Imaging in Biomedical Research (BIOL31631)

Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT)
Dr. Herv Boutin University of Manchester, UK

Main imaging techniques

Scanner X CT scan (Hounsfield, 1973)

Anatomical information

Positron Emission Tomography (PET) (Brownell, 1975) Single Photon Emission Tomography (Hill, 1978) Magnetic Resonance Imaging & Magnetic Resonance Spectroscopy (Damadian, 1977 Mansfield 1977)

Functional and pharmacological information

Anatomical and functional information

Overview
Where is the signal coming from? The positron emission and annihilation. The PET scanner and accessories. Different radiotracers to probe different functions. PET imaging. Single Photon Emission Computer Tomography (SPECT). Summary.

Principles of PET
Emission / annihilation

O N N Cl

CH3

1. e+ emission
11 CH CH3
3

CH3

~1mm

e+

2. Annihilation e+ + e-

ephotons of 511keV

2 co-incidents

The average travelling distance of the e+ determines the maximum spatial resolution of PET (~1mm).

Principles of PET Emission / annihilation

Unstable isotopes, such as Fluorine-18 [18F] or Carbon-11 [11C], become more stable by converting 1 proton into 1 neutron; When this happens, 1 positron (e+ or A positron (e+ or mass);
+) +)

and 1 neutrino ( ) are produced;

-)

is a positively charge electron (e- or

(i.e. same

Because electrons (e- or -) are so abundant in the matter, the e+ immediately annihilates with an e-;
This annihilation releases energy by producing 2 co-incident photons .

18 9

18 9 8

11 6

10

11 5 5

( 511keV )

Positron Emitting Isotopes

The unstable radioisotopes used for PET imaging are artificially created by nuclear reaction in a cyclotron. In PET imaging radionuclides that emit positrons are chemically added to

molecules;
These molecules are then introduced in the body (injection, inhalation). Hundreds of isotopes can be created this way. The most commonly used

for PET imaging are

11C, 18F, 15O, 13N.

The isotopes do not lose their biological activity, i.e. H215O behaves like H216O.

The Cyclotron

1. Negative hydrogen ions are accelerated to 11 MeV by D-shaped electromagnets; 2. The beam is extracted from the cyclotron by passing through a thin carbon foil, which strips off the electrons, leaving protons; 3. The protons are swept out of the beam and hit the target to form the isotopes.

4. The nature of the target (material) determines the radionuclide produced.

Negative ions (H-)

Positron Emitting Isotopes

Radioisotopes
11C 13N 15O 18F 68Ge

Half-life (min)
20.39 9.96 2.04 109.77

photon max. energy (Mev) 0.96 1.19 1.73 0.63

Range in water (mm)

1.1 1.4 2.5 1.0

68Ga
64Cu 89Zr

3.9105 (270d) 67.83

762.02 (12.7h) 4704.6 (3.27d)

N/A 1.90
1.34 0.90

1.7
-

Most positron emitting isotopes have a half life in the range of minutes.
For example 15O has a half life of 2 minutes. This means that in 2 minutes half of the original amount has disappeared.

Positron Emitting Isotopes

Too long half lives are bad for the subject as it would still receive a radioactive dose after the scan is over. The short half lives of the isotopes reduce the radiation exposure of the patient but create the problem of storing and maintaining the isotopes. Therefore most PET facilities create their own isotopes on site; Resources intensive; Expensive (equipment + personnel)

Principles of PET
Detection of the 2 photons

From http://en.wikipedia.org/wiki/Positron_emission_tomography

Principles of PET
Detection of the 2 photons

Kandel p.377

1. PET imaging is based on the detection of the photons; 2. and the 3D reconstruction of the signal.
Diagram courtesy of Bioteach at UBC

The PET Scanner

Clinical scanners

Courtesy Drs M. Jones, P. Tyrrell, A. Gerhard and K. Herholz; University of Manchester.

Courtesy of University of Erlangen, Erlangen, Germany And Siemens: http://www.medical.siemens.com

Preclinical scanners

Wolfson Molecular Imaging Centre, University of Manchester. (http://www.mhs.manchester.ac.uk/imagingfacilities/).

The PET Scanner

The PET scanner on the right consists of multiple detection rings. The resolution depends on the size and type of detectors, the diameter or the rings (the closer to the object the better).
Photo multiplier Scintillator crystals

Detector block

Principles of PET Summary

PET experiments use radionuclide that emit a positron (e+ or +); A positron (e+ or +) is a positively charge electron (e- or
-)

(i.e. same mass) rays which

When the e+ annihilates by collision with electrons, it emits two travel in opposite directions;

By coincidence detection the origin of the

rays can be calculated;

This is used to generate a picture of the distribution of the isotope in the tissue;

Mathematical computing can then be applied to the data to calculate

pharmacological parameters or metabolic rates.

Positron Emitting Radiotracers

There are hundreds of molecules that can be labelled with e+ emitting nuclides; PET imaging requires to chose appropriately both the biological target and the molecules to be radiolabelled; There are many constraints that need to be addressed to develop a good radiotracer (specificity to the target, difficulty of the radiochemistry, etc..).

Depending on the role of that molecules in the normal metabolism or

physiological function different processes can be imaged with PET.

