1.

Introduction
In 1997, The National Cancer Institute published study results, which predicted that by
2002, cancer would surpass cardiovascular disease as the number one cause of death in
the United States of America [1]. Nearly ten years later, this continues to be the
prevailing trend. Metabolic changes in a body structure precede anatomic changes in the
case of most diseases. Early detection of metabolic changes in a patient’s system will
allow physicians to start early and less aggressive treatment regimes.
1.1 Medical Imaging Capabilities
Optical imaging of the brain has often been used, as its optical contrast can be used to
simultaneously assess both oxyhemoglobin and deoxyhemoglobin molecules. It can also
detect intracellular events that are related to neuronal activities with quick and direct
response to simulation. However limitations have been encountered with transcranial
imaging using optical techniques, and the resulting spatial resolution is poor due to the
large amount of light scattering in biological tissues. [2,3,4]
However studies using photoacoustic tomography in biological tissues have shown an
improvement in spatial resolution and contrast when compared to optical and ultrasonic
imaging modalities [5,6,7].
Ultrasound imaging has had success with assessing pneumonia, fluid collection in the
pleural cavity, and defining its structure and form in the lungs. However its ability to
image lungs is hindered due to its inability to penetrate lung tissues. Recent studies have
focused on the noninvasive measurement of lung elasticity in order to characterize lung
diseases such as idiopathic pulmonary fibrosis and acute respiratory distress syndrome.
[8,9,10,11]
Nuclear imaging capabilities allow the extent of a disease process to be imaged based on
changes in cellular function and physiology. It differs from “non-nuclear” imaging
capabilities (i.e., not using radioisotopes), in that imaging is not predicated on physical
changes in tissue and structural anatomy. In this manner, the chemical and physical
processes occurring in a living organism can be mapped. Examples of nuclear and non-
nuclear imaging modalities have been included below in Table 1.1.1.
Table 1.1.1: Imaging capabilities used in medical assessment and treatment
“Non-Nuclear” Imaging Capabilities Nuclear Imaging Capabilities
Magnetic Resonance Imaging (MRI) Single Photon Emission Computed
Tomography (SPECT)
Computed Tomography (CT)
Scintigraphy
Photoacoustic
Ultrasonography
Positron Emission Tomography (PET)
Optical
1.2 Overview of Nuclear Imaging
Nuclear medical imaging uses radionuclides, which are combined with existing
pharmaceutical compounds to create radiopharmaceuticals. Please see Fig 1.2.1 for a
schematic of the nuclear imaging process. The radiopharmaceutical is then administered
to the patient in either oral or intravenous form. Upon entering the body, the
radiopharmaceutical attaches to a specific cellular receptor on an organ. Radioactive
decay of the radionuclide ensues and in the process, gamma rays and/or subatomic
particles are emitted. A gamma camera translates the gamma ray information into a
readable image, which is then analyzed in order to formulate a diagnosis and proceed
with recommendations for treatment options.

Fig 1.2.1: Nuclear imaging overview schematic

2. Nuclear Medical Imaging Fundamentals

2.1 Gamma Camera
The gamma camera is used extensively in nuclear imaging modalities, and is also
referred to as the scintillation camera and the Anger Camera, after Dr. Hal Anger of the
University of California, Berkeley, who developed the camera in 1964. The resulting
pictures from the camera capture the distribution of gamma ray or positron-emitting
isotopes in vivo. The resulting pictures are similar to those yielded from a mechanical
scanner and are generated in less time. The camera is sensitive to all body structures in
the field of view during the exposure time, thus the camera does not physically scan over
a region in the classical sense. [13]
A schematic of the gamma camera set-up in the imaging process has been provided in Fig
2.1.1 below. The gamma-ray photons emitted from the patient, as a result of radioactive
decay comprise the signal that passes into the camera through collimators. The collimator
narrows the beam by aligning the beam in a specific direction such that the spatial cross-
section of the beam is reduced. The signal then strikes the detectors or scintillators, which
are typically comprised of thallium-activated sodium iodide crystals. [13]
Fig 2.1.1: Schematic of gamma camera set-up

A close-packed hexagonal array of photomultiplier tubes are coupled to the crystal

through an optical light guide. The phototubes view overlapping areas in the scintillator,
and the light is subsequently divided among the photomultiplier tubes. The light spots
appearing on the crystal are then amplified in an amplifier. The scintillations are
reproduced on an oscilloscope as point flashes of light in the same relative positions in
which they occurred in the scintillator. An analog computer is then able to identify the
positions, which are outputted in <x,y> position co-ordinates, and the brightness of each
spot occurring in the crystal. The flashes which are photographed over a period of time
are then synthesized in order to create an image of the subject. [13]
The collimation method of choice is dependent on the sensitivity and resolution required
for a given subject (i.e., structural component of the body) and the radionuclide [13]. For
example, metastable technetium-99 (Tc-99m) will undergo gamma emission, thus
pinhole and multichannel collimation methods could be selected for imaging purposes.

