Download Molecular imaging: Techniques and current clinical applications

Molecular imaging: Techniques
and current clinical applications
David Bonekamp, MD, PhD, Dima A. Hammoud, MD, and Martin G. Pomper, MD, PhD
T
he Task Force of the Society of
Nuclear Medicine (SNM) Molecular Imaging Center of Excellence (MICoE) defines molecular
imaging as the “visualization, characterization and measurement of biological processes at the molecular and
cellular levels in humans and other living systems.”1
In the context of translation into
clinical practice, molecular imaging
would perhaps better be known as
“molecular diagnostic imaging,” to
distinguish it from “classical diagnostic imaging.” Unlike the latter, molecular imaging goes beyond structural
assessment, and probes disease-specific abnormalities at the molecular
level, putting it at the frontiers of biomedical science where new genetic
and molecular causes of disease are
continually being discovered.
However, molecular imaging is not a
new concept. For example, positronemission tomography (PET) has
proved capable of imaging molecular
processes such as blood flow in the
brain and other organs using O-15
water, as early as the 1970s.2 Yet, molecular imaging has only recently been
Dr. Bonekamp is a resident and Dr.
Pomper is a professor in the Russell H.
Morgan Department of Radiology and
Radiological Science, Johns Hopkins
Medical Institutions, Baltimore, MD;
and Dr. Hammoud is a Staff Clinician,
Department of Radiology and Imaging
Sciences, National Institutes of Health/
Clinical Center, Bethesda, MD.
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defined as a separate field. This was
probably instigated by the completion
of the human genome project in April
20033,4 and the recognition that many
diseases have molecular and cellular
causes. It is now recognized that imaging of processes intrinsic to metabolism, cell signaling and gene expression
is possible. The evolution of our
knowledge of molecular mechanisms
of disease and the progress of imaging
technology are happening rapidly and
in parallel, fostering their combined
application in molecular imaging.
Molecular imaging systems
Simply put, a molecular imaging
system typically consists of a target, an
agent and an imaging modality. Molecular imaging necessitates the interaction of the target with a “labeled” agent
that can be detected externally by one
or more modalities.
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Agent-target interaction
Three major ways of agent-target
interaction are recognized (Figure 1).
Targeted binding: Here, the labeled
agent selectively binds to its target, for a
long enough period to allow external
detection by an imaging modality. One
example is neuroreceptor imaging in the
brain, such as with 11C-raclopride,
which binds to the type-2 dopamine
receptor. The interaction is detected
externally by PET imaging (Figure 1A).
Imaging agent accumulation in the
cell: This usually results from enzymatic action that modifies the structure
of the agent. The best example is 18Ffluorodeoxyglucose (FDG), which,
once inside the cell, is acted upon by
hexokinase, resulting in a phosphorylated version that can neither cross the
cell membrane again nor undergo glycolysis. This results in the accumulation
of FDG in highly metabolic cells, such
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FIGURE 1. Different types of molecular imaging agent-target interactions. Targeted binding
(A), imaging agent accumulation in the cell (B) and activation of imaging agent by cellular
components (C).
FIGURE 2. Molecular genetic imaging. A reporter gene (e.g., HSV1-tk gene) is genetically
linked to a promoter of the endogenous gene of interest. When the gene of interest is
expressed, both the endogenous gene product and the reporter-gene product (HSV1-tk, protein) are produced. HSV1-tk then acts on its substrate (labeled probe such as 124I-FIAU),
which gets phosphorylated and is trapped in the cell, thus enabling imaging using PET.
Detection of uptake on PET indicates (indirect) expression of the gene of interest.
as in cancer or infection/inflammation.
The interaction can be detected externally by PET imaging (Figure 1B).
Activation of imaging agent by cellular components: The cellular components are usually enzymes, resulting in
signal amplification. One example is
bioluminescence in which the luciferase
enzyme expressed by the target cell acts
May 2010
on injected luciferin. Emitted light is
then detected externally by specialized
cameras (Figure 1C).
