Transcript Module 3 (PET Contrast Agents)

BIOE 498/598 DP
PET and SPECT Imaging
Topics to Cover
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History of nuclear imaging
Why nuclear imaging
Types of nuclear imaging- PET and SPECT
Principles of PET and SPECT
PET agents
Specific examples- Cancer
Specific examples- Cardiovascular
Specific examples- Neuro
History of Nuclear Imaging
• George Charles de Hevesy was first to
identify
the
radioisotope
tracer
principle.
• In 1923, he used 10.6 hour lead-212 to
study the uptake of solutions in bean
plants, noninvasively. Used small, nontoxic amounts given the sensitivity of
the radioactivity techniques.
• The first experiment in animals used Bi210 to label and follow the circulation of
Bi-containing antisyphilitic drugs in
rabbits.
• In a later book with Fritz Paneth, the
tracer method was introduced as the
use of radioelements as indicators.
•The first practical application
of a radioisotope was made by
George de Hevesy in 1911.
•He suspected that meals that
appeared regularly might be
made from leftovers.
•To confirm these suspicions
de Hevesy put a small amount
of radioactive material into
the remains of a meal.
•When the same meal was
served, it was radioactive!
George de Hevesy : Nobel
prize in 1943 and the Atoms
for Peace award in 1959.
1934 photo of Livingston and
Lawrence with the 27” cyclotron
The Advantage of Radionuclides for Targeted
Imaging, especially Low Density Sites (<20 nM)
If 10 mCi at a specific activity of >1000
µCi/nmol: 10 nmol/70 Kg
For Gd MRI:
Iron oxide (T2) increases sensitivity.
For CT:
Iodinated contrast media
Optical imaging and Ultrasound
<0.2 nM
10-100 µM
>100 µM
?
Imaging Modalities Comparison
Schematic view of a detector
block and ring of a PET scanner
• Nuclear imaging technique that produces a 3D image of functional processes in the body
• Detects pairs of  rays emitted indirectly by a positron-emitting radionuclide (tracer)
• 3D-images of tracer concentration within the body are then constructed by computer
analysis.
• In PET-CT or PET-MR scanners, 3D-imaging is accomplished with the aid of a CT X-ray/MR
scan performed on the patient during the same session, in the same machine.
Principles of PET
First, a targeted imaging agent containing a positron emitting radioisotope is administered to the subject. Positrons are
emitted from each imaging agent only once; these positrons travel short distances and collide with electrons in the
surrounding tissues (annihilation), resulting in the production of two  rays, (energy 511 keV), traveling at opposite
directions to one another (180° apart).
Following the detection of gamma rays by the PET detector, the location of annihilation events are calculated by
observing multiple events. The resulting electrical signals are converted into sinograms that are reconstructed into
tomographic images.
Images demonstrating the noninvasive visualization of an orthotopic brain tumor (2.5 mm in diameter) in a rat via the
use of ([18F]FDG), as early as 10 days (D10) after implantation. Pinks arrows show tumor, and red arrow shows wound
due to intracerebral implantation of tumor cells
Principles of SPECT
First, a targeted SPECT imaging agent (containing a  emitting radioisotope) is administered to the subject and the
gamma rays are detected via a gamma camera (rotated around the subject). The detected gamma rays are then
reconstructed into tomographic images, providing information on the location of the imaging agent in the subject.
B: SPECT images demonstrating the utility of visualizing gastrin-releasing peptide receptor (GRPR), a receptor often
found in high levels in prostate cancer, via the administration of [99mTc]-HABN in mice bearing human prostate
xenografts. Arrows point to tumor; clear visualization of tumor is possible at 4 h post-injection (p.i.)
Comparative Lung Cancer Detection with
using 18F-FDG
Transaxial images of CT (left) and FDGPET/CT (right) in three different patients.
A: A male smoker with 2 cm lump in left
lung (red cross hair). With CT alone the risk
of this lump being cancer is 50%. The lump
has a very high FDG uptake, which is typical
for fast growing cancers and the combined
image indicates an 80% risk of cancer.
B: A non-smoking female with a 1.5 cm
lesion that has no FDG uptake (the large
yellow area is the heart muscle). The
negative predictive value of the combined
image is 99%.
C: CT with a bone window setting is
negative for bone metastases. PET shows
two small metastases with very intense
uptake.
FDG-PET/CT for Staging and Treatment in
Lymphoma
Combined coronal [18F]-FDG PET/CT images from a
25-year old woman, who was diagnosed with
aggressive Non-Hodgkins Lymphoma. Prior to PET/CT
the patient was known to have disease in the neck
and mediastinum. The left image was obtained
before treatment and showed extensive growth of
tumors not only in the neck and mediastinum, but
also in abdominal lymph nodes, bone marrow, liver
and spleen. This image dramatically changed the
disease stage and the associated treatment. The
image to the right shows the same view after three
courses of a standardized chemotherapy regime,
typically given in 8 courses. The mediastinal lumps
remain visible on CT, termed ”partial anatomical
remission”, but neither these lumps nor any of the
previously diagnosed lymphoma locations show
pathological FDG uptake, a pattern of findings
termed ”complete metabolic remission”. This finding
after treatment is highly predictive of treatment
success without any need of therapy changes. On the
other hand, remaining FDG uptake in any of the
known lumps is associated with a high likelihood of
recurrence.