Table 2.1.1: Nuclear imaging collimating methods

Positron Coincidence Pinhole Multichannel
Subject Size Small Small Large
Large
Emission Positron Gamma Gamma
Based on the type of radionuclide, which thereby influences the type of emission, and the
size of the subject, a collimator is chosen that will produce the best sensitivity and
resolution as per Table 2.1.1. A multichannel collimator (MCC) contains several holes in
the collimator, and of the three collimating methods listed in Table 2.1.1, the MCC is
mostly used due to its versatility. The main advantage of the MCC is the flexibility to use
various combinations of hole diameters, lengths and thicknesses. Challenges lie in the
mathematical analysis of the resulting image. Certain shapes or irradiated areas that
appear on the image are dependent on the shape of the holes, their distribution pattern
within the collimator, as well as the placement of the point source of interest with respect
to the positions of the holes. When pinhole and positron coincidence collimating methods
are used, the point source in the subject of interest is imaged as a disc on the scintillator.
However with MCC, the gamma rays that are emitted from the point source can strike the
scintillator in several areas as they may travel through more than one hole to reach the
detector. [13]
2.2 Radioisotopes
Chalk River Laboratories in Chalk River, Ontario, Canada supply 33% of the global
supply of radioisotopes, and most of the North American supply. 99Mo is produced from
the fission of 235U, and following its extraction, it is shipped to radiopharmaceutical
storage facilities across North America. This is done within a few days of being
produced, as it has a half-life of 2.75 days (66 hours). 99Mo undergoes a β – decay
reaction as per:
99
Mo® 99m Tc + e - + v e
and releases the metastable 99Tc compound, 99mTc. 99mTc is then administered to the
patient via a radiopharmaceutical and decays inside the patient to its ground state 99Tc.
This decay results in the emission of a gamma photon, which is then detected by a
gamma camera.
Select radioistopes along with their uses have been summarized in Table 2.2.1 for
reference based on a compilation of various literature studies.
Table 2.2.1: Select nuclear medical isotopes [17,41]
Half Life Type of
Isotope Imaging Device Subject Scanned
(min) Emission
18
F 110
11
C 20
15 Brain, heart
O 2
13
N 10 PET Positron
64
Cu 762 Tracer
124
I 6004.8 Tracer
82
Rb 3900 Myocardial perfusion
123
I 780 Thyroid
99m
Tc 2160 Heart muscle, brain, thyroid,
SPECT,
lungs, liver, spleen, kidney, gall
Scintigraphy
bladder, bone marrow, salivary
Gamma gland, lacimal gland
133
Xe 7488
81m Lung
Kr 0.0036
201 Scintigraphy
Tl 1752 Cardiac tissue, low-grade
lymphomas