Agent labeling and amplification
strategies
Prior to agent-target interaction, substantial work goes into the labeling
process of the imaging agent. The most
common labeling method is probably the
use of modified injectable agents adapted
from known drugs/molecules.5-10 For that
purpose, the in vivo characteristics of the
labeled molecules need to be determined
first. Favorable characteristics include,
high specific activity of the label (to
avoid drug toxicity and preserve tracer
characteristics); high site selectivity and
specificity; appropriate binding affinity;
suitable hydro/lipophilicity and size
(which govern transport across barriers);
suitable metabolism (metabolites are
likely to carry the label but exhibit
altered specificity); low immediate excretion (renal, hepatic) or sequestration
(drug resistance transporters, phagocytes); low non-specific binding (as
the background signal reduces contrast);
and, the ability to achieve high local
concentrations.11-15
Limitations of the use of injectable
molecular imaging agents of different
modalities can be explained to a great
extent by their pharmacological properties. For example, ultrasound contrast
agents (in the form of microbubbles)
and magnetic resonance imaging (MRI)
iron nanoparticles are relatively bulky,
and are restricted by body membranes
such as the vascular endothelium, the
blood-brain barrier or the cell membrane; they are restricted much more
than low–molecular-weight agents.16-25
Radionuclide-based labeling techniques,
on the other hand, provide the ability
of replacing atoms of biological molecules with their radioisotopes, resulting
in radiolabeled injectable agents that ideally are chemically identical (same size,
chemistry and charge) to their unlabeled
state. Positron-emitting radioisotopes
lend themselves to these techniques,
because they include the lower–massnumber elements of the periodic system,
which are major components of biological molecules, such as carbon, nitrogen,
fluorine and oxygen.5,7,8,26-38
Another form of labeling is indirect,
using reporter genes. This constitutes
the basis of molecular genetic imaging.
In this case, a reporter gene (the product of which can be detected externally), is genetically linked (ex vivo) to
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FIGURE 3. B-mode ultrasound image of the left kidney of a 9-week-old mouse (A) and the same kidney following intravenous administration of
ultrasound contrast and application of power Doppler (B). The kidney vasculature is visualized to the level of the interlobular vessels (arrows); A
= aorta. (Reprinted, with permission, from the Annual Review of Biomedical Engineering, Volume 9 ©2007 by Annual Reviews
www.annualreviews.org).
FIGURE 4. Bioluminescence image of a
mouse bearing a U87 human glioma tumor,
which was engineered to express firefly
luciferase stably in a proliferation-dependent
manner. When the tumor is exposed to Dluciferin, light is emitted and can be
detected, generating an image. (Image
courtesy of Hyo-Eun Bhang, PhD, Baltimore, MD)
a promoter of the gene of interest in
such a way that when the gene of interest is expressed, the reporter gene
product (protein) is produced, enabling
imaging (Figure 2). One such example
is the use of the herpes simplex virus
type 1 thymidine kinase gene (HSV1tk) as a reporter gene. When the gene
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of interest is expressed in the cell, the
HSV1-tk gene is simultaneously transcribed to HSV1-tk mRNA and then
translated to TK. TK can then phosphorylate one of its substrates, such as
iodine-124 fluorodeoxy arabinofuranosyl iodouracil (124I-FIAU). The
phosphorylated 124I-FIAU cannot cross
the cell membrane and is sequestered
within the cell, becoming amenable to
PET imaging. The phosphorylated 124IFIAU is thus an indirect indicator of
the expression of the gene of interest.39-42 Many new imaging agents for
human reporter genes are subject to
active research in anticipation of their
use in human gene therapy.