Nuclear Imaging Contrast Agent Essentials
Isotopes with short half-lives such as C-11 (~20 min), N-13 (~10 min), O-15 (~2 min), F18 (~110 min)., or Rb-82(~1.27 min).
Incorporated either into compounds normally used by the body such as glucose (or
glucose analogues), water, or ammonia, or into molecules that bind to receptors or
other sites of drug action.
Trace biologic pathways of tracers in humans.
Clinical PET scanning uses fluorodeoxyglucose (FDG or fludeoxyglucose), an analogue of
glucose that is labeled with F-18 essentially in all scans (>95%) for oncology and most
scans in neurology.
Due to the short half-lives of most positron-emitting radioisotopes, the radiotracers
have traditionally been produced using a cyclotron in close proximity to the PET
imaging facility.
Rb-82 generators have become commercially available. These contain strontium-82,
which decays by electron capture to produce positron-emitting rubidium-82.
PET Radionucleotides
T1/2 (min)
82Rb
1.3
11C
20
13N
10
15O
2.05
18F
109.6
18F
109.6
E+ (kev)
3350
960
1190
1720
635
635
Nuclear Reaction
82Sr generator
14N (p,) w. 6 ppm O
2
16O (p,)
14N (d,n) w. 2% O
2
20Ne (d,) w. 0.5%F
2
18O (p,n)
76Br
3980
571
2134
75As
64Cu
124I
966
762
5976
(,3n)
64Ni (p,n)
124Te (p,n)
PET and Nuclear Medicine Imaging Agents
Elimination half-life: 110 min (at 70%)
16 min (at 20%)
Excretion 20%
Radioactivity renally excreted in 2 h
FDG: 18F-fluorodeoxyglucose (FDG) is a
radioactive sugar molecule, that, when
used with PET imaging, produces images
that show the metabolic activity of tissues.
In
FDG-PET
scanning,
the
high
consumption of the sugar by tumor cells,
as compared to the lower consumption by
normal surrounding tissues, identifies
these cells as cancer cells. FDG is also used
to study tumor response to treatment.
Mechanism of [18F]FDG signal amplification
James M L , and Gambhir S S Physiol Rev 2012;92:897-965
The small molecule imaging agent [18F]FDG is an analog of glucose, whereby the 2-carbon hydroxyl group of glucose is
substituted with a fluorine atom. Like glucose, [18F]FDG is taken up by cells via the glucose transporter (GLUT1) and
phosphorylated by hexokinase II (HKII) to form [18F]FDG-6-PO4; however, (unlike glucose), further metabolism is
prevented due to the absence of the required 2-carbon hydroxyl, and hence [18F]FDG remains trapped within the cell.
[18F]FDG-6-PO4 accumulates in cells over time, leading to signal amplification and making this imaging agent a
suitable indicator of hexokinase II activity as well as a cell's need for glucose.
©2012 by American Physiological Society
PET and Nuclear Medicine Imaging Agents
64Cu-ATSM:
64Cu
diacetyl-bis(N4methylthiosemicarbazone), also called
ATSM or Copper 64, is an imaging agent
used in PET or PET/CT for its ability to
identify hypoxic tissue (tissue with low
oxygen).
64Cu half-life - 12.7h
Decays: 17.86 (± 0.14)% by positron
emission to 64Ni, 39.0 (± 0.3)% by beta
decay to 64Zn, 43.075 (± 0.500)%
by electron capture to 64Ni, and 0.475
(± 0.010)% gamma radiation/internal
conversion.
PET/CT shows decreased retention of 64Cu-ATSM in
ArKO tumor–bearing mice. Whole-body PET/CT
images were acquired for wild-type (A) and ArKO
tumor–bearing (B) mice 1 h after the intravenous
injection of 3.7 MBq (100 μCi) of 64Cu-ATSM. Images
show protuberant abdomen in ArKO tumor–bearing
mouse and clearly decreased activity in right side of
enlarged liver (circles).
18F-fluoride: 18F-fluoride
is an imaging agent
for PET imaging of new bone formation. It can
assess changes both in normal bone as well as
bone tumors. As a result, it can be used to
measure response to treatment.
Hydroxyapatite and aluminum
hydroxide nanoparticles labeled with
[18F]-fluoride
Normal distribution of the tracer was visualized throughout
the entire skeletal system, except for mild degenerative
changes in the lower lumbar vertebrae (arrows). There was
no evidence of skeletal metastatic disease.
http://pubs.rsc.org/en/content/artic
lelanding/2011/dt/c0dt01618g#!div
Abstract
Gallium Scans
Gallium: Gallium attaches to areas of
inflammation, such as infection. It also attaches
to areas of rapid cell division, such as cancer
cells. It can take gallium a few days to accumulate
in the affected tissue, so the scan may be done 23 days after the gallium is administered. (Gallium
Citrate or Nitrate)
•Produced by a cyclotron.