3. Non-Nuclear Medical Imaging Modalities

A description of Magnetic Resonance Imaging (MRI) and Computed Tomography (CT)
have been included in sections 3.1 and 3.2 respectively, and have been critiqued based on
their uses, strengths and limitations in imaging studies.
3.1 Magnetic Resonance Imaging
MRI is predicated on nuclear magnetic resonance, and does not make use of ionizing
radiation. Strong magnetic field gradients cause nuclei at different locations to rotate at
different speeds. The gradients in each direction can be used to construct a 3-dimensional
image [14]. MRI provides appreciable spatial and contrast resolution. The strong spatial
resolution allows the ability to distinguish two separate structures that are separated from
each other by a short distance. The strong contrast resolution allows distinction between
two similar tissues. Based on these abilities, MRI provides appreciable contrast between
various soft tissues and is used widely in imaging of the brain, heart, muscles and various
cancers. [14,15,16]
3.2 Computed Tomography
Tomography is the imaging by sections through any kind of penetrating wave. Several
tomographic capabilities have been listed in Table 3.2.1 with their associated penetrating
wave for reference.
Table 3.2.1: Tomographic imaging capabilities
Imaging Capability Type of Penetrating Wave
Computed Tomography (CT) X-ray [17]
Single Photon Emission Computed Gamma ray [17]
Tomography (SPECT)
Magnetic Resonance Imaging (MRI) Radiofrequency [14]
Positron Emission Tomography (PET) Positron-electron annihilation [17]
In computed tomography, narrow X-ray beams are made at several projections around an
object in transmission. These transmission measurements are inputted to a tomographic
reconstruction software algorithm from which 3-dimensional images, or tomograms, are
formed. [17]
Table 3.2.2: Advantages and disadvantages of computed tomography
Advantages Disadvantages
High resolution from multiple projections Ionizing radiation exposure
Strong indicator of anatomical Adverse reaction to contrast agent
structures/changes
Artifacts
Since data is collected from multiple projections, the resulting tomogram has a high
resolution. New multidetector CT machines with near isotropic resolution allow the
scanner to produce data that can be reconstructed in any desired plane without losses in
image quality [16]. Furthermore, CT is a powerful tool for indicating changes in
anatomical structures [17]. A summary of key advantages and disadvantages have been
provided in Table 3.2.2 for reference.
The patient receives a higher ionizing radiation dose in the process of generating a higher
resolution tomogram [16,17]. Radiopharmaceuticals used in CT emit ionizing radiation
that travels short distances within the body. This radiation could cause damage to
surrounding local cells and organs. Depending on the extent of damage, these structures
could display unwanted side effects. There is a trade-off between the risk of radiation-
induced damage versus not receiving assessment and treatment.
Contrast agents are injected into the blood stream in order to enhance the contrast of a
certain structure or fluid. Some patients experience allergic reactions to select contrast
agents. Contrast agents of choice in CT applications are those which contain elements
having a higher atomic number than that of the surrounding tissue, such as iodine and
barium based contrast agents. [16,17] CT excels at imaging tissue made of elements of
higher atomic number than that of its adjacent tissue.
In comparison with MRI, contrast agents, which have paramagnetic properties, are
chosen for MRI applications, such as gadolinium-based chelates. Studies based on similar
dosage levels indicate that gadolium chelates are safer than iodine-based compounds,
which are typically used in CT studies. In particular gadolinium chelates have lower
nephrotoxicity, or a less detrimental impact on the kidneys when compared with iodine-
based contrast agents. [18,19] Therefore patients suffering from kidney damage are better
suited to undergo MRI testing as opposed to CT. However there is a low, but not one that
can be ignored, risk of nephrogenic systemic fibrosis in patients who suffer from an
advanced and severe form of kidney failure who would require dialysis following
imaging treatment with certain gadolinium-containing agents [18,19]. Thus gadolinium-
containing contrast agents are only administered to patients when necessary and dialysis
is performed following the scan in order to immediately remove the gadolinium from the
body. [19]
CT-specific artifacts, or disturbances in the image, are also prevalent. Streaking is an
observed phenomenon that is seen around structures, such as bone or metal implants, that
can block X-rays [16]. This phenomenon is not commonly prevalent with solid tumours
in the abdomen and the chest, which is why CT-based technologies are a preferred choice
for solid tumors imaging and therapy [20]. A difficult parameter to regulate is the
thickness of the image slice. When the slice thickness is great, blurring ensues, as the
scanner has difficulty in differentiating between small amounts of high-density material
and large amounts of low-density material. The scanner is unable to reconcile these
differences and a distorted image is produced. If the slice thickness is insufficient, this
might result in a low signal to noise ratio, and the signal would not be able to penetrate
through the region of interest in the anatomy. [17]
A summary of key advantages and disadvantages of CT and MRI has been provided in
Table 4.1.2.

