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Validation

J. Murphy et al., Radiother Onc, 2011

Radiochemistry Imaging Technology Targets and Radiotracers Quantitation

Quantitative Imaging NetworkRadiochemistry Imaging Technology Targets and Radiotracers Quantitation

The QIN is an NCI-sponsored collective of 21 research teams spanning 19

institutions working to standardize imaging acquisition and analysis methods

in order to facilitate the widespread use of imaging as a quantitative biomarker

for cancer research and treatment.

Summary

• Radiochemistry of a large number of PET probes is

established and translatable.

• Clinical PET/CT scanners are capable of imaging

positron-emitting probes at sub-picomolar levels with

spatial resolutions of 4-5 mm.

• A variety of molecular and cellular processes are

imageable with PET.

• Current challenges to integration of PET images in

radiotherapy planning are establishment of robust

segmentation methods and the cost of multicenter

deployment and evaluation of these methods.