•Charged particle bombardment of enriched 68Zn.
•The 67gallium is then complexed with citric acid
•The half life of gallium-67 is 78 hours.
Gallium-67 photo-peaks:
Energy Abundance
93 keV 40%
184 keV 20%
300 keV 17%
393 keV 5%
Imaging og biopsy-proven enteococcus faecalis
spondylodiscitis at L4-L5.
Left: increased uptake at vertebral endplates
adjacent to L4-L5 disc space on bone scan
SPECT/CT.
Middle: discordant increased Ga uptake within
disc space itself.
Right: corresponding hyperintensity in verbral
bodies and L4-L5 intervertebral disc space on T2weighted MR imaging
Technetium (99mTc) tetrofosmin
Half-life: 6.0058 h; Parent isotopes 99Mo (65.976 h);
Decay products: 99Tc
Tc-99m tetrofosmin is rapidly taken up by myocardial
tissue and reaches its maximum level in
approximately 5 minutes.
About 66% of the total injected dose is excreted
within 48 hours after injection (40% urine, 26% feces)
The severity of Diabetic Foot Infection can be best
measured by determining the anatomic and
physiologic parameters by utilizing 99mTc-WBC
SPECT/CT images.
This gives information regarding intensity, number,
and location of lesions, as well as radiographic
evidence of adjacent disrupted bone architecture)
Evaluation of a radiolabeled binding aptamer
([99mTc]-TTA1) specific for extracellular matrix
protein tenascin-C, vs a radiolabeled
nonbinding aptamer, in mice either bearing
glioblastoma (U251) or breast cancer (MDAMB-435) tumor xenografts using planar
scintigraphy. The results show rapid tumor
uptake and fast blood clearance of the binding
aptamer [99mTc]-TTA1, affording a tumor-toblood ratio of 50 within 3 h.
Scintigraphic images obtained at 18 h depict
the tumor as the brightest structure and
demonstrate the almost complete clearance of
[99mTc]-TTA1 from the body, whereas the
tumor cannot be visualized using the
radiolabeled nonbinding aptamer. [99mTc]TTA1 could also be used to detect breast tumor
xenografts (MDA-MB-435) at 20 h, illustrating
the use of this aptamer for detecting different
tumor types.
Molecular imaging of neuro-inflammation
in patients with mild Alzheimer's disease
Example of a clinical (AD) using [11C]PK11195, positron emission tomography (PET), and magnetic resonance
imaging (MRI). This figure shows brain PET images coregistered with MRI images for a normal elderly subject
(A) and a patient with mild AD (B). Arrows represent regions of increased [11C]PK11195 binding found in mild
AD patient and not in elderly control.
Tumor & kidney
MicroPET images (coronal) of mice with BT-474
tumors with Ga-68-DOTAcHF at 3 h before and 24 h
after 17-AAG
Nat Biotechnol. 2004;22:701-6
Nuclear imaging of Detecting
Cardiovascular disease
Clinical and preclinical PET imaging of stem cell
transplantation
A, Human PET imaging of the engraftment of 18F-FDG–
labeled circulating progenitor cells after intracoronary
infusion. Representative
coronal PET (left), transverse PET (top middle),
and transverse PET/CT (bottom middle) images
of 18F-FDG–labeled circulating progenitor cells
4h after intracoronary infusion via the left
anterior descending coronary artery in a
patient with 92-day-old anteroseptal wall
infarction. Cell accumulation (grayscale for the
coronal image; color scale for the transverse
images) is clearly visualized in the anteroseptal
wall of heart (H; 2% at 4 hours), liver (L),
spleen (S), and bone marrow within the
skeleton. Images courtesy of Won Jun Kang at
Yonsei University, South Korea.132 B, PET
imaging of reporter gene/probe-labeled
embryonic stem cells. A mouse underwent
intramyocardial injection of mouse embryonic
stem cells expressing HSV1-sr39tk PET
reporter gene, followed by 18F-FHBG and 18FFDG scans 2 weeks later to assess cell viability
and
myocardial
glucose
metabolism.
18
Representative transverse
F-FHBG (top
18
right),
F-FDG (middle right), and18FFHBG/18F-FDG fusion (bottom right) images
show the location of implanted cells
(arrowheads) in the anterolateral wall of the
LV, where cells were implanted.
Monitoring Therapy with Nuclear Imaging
18F-FDG
uptake of human carotid and aortic atherosclerotic plaques in response to simvastatin
therapy. Coronal 18F-FDG PET images (top 2 rows) of human carotid (upper white arrows) and
aortic (lower white arrows) atherosclerotic plaques at baseline (left column) and 3 months after
treatment (right column) with either dietary management (top row) or simvastatin (bottom 2
rows). 18F-FDG uptake is attenuated in both carotid and aortic atherosclerotic plaques treated
with simvastatin, as clearly demonstrated in the transverse PET/CT images (bottom row) of a
left carotid plaque (black box). Plaque 18F-FDG uptake is not influenced by dietary
management.