In contradistinction to indirect labeling, direct cell-labeling techniques are
also used in molecular imaging to
introduce a label into cells in vitro,
before transplantation. One example is
the use of the highly derivatized crosslinked iron oxide nanoparticle
(CLIO–HD) to label killer lymphocytes ex vivo prior to reintroduction of
the labeled cells into the system.43
These iron oxide particles provide
strong negative contrast when imaged
with MRI. After reintroduction of the
labeled cells, the 3-dimensional distribution of infiltrating T-cells across the
whole tumor can be detected using
MRI, with simultaneous assessment of
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both cellular recruitment and therapeutic efficiency.43
Molecular imaging modalities
There are 4 main categories of molecular imaging modalities: ultrasound,
optical imaging, MRI and nuclear medicine techniques. The choice of the
imaging modality is determined based
on the temporal and spatial resolution;
field of view; sensitivity of the imaging
system; depth of the biological process;
the molecular or cellular process to
image (protein vs. cell); and, the availability of suitable probes and labels that
can be delivered to the imaging target.
Ultrasound
Molecular imaging with ultrasound
commonly utilizes specialized contrast
agents, usually in the form of small
acoustically active gas-filled microbubbles that possess high echogenicity,
sufficient to elicit signal from as little
as a single microbubble (femtoliter
~10-15 liter volume). The microbubbles
are often coated with lipids, proteins or
polymers, with diameters of >1µm,20
which confines them to the intravascular space. This is why relevant targets
are usually those expressed on the
endovascular structures or intravascular cells such as angiogenesis, inflammation and intravascular thrombi.16
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The use of ultrasound in molecular
imaging is largely limited to animal
applications (Figure 3). Excellent
reviews on the use of ultrasound in
combination with targeted microbubbles and ultrasound-induced drug
delivery exist.17-20
Optical techniques
Optical techniques include 2 major
classes: fluorescence and bioluminescence imaging. Fluorescence refers to
the property of certain molecules (fluorophores) to absorb light at a particular
wavelength and to emit light of a longer
wavelength after a brief interval known
as the fluorescence lifetime.44 Fluorescent reporters carry such fluorophores.
Two-dimensional planar fluorescence
reflectance imaging (FRI) technology
has evolved into 3-dimensional fluorescence-mediated tomography (FMT),45,46
which is capable of deep tissue penetration, using sophisticated computational
analysis methodology to reconstruct the
in vivo distribution of intravenously
injected fluorescent probes.47 Photon
wavelength influences the depth resolution of optical imaging techniques.
Near-infrared photons currently provide
the greatest wavelengths (650 nm to 900
nm) and the best depth of penetration
(>1 cm).
Bioluminescence imaging uses
reporter genes that lead to expression of
luciferase proteins. Upon injection of
the substrate, luciferin, light is emitted
as a result of a chemical reaction involving luciferase, luciferin, oxygen and
ATP. The emitted light is detected externally.48 As opposed to fluorescence
imaging, no excitation light is required.
Luciferase proteins are derived from
different organisms, such as bacteria,
fireflies, red and green click beetles, and
renilla reniformis (sea pansy). Firefly
and red click beetle luciferases emit
longer wavelength photons.49
Optical imaging techniques are
characterized by their spatial resolution varying from several millimeters
to micrometer resolution, and by their
excellent sensitivity. However, their
use is limited to small animals and sur-
May 2010
face and fiber optic imaging in nonhuman primates and humans (Figure 4).
MRI technique
While MRI provides very high resolution (up to 10 µm) and unlimited
depth of penetration, it is, however,
limited by low sensitivity, with
detectabilities in the milli- to micromolar (10-3 to 10-6) range.50 Therefore,
amplification techniques are often
needed to image molecular processes
in vivo.
The best recognized MRI amplification technique is the use of iron oxide
particles as contrast agents. These provide negative MR contrast through
local increase of the relaxivity (R1 and
R2) of the tissue.51-55 Superparamagnetic iron oxide (SPIO) particles are
becoming increasingly popular as they
provide the strongest contrast available
for MR imaging, while they are
biodegradable by cellular enzymes.