4. Nuclear Medical Imaging Modalities

4.1 Positron Emission Tomography (PET)

PET relies on electron-positron annihilation, unlike SPECT and scintigraphy. In PET, a

radioactive tracer is injected into the blood stream, which then attaches onto a
biologically-active receptor on a cell. The tracer becomes concentrated in the local tissue,
and the concentration of tracer in the tissue is recorded as the tracer undergoes
radioactive decay. [17]
In order for position-electron annihilation to occur, the radionuclide that is selected for
the PET imaging must be one that undergoes β+ decay. These isotopes are typically made
in a cyclotron. In a β+ decay reaction, a positron is emitted and travels approximately 1
mm in the tissue. As the positron travels in body tissue, it loses kinetic energy and
decelerates until it can interact with an electron. The resulting encounter annihilates the
electron and positron, and results in the production of two gamma photons, which move
in opposite directions as per the following reaction:

e- + e+  2γ
The detection system must simultaneously detect the annihilation photon pair moving in
opposite directions. PET scanners use coincidence detection circuits instead of a physical
collimator, hence this detection method is also known as electronic collimation. The PET
scanner detects and localizes the simultaneous back-to-back annihilation photons. Since
the point of annihilation is close to the point of positron emission, this provides a good
indication as to the location of the radioactive atom was in the body. [17,21]
In comparison with single photon emission methodologies such as SPECT, although a
single detector can be used in PET, as is the case with SPECT, the detection and
localization of a single photon indicates little about where it came from in the body. In
technologies like SPECT, the direction of the photon can only be determined by using
absorptive collimation, which only allows photons emitted in a certain direction to
impinge on the detector. This therefore reduces the number of events that are detected for
a given amount of radioactivity in the body by at least one or two orders of magnitude in
comparison with electronic collimation. Electronic collimation also allows events to be
collected from several directions simultaneously, thus images can be constructed rapidly
using tomography. [16,17,22]
PET radionuclides are independent of the element involved or the energy of the emitted
positrons. They lead to the emission of two, 511 keV annihilation photons. The PET
scanner can be designed and optimized for imaging all positron-emitting radionuclides at
a single energy. A disadvantage of PET systems is that they cannot perform radionuclide
studies will multiple radionuclides and distinguish between the radionuclides based on
the energy of the emissions. The resolution of PET is limited by the positron range of the
selected radionuclide, the acolinearity of the annihilation gamma rays, and the intrinsic
spatial resolution of the detectors. For full-body PET scanners with large diameters,
blurring of image resolution due to acolinearity is approximately 2 mm full width at half
maximum, whereas for animal PET scanners, this effect may be ten times as small. When
radionuclides of small positron range, such as 18F and 64Cu are used, the image resolution
of most animal PET scanners is limited by the detector’s intrinsic spatial resolution.
[17,22,23]
PET can be used to trace the biological pathway of any radio-labeled compound. New
studies on Telmisartan, an antihypertensive drug, combined with 11C in order to assess
whole-body pharmacokinetics by measuring radioactivity uptake levels in the body [24].
In broader applications of tracing pathways, fluorodeoxy-D-glucose (FDG) has been a
long-standing radiopharmaceutical in PET applications. FDG is a glucose analog, where
one of the oxygen groups in the glucose molecule has been replaced by the radioactive
18
F. FDG is used in assessing healthy cell activity in brain, liver and cancer cells. In
particular, the presence and/or extent of Alzheimer’s disease is widely examined using
FDG. Since FDG is a glucose analog, the extent of its uptake provides an indication of
brain activity. FDG cannot proceed far in cellular respiration, and its metabolism is
terminated within the first stage of cellular respiration, glycolysis, due to the absence of
an oxygen atom. When the FDG is phosphorylated by hexokinase in the glycolysis stage,
the resulting FDG molecule is in a new conformation, which is not favourable in
proceeding onwards with cellular respiration. In order for the cellular respiration to
proceed, the phosphate group would have to be removed, which cannot be done by most
cells in the body, with the exception of liver and kidney cells. This results in FDG staying
trapped in the brain cells. [22,24]
The below image is a transaxial slice of the brain of an 80 year old female patient taken
from a PET scanner. Early Alzheimer’s disease affects the parietal, temporal and
posterior cingulate cortices of the brain. Defects in these regions are characterized by
asymmetry and mild hypometabolism of the left temporal cortex (C in Fig. 4.1.1 below),
which is indicative of low glucose uptake, or cold spots. Hot spots are indicative of high
tracer concentration, or high glucose uptake. Brain cells that have normal and healthy
activity will experience a high rate of glucose uptake. [12,22]

Fig 4.1.1: PET Transaxial slice of the brain [22]