Examples of biomedical applications

Radiotracers
[15O]carbon monoxide [15O]carbon dioxide [15O]water [13N]ammonia [15O]di-oxygen (O2) [18F]FDG [11C]Methionine [18F]FLT [18F]FMISO [11C] DASB

Applications
blood volume blood flow blood flow blood flow oxygen metabolism glucose metabolism Amino acid uptake (protein synthesis/cell proliferation) Thymidine uptake (cell proliferation) hypoxic tissue Serotonin transporter

[11C] MDL 100,907

[18F]A85380 [11C]SCH23390

Serotonin 5-HT2A receptors

nicotinic acetylcholine receptors dopamine DI receptor

[11C]Flumazenil
[11C]PK11195 & [18F]DPA-714 [11C]PIB & [18F]AV-45 [11C]Verapamil [18F]F-DOPA

central benzodiazepine receptor

peripheral benzodiazepine receptor amyloid plaque: Alzheimer's disease P-glycoprotein transporter Dopamine synthesis

Examples of radiotracers
[18F]-deoxyglucose

18F-fluorodeoxyglucose

(FDG) is an analogue of glucose;

18F-deoxy-glucose

The important difference between

18F-deoxyglucose

and glucose is that

is NOT metabolised but accumulates in the cells.

The amount accumulated is an index of the metabolic rate of glucose (in the case of the brain: Cerebral Metabolic rate = CMRglc). The uptake of any radiotracer is quantified as amount of radioactivity per

unit of volume (e.g. kBq/cm);

The analysis of this quantification by mathematical model can provide more precise information (i.e. receptor concentrations (Bmax); or in the

case of FDG: CMRglc).

PET imaging of Visual activity

The visual cortex lights-up

1- Injection of [18F]FDG 2- Stimulation of the visual system Increase in activity in the visual cortex = increase in metabolism = increase in glucose consumption

Huettel et al . 2001

PET imaging of Visual activity

The visual cortex lights-up

Simple visual task

Research of an object in a complex image

Huettel et al . 2001

The FDG uptake (= brain activity) varies with the complexity of the task

Neuroinflammation and -amyloid plaques in Alzheimer patients

Drzezga A et al. (2008) Neuroimage 39:619-633.

Neuroinflammation and -amyloid plaques in Alzheimer patients

-amyloid plaques co-localise with neuroinflammation in AD patients.

binding potentials and corresponding PIB ratio images in two patients with PIB positive mild cognitive impairment (MCI)

11C-(R)-PK11195

Okello A. et al. (2009) Neurology. 72:56-62.

Neuroinflammation in rat after experimental stroke

0.7 0.6

0.5
0.4
%ID/cm3

0.3
0.2 0.1

[11C]PK11195

0.0

[18F]DPA-714

PET can be successfully used in small animals (rodents) to study in vivo models of disease, physiological processes or to develop new tracers that can be implemented in patients.

[18F]-DOPA
Tracer kinetic models are based on prior knowledge of the uptake in different tissues over time.

This way substrate concentrations up to nanomoles per gram can be extracted.

This makes PET the ONLY imaging method to get quantitative figures about the concentrations and volumes of substances involved in the metabolism!

Distribution of L-6-[18F]fluroro DOPA in the human brain as a function over time after injection.
from Toga et al. Brain Imaging: The Methods

Single Photon Emission Computer Tomography (SPECT)

Single Photon Emission Computer Tomography (SPECT) is similar to PET technology but with some differences

But uses longer half-life isotopes and is therefore more widely

available (Does not need a Cyclotron on site)! SPECT uses isotopes that emit single photon radiation in the form of rays like [133Xe],
123iodine

and 99technetium:

[133Xe] is inhaled; [123I] and [99Tc] are use to radiolabel compounds as in PET radiochemistry.

Single Photon Emission Computer Tomography (SPECT)

Differences between SPECT and PET technologies Instead of rings of detector for PET scanner, in SPECT scanner the detector rotates 360 around the subject (similarly to CT). Multi-detector scanner can reduce the scanning time. SPECT radio-nuclides emit photons directly (there is no

annihilation involved as in PET). Resolution of SPECT (~5mm in human) is lower than PET (~2mm);

But higher in preclinical scanner (SPECT: <1mm / PET ~1mm)

(requires the use of pin-hole collimators).

Summary: Advantages of PET / SPECT

Only quantitative techniques able to put numbers in vivo on metabolic

or pharmacological processes dynamically.

Almost infinite numbers of parameters can be imaged; Although the right target (physiological or pathological biomarker) and the
radiotracer must be available or developed.

Non-invasive technique.

Summary: Disadvantages of PET / SPECT

Radioactivity: each subject is limited to a maximum of 12 doses of [15O]labelled tracers, i.e. 12 scans or two doses of [18F]-labeled tracers.

The short half life of PET tracers require a cyclotron expensive and
staff consuming.

Bad temporal (~30sec) and spatial (~2-9mm) resolution.

Scientific question
Are microglial activation and amyloid deposition co-localised in the brains of subjects with and without AD?

Methods
5 control subjects, 6 patients with mild cognitive impairment [MCI], and 6 patients with mild to moderate AD;

Neurological assessment;
PET scan with: o [11C]PiB for -amyloid deposition; o and [11C](R)-PK11195 for neuroinflammation (microglial activation).

Main findings

5 subjects PiB-

12/17 subjects PiB+

6/6 AD patients 4/6 MCI patients

2/5 control

PiB uptake = amyloid load:

AD patients > MCI > control.

Main findings / Conclusions

No significant increase in PK11195 uptake between AD, MCI and control No significant increase in microglial activation between PIB+ and PIB Seems to indicate that there is no detectable microglial activation in AD

Discussion
But several post-mortem and other in vivo PET imaging (e.g. Okello A. et al. (2009) Neurology. 72:56-62) showing microglial activation in AD!! Microglial activation / neuroinflammation is a late consequence of AD? PK11195 is not a sensitive enough tracer to detect microglial activation in AD or MCI? (poor sensitivity of this tracer reported before) Is microglial activation good or bad in AD (clearance of -amyloid)? Very important implications for the understanding of AD and development of AD therapies