Their surface coating dextrans facilitate linking to ligands.56 Detection is
possible at micromolar concentrations
of iron, and sensitivity is sufficient for
T2*-weighted imaging.52
Cells labeled with iron oxide are
used for monitoring of cell trafficking
in vivo. The labeling can be done
through systemic IV injection of the
particles, which are then incorporated
inside macrophages through phagocytosis. The migration of macrophages
can then be monitored externally using
MRI (Figure 5).57-59 Labeling can also
be performed through in situ injection
of iron oxide particles near areas of
stem-cell formation such as the subventricular zone of the brain.60,61 The most
common technique though is in vitro
labeling of cells prior to injection.62-64
Nuclear medicine techniques
Nuclear medicine techniques provide
practically unlimited depth penetration
and have very high sensitivities, in the
nanomolar (10-9) range.65,66 Production
of radiotracers with high specific
radioactivity yields detectable radioactivity while maintaining low pharmacological doses. Although PET and single
photon emission computed tomography
(SPECT) cause radiation exposure and
have relatively low resolution (2 mm to
5 mm for PET, 8 mm to 12 mm for
SPECT),65,66 nonetheless they are the
most commonly used human molecular
imaging modalities. As a result of
applicability of the tracer principle to
radiopharmaceuticals used in human
studies (only a very small quantity of
the radiopharmaceutical is introduced,
too small to exert any pharmacologic
effect), the United States Food and
Drug Administration (FDA) approval
of new radiopharmaceuticals is generally much less complicated than for
other modality imaging agents.
PET tracers are, in general, easier to
quantify; reliable kinetic modeling is
established for many tracers. PET has
approximately 100 times higher sensitivity than SPECT, in large measure due
to the ability to avoid using collimators
during imaging.67 The most commonly
used PET radionuclides are 11C (halflife ≈ 20 min) and 18F (half-life ≈110
min). SPECT tracers, in general, have
longer half-lives, allowing the study of
molecular processes that evolve over
longer times. SPECT provides many
readily useable radiotracers, and a local
cyclotron is not needed for operation.
Small animal molecular imaging
Small animal molecular imaging represents the vast majority of molecular
imaging applications at the present time.
This mirrors the fact that molecular
imaging is becoming an integrated and
indispensable tool for modern life sciences. Medical application is expected
for the most successful, least harmful
and most reliable techniques, and clinical usefulness remains the true final
proving ground.
Molecular imaging in small animals
is facilitated by the adaptation of the
imaging systems. Preclinical smallanimal imaging PET, SPECT, MRI and
CT scanners68-75 provide high-resolution imaging. Also, there is increasing
availability of mouse models of human
diseases, such as cancer, atherosclerosis and neurological diseases.76-83
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FIGURE 5. Conventional MRI (A,D,G) obtained 24 hours after the administration of lymphotropic superparamagnetic nanoparticles (B,E,H) and corresponding histologic findings
(C,F,I). A normal lymph node in the left iliac region shows homogeneous decrease in signal
intensity due to the accumulation of superparamagnetic nanoparticles (arrows in A and B).
Histology documents normal lymph node architecture (C). A normal-sized iliac lymph node
shows no drop of signal after administration of superparamagnetic particles due to complete
replacement by tumor (arrows in D and E) which was validated by histology (F). Partial
replacement of the lymph node by tumor results in partial drop of signal (arrows in G and H).
This was also validated by histology (Panel I).
Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult
lymph node metastases in prostate cancer. N Engl J Med. 2003;348:2491–2499. (Reprinted,
with permission, from The New England Journal of Medicine, ©2003 Massachusetts Medical
Society. All rights reserved.)
Current applications of
molecular imaging
Oncology
Translational molecular imaging
brings promising experimental therapies and diagnostic tests to the clinic,
after extensive evaluation in experimental models. Frequently used
modalities include PET and SPECT, as
well as a few MRI applications. Optical techniques and ultrasound applications remain of limited use (for reasons
outlined previously) but they retain
high potential. For example, fluorescence imaging is being investigated as
an enhancement of fiber-optic detection of colon cancer.84,85
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FDG is the most widely used molecular imaging agent in oncology. Since its
inception as a marker of metabolism in
tumor cells, FDG has played a major
role in the diagnosis, evaluation and follow-up of different tumors, including
lymphoma, lung cancer, brain cancer,
head-and-neck tumors, melanoma, and
breast cancer (Figure 6).86-108 Unlike
normal cells, where glycolysis is inhibited by the presence of oxygen (Pasteur
effect),109,110 FDG uptake in tumors is
reflective of increased glycolysis, even
in the presence of oxygen (aerobic glycolysis or Warburg effect),109 which is
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facilitated by overexpression of glucose
transporters and glycolytic enzymes in
malignant cells.111-114
However, FDG-PET has limitations.