Furthermore, FDG-PET results can serve as a prognostic tool to determine whether

cognitive decline could occur more quickly than is expected for normal brain activity at
the age, during the first several years after the initial PET evaluation [15,22,23].
There is on-going research being conducted on appropriate radiotracers for new target
molecules and processes. Table 4.1.1 contains the findings of select recent PET studies
focused on different radionuclides and their use in high-precision radiotherapy.
Table 4.1.1: Radionuclide choices for high-precision radiotherapy [16]
PET Tracer Variable Target
Clinical PET [18F]Choline
Prostate cancer
Studies [11C]Choline Lipid metabolism
[11C]Methionine
Brain tumour
[68Ga]DOTATOC Protein synthesis
[18F]Fluoromisonidazole Hypoxia marker Head-neck cancer
 lung cancer
11
[ C]Acetate Cell proliferation Prostate cancer
marker head and neck
[13N]NH3 Radiation necrosis Brain tumour
[18F]FLT Cell proliferation Murine SCCVII
Pre-clinical marker tumours
PET studies [18F]FBPA-F Boron carrier in boron Brain tumour
neutron capture therapy
In comparison with SPECT, PET can detect radionuclide concentrations as low as 10-12
mol/L. Furthermore its sensitivity is 106 times higher than that of MRI. Thus this makes it
a highly sensitive imaging modality. PET also has the ability to calculate the amount of
radioactivity that is specifically located in a given region, and based on signal intensity
differences, quantitative determinations can be made. [20,22]
Comparisons of PET as an imaging modality with CT and MRI have been included
below on Table 4.1.2.
Table 4.1.2: Advantages and disadvantages of CT, MRI and PET [16]
CT MRI PET
Patient
Fast scan Minimally invasive In PET-CT,
procedure anatomical and
functional
information
Strengths obtained in single
study
Potential to reduce motion No radiation
artifacts with correction associated with
methods imaging
High ionizing radiation Claustrophobia Long acquisition
exposure (smaller patient scan
bore)
Limitations
Complications in Intravenous
patients with loose injection of
metal implants radiopharmaceutical
Imaging
Strengths Highly accurate spatial Superior soft tissue Providing functional
information imaging with and biological
excellent spatial information
resolution
Electron density information Multiplanar Can detect
for dosimetry capability to image metastatic lesions
in any oblique plane that would have
been missed in
conventional
imaging
 Cortical bone information to Providing functional Assesses the spread
create digitally reconstructed information of certain varieties
radiographs of lymph nodes with
greater precision
than CT
Sub-optimal soft tissue Magnetic resonance Limited spatial
imaging image distortion resolution and lesion
detectability
Lack of functional and Lack of electron Important inter-
biological information density information observer variability
Limitations for dosimetry
Lack of cortical Variable effect of
bone information to thresholds or other
create digitally criteria used to
reconstructed define tumour
radiographs margins

A fundamental liming factor with PET is its reliance on radioisotopes with short half-
lives, as per Table 2.2.1. Cyclotrons are required in order to produce such isotopes, which
is a costly endeavour. Furthermore, the short half-life of the radioisotope often requires
that the cyclotron itself be located on-site at the treatment facility. 18O in particular has a
half-life of 2 minutes, thus the radioisotope would have to be pumped from the cyclotron
directly to the examination room [16]. Though there is an increasing prevalence of
hospitals acquiring cyclotrons, the uptake is slow.
4.2 Scintigraphy

In scintigraphy, the radiation from the gamma-emitting radionuclide is captured by the

Anger camera, and is then formed into a two-dimensional image. Scintigraphy is used in
the imaging of a variety of subjects including, but not limited to, the biliary system (bile
duct), lung, bone and the heart [25,26]. 99mTc is most commonly used in scintigraphy
applications due to its ability to target specialized endothelial cells in the body found in
bone marrow, spleen and liver [23]. Thus an intense signal can be generated which is
then interpreted by the gamma camera.
Lung scintigraphy is used in the diagnosis of pulmonary embolism, or the blockage of
main lung arteries. In a two-part scan process, ventilation is first analyzed when the
patient inhales gaseous xenon or a technetium-based pharmaceutical compound in aerosol
form. A perfusion scan follows, where the patient is given 99mTc macroaggregated
albumin by injection [25]. A gamma camera captures the results of the scans, as per
images ‘a’ and ‘b’ in Fig 4.2.1. In Fig 4.2.1, scintigraphy images from a rat lung are
compared with SPECT-based results. The fundamental limitation of scintigraphy is its
ability to generate solely two-dimensional images. The SPECT images in ‘c’ and ‘d’
show that lung morphology can be viewed from several angles by rotating the structure
along a desired plane, which thereby produces a more holistic view of the extent of
disease and tumor uptake. However scintigraphy continues to be used due to its lower
cost and greater availability. [23,25,27]
Fig 4.2.1: Scintigraphy and SPECT images of breast adenocarcinoma tumors in female rat lungs.
(a) normal female rat scintigraphy result; (b) tumor-bearing female rat scintigraphy result; (c)
normal female rat SPECT result; (d) tumor-bearing female rat SPECT result [27]

In the assessment of fractures in bone, 99mTc is combined with an existing pharmaceutical

compound, methyne-diphosphonate (MDP), which has an affinity for bone. When the
MDP-99mTc complex is injected into the blood stream, it is taken up in the calcium
hydroxyapatite mineral phase of the bone [25]. Analysis of the resulting 2-D image
shows regions of varying tracer uptake. Regions of high tracer concentration are
indicative of increased physiological function, which in this case, would be associated
with fracture.
In particular, high-sensitivity whole body examination can be achieved with skeletal
scintigraphy. It is a readily available technology and a cost-effective methodology in
hospitals and medical facilities. In comparison to X-ray based technologies, such as
computed tomography, skeletal scintigraphy is a more sensitive method of assessment.
99m
Tc-labeled phosphonate compounds are used in the process, and have an average
effective dose of 4 mSv, which is lower than CT-based methods. [23]
However skeletal scintigraphy has been found to lack specificity, as phosphonate has a
tendency to accumulate in various locations including, but not limited to, regions of
malignancy, infections due to fracture, arthritis, arthrosis and benign bone tumors [23].
This poses challenges in differentiating between specific processes, and thus complicates
subsequent treatment options.
Recent studies from 2005 onwards have reported that the early stages of skeletal
metastases in bone marrow and resulting bone deterioration can be detected using MRI
faster than scintigraphy [23,28,29,30,31]. Fig 4.2.2 below compares imaging scans
obtained from a 55-year old female with breast cancer. The two images on the left (a)
were obtained using skeletal scintigraphy, and the two images to the right (b, c), were
obtained using MRI. The scintigraphy-derived image does not indicate increased tracer
uptake in the axial regions, which is indicative of metastases. In contrast, the MRI-
derived image indicates regions of increased uptake as indicated by the white arrows in
Fig 4.2.2 b,c. However, the scintigraphy-derived image was able to capture metastasis of
a tumour on the left shoulder as is indicated by the black arrows in Fig 4.2.2 a, however
this was missed in the MRI-derived image, as the lesion was outside of the acceptable
field of view of MRI. [23]

Fig 4.2.2: Scintigraphy (a) and MRI (b,c) images from a 55 year-old female with breast cancer

As was the case with lung scintigraphy, SPECT, having a three-dimensional structure
imaging capability, allows for greater specificity and has a greater anatomical localization
of tracer accumulation [23, 27]. 18F-FDG is often used in such an applications, as it serves
as a measure of glucose uptake. In particular, enhanced glucose uptake is characteristic of
malignant cells [20].
4.3 Single Photon Emission Computed Tomography (SPECT)
In SPECT, gamma photons are emitted from the patient, and the gamma camera then
acquires two-dimensional images from multiple angles. A tomographic reconstruction
algorithm can then be used to combine the two-dimensional images to generate a three-
dimensional image. Based on the reconstructed image, slices can be view along any
desired axis of the body, which is similar to MRI, PET and CT [17].
Recent studies with SPECT use 123I-MIBG (Metaiodobenzylguanidine), which is
preferentially taken up by malignance cells associated with cancer types such as
neuroblastoma and thyroid cancer, in measuring cardiac activity [32,33]. The activity of
123
I-MIBG is measured in order to gauge the prognosis in patients with chronic heart
failure.
SPECT studies with 123I-MIBG have been performed since 1998 in the examination of
Merkel Cell Carcinoma, a rare malignant skin tumour which targets the epidermis layer
of the skin of the head and neck, and affects older patients. In Fig 4.3.1, the image on the
left is a CT scan, which shows a mass of dimensions 1.5 x 3 cm in the right eyelid, while
the SPECT image on the right shows increased activity of 123I-MIBG in the tumour of the
eyelid. Thus while CT alone is useful in staging the process of MCC, it is difficult to
quantitatively analyze and evaluate MCC using anatomical imaging alone. [32]

Fig 4.3.1: Right eyelid displaying tumour structure in CT image (left hand side) and tumor uptake
in SPECT image (right hand side) [32]

Based on perfusion studies, SPECT has been observed to have poorer spatial resolution
than PET images [22]. However SPECT uses radioisotopes that have longer half-lives,
and are easily obtained and procured (i.e., a cyclotron is not required).
SPECT is commonly used on-site when non-diagnostic scans are obtained during testing
[17]. A non-diagnostic scan or sample is one where the physician cannot determine
whether the subject being examined is benign or malignant. In the event that a non-
diagnostic scan is obtained from another nuclear medical imaging scan such as
scintigraphy or PET, the gamma camera can immediately be re-configured for SPECT
acquisition while the patient remains on the table [17].

The gamma camera is then rotated around the patient. A full 360° rotation is done for
optimal construction. Images are captured for every 3-6 degrees or rotation with 15-20
seconds per projection [17]. Alternatively, multi-headed SPECT cameras can be spaced
equally apart from each other in order to speed calculations.

5. Combined Capabilities

Analysis from the literature review indicates that after examining the advantages and
disadvantages of various nuclear and non-nuclear imaging techniques, one imaging
technique alone is not capable of imaging all subjects with perfect resolution and
negligible radiation exposure. A combination of modalities optimizes the strengths of
both imaging techniques involved. The radiation exposure is minimized by running both
modalities in one session. Single systems are continuing to be used depending on various
factors such as equipment availability, pre-existing health conditions of the patient and
the associated costs.
5.1 Positron Emission Tomography – Computed Tomography (PET-CT)
The PET-CT system was developed by Ronald Nutt and David Townsend, and was
named as Time Magazine’s Medical Invention of the Year in 2000. Images are acquired
from both PET and CT sequentially in the same session from the patient. The images
from both scans can then be combined to yield a single, superimposed two-dimensional
or three-dimensional image as per Fig 5.1.1 below.
Despite slow uptake due to high initial costs, its current uses include, but are not limited
to, oncology, surgical planning, radiation therapy and cancer staging.
Recent studies have been focused on the detection of Alzheimer’s disease since many
neurodegenerative diseases produce significant brain alterations in brain function, which
are detectable with SPECT, PET and PET-CT, though CT and MRI structural images do
not indicate any abnormality [23]. The combined PET-CT image in Fig 5.1.1 indicates
structural and metabolic information about the extent to which the disease has
progressed. Thus PET-CT can be used to determine the metabolic function of the brain in
the early detection of Alzheimer’s disease before is structurally and physically evident,
which will aid in less aggressive and less invasive treatment options.

Fig 5.1.1: Separate and combined CT, PET and PET-CT images of the human brain in the
detection of Alzheimer’s disease [12]

Recent studies using 82Rb in PET-CT have shown a 17% increase in the sensitivity of
image results and quality in patients with heart vessel-related disease. In this set-up,
cardiac and vascular anatomical abnormalities and their associated physiological
consequences can be identified in a single session using the combined capability of CT
and PET respectively. The combined system allows for the detection and the
quantification of the extent of calcified and non-calcified plaques that are responsible for
coronary artery disease. [20]
As is the case with all CT-based modalities, the major limiting factor to patients is the
higher ionizing radiation exposure. The effective radiation doses for adult patients
undergoing cardiac nuclear imaging range between 9.3 x 10-4 mSv/MBq with 15O-water
to 2.1 x 10-1 mSv/MBq with 201Tl-chloride [20[. Secondly, there is a higher cost
associated with the PET radionuclides used in PET-CT studies.
5.2 Virtual Pinhole PET (VP-PET)
Virtual Pinhole PET is a new imaging modality based on Pinhole SPECT, and is typically
used in the imaging of small regions with very high resolution [21,35]. A Pinhole SPECT
system, shown in Fig 5.2.1A is comprised of a pinhole collimator, a rotating mechanism
and a gamma camera. The set-up is designed to allow projection data to be collected from
several angles. The radiation is projected through the pinhole collimator onto the surface
of the gamma camera. [21]
However it has been shown that the sampling uniformity and the reconstructed image
resolution can be improved by perturbing the subject being imaged by introducing a
small offset between the centre of the detector and the centre of rotation in a PET system
itself [21,36,37,38]. This new geometry does not significantly deviate from traditional
PET geometry, and functions akin to a pinhole collimator, and is thus referred to as a
“virtual” pinhole [21].

Fig 5.2.1: Pinhole-SPECT set-up (A);VP-PET set-up (B) [21]

NB: COR means Centre of Rotation
The VP-PET set-up uses asymmetric detector sizes, which creates a region with high
spatial resolution near the small detector. This produces high spatial resolution for
localized regions of the body that are close to the surface, which is advantageous when
very specific and high resolution is required for certain regions [21,35]. Since VP-PET is
based on electronic collimation, its sensitivity is theoretically significantly greater than
that of Pinhole SPECT using multiple holes in the pinhole collimator [21].
However a drawback in VP-PET lies in the difficulty associated with increasing the
angular coverage and considering regions that are not close to the surface without
compromising the detection efficiency between high and low resolution detectors [35].
Hence its high resolution is limited by its small field of view. Certain imaging
applications involving brain and breast tissue would give a preference to a small field of
view in order to obtain high resolution results. Breast tissue studies with VP-PET have
shown that the activity concentration of 18F-FDG is approximately 32-fold higher than
that of whole-body PET, assuming that a 370 MBq dose of 18F-FDG was administered
intravenously and distributed evenly in a patient with a body mass of 70 kg following an
uptake period of 40 minutes [21].

6. The Future of Nuclear Medicine

Despite advancements and improvements in resolution and tomographic capabilities,
there still exist several practical concerns with nuclear imaging as a whole. Radioisotopes
associated with PET-CT and CT, are associated with high levels of ionizing radiation,
due to their longer half-lives. Current research efforts are focused on the selection of
radiopharmaceuticals that would emit radiation that travels a short distance within the
body. [16,24,39] This would limit adverse side effects and could ultimately limit the
damage to non-involved structures and/or organs. Current and newer studies in the area
of nuclear medical imaging point to the use of combined imaging systems using nuclear
and non-nuclear modalities.
Increasingly used modalities are SPECT-MRI and PET-MRI, which combine the
capability of PET and SPECT to image metabolic abnormalities associated with disease,
and the ability of MRI to image soft tissue. In a PET-MRI system, faster tomographic
reconstruction can be achieved due to electronic collimation. Furthermore, ionizing
radiation exposure could be limited in PET-MRI due to the use of isotopes with shorter
half-lives. Studies using SPECT-MRI systems have shown some success with specific
types of scar tissue in the heart. Such systems are vital in order to optimize the treatment
in patients who suffer from heart diseases such as ischaemic left ventricular dysfuntion.
Radiopharmaceuticals such as 99mTc-compounds in SPECT and 18F-FDG in PET would
provide metabolic information based on changes in myocardial perfusion and glucose
uptake respectively. The MRI modality provides information and the ability to visualize
scar tissue with high spatial resolution, which allows differentiation between different
scar tissue types, such as subendocaridal and transmural scar tissues. However, contrast-
enhanced MRI is limited in its ability to capture the physiology of myocardiam that is not
scarred. The incorporation of a nuclear imaging modality allows for the physiology of
non-scarred myocardium to be analyzed. [15,23]
Another approach would be in using VP-PET as a magnifying tool for a specific region
of interest as opposed to a replacement for a full-body PET scan [35]. In this scenario, if
further information or greater resolution is required for a specific target area following a
whole-body PET scan, one could switch to VP-PET and focus on that target area of
interest. [21,35]
There is an increasing shift in grouping nuclear medical imaging with molecular
medicine. The focus of this area of study would be based on the function and the usage of
imaging agents that are specific to particular disease process. Specific probes would be
investigated or developed in order to better characterize and quantify cellular and
subcellular processes.

Recent studies show the coupling of lipid nanoparticles, or liposomes, with copper-based
radionuclides, due to their ability to serve as scintigraphic radiotracers for the
visualization of tumours.

The favourable co-ordination chemistry of copper allows for the utilization of several
chelator systems that can be linked to biological molecules. In particular, 64Cu is useful in
PET applications due to its short positron range and low maximum positron energy, of
0.66 MeV. Thus the resulting images obtained from PET scanning are of a high
resolution and quality. Such initiatives provide greater insight on the nature of tumours,
and allow an enhanced ability in the visualization and quantification of drug
concentration and gene expression. Furthermore, the physiological function of cells in the
body can be monitored continuously and in a non-invasive manner.

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