For example, in brain tumors, FDG use
is limited by high background uptake of
the tracer, since the brain uses glucose
as its main source of energy (Figure
6).115 The use of FDG-PET in prostate
cancer is also limited by low tracer
uptake of tumor cells which can overlap
with uptake in benign prostate hyperplasia (BPH)116-118 and the anatomic
location of the prostate gland in close
proximity to the urinary bladder.119
Such limitations have instigated the
evaluation of alternative molecular and
cellular targets, such as amino acid
transport, DNA synthesis, fatty acid
metabolism and angiogenesis.
Proliferating tumor cells are characterized by increased amino acid transport across the cell membrane120, which
can be evaluated using radiolabeled
amino acids such as 11C-methionine
(MET).120,121 In brain tumors, the superiority of MET over FDG in the evaluation of disease extent, surgical planning,
evaluation prior to stereotactic biopsy,
follow-up and evaluation for recurrence, has been demonstrated.122-130
This is probably due to the lower background uptake of MET, resulting in
higher tumor-to-background ratios and
better visualization of the tumor. The
main limitation, however, is in the short
half-life of 11C prohibiting smooth clinical translation. 18F-labeled amino acids
are thus being evaluated, such as 18FFET,131,132 18F-DOPA133,134 and 18FACBC.135,136
DNA synthesis is another molecular
imaging target in tumors. Imaging of
thymidine kinase 1 (TK1), an enzyme
overexpressed during the DNA synthesis
phase of the cell cycle, reflects cellular
proliferation.137-140 18F-Fluorothymidine
(FLT)29,30,141,142 is a radiolabeled nucleoside analog that is phosphorylated by
TK1, rendering it unable to leave the cell.
FLT has been successfully used in the
original evaluation as well as the followup and assessment of treatment response
in many tumors such as lung cancer143,
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FIGURE 6. 39-year-old woman with right frontoparietal glioblastoma multiforme (GBM) presenting for follow-up. FDG PET scan (A), corresponding enhanced T1-weighted scan (B) and
fused images (C). Markedly increased FDG uptake in the right frontoparietal region, corresponding to heterogeneous enhancement on MRI (arrows), is compatible with viable highgrade tumor. Note physiologic increased FDG uptake in the left cerebral hemisphere.
lymphoma144, head-and-neck cancer145,
and breast cancer (Figure 7).146
Besides nuclear medicine techniques,
MR applications of molecular imaging
in oncology exist, such as the use of
coated iron oxide particles to detect
metastatic disease in lymph nodes or the
liver.23,147-150 When injected systemically, iron oxide particles that are phagocytosed by macrophages are then
transported to the lymph nodes. A
metastatic lymph node, in which the
normal macrophage population has been
replaced by tumor cells, will demonstrate partial or no drop in signal, while a
normal lymph node, in which the iron
particles have localized, will have
decreased signal and provide detailed
characterization independent of typically accepted size criteria (Figure 5).23
Inflammation and infection
FIGURE 7. 49-year-old patient with history of non-Hodgkins lymphoma, with suspected partial
response to treatment. FDG (A) and FLT (B) PET scans demonstrate increased FDG and FLT
uptake corresponding to enlarged level II cervical lymph nodes, compatible with residual disease (small black arrows). Note increased physiologic uptake of FLT in the bone marrow
(solid black arrow). (Courtesy of Esther Mena Gonzalez, MD, and Peter Choyke, MD,
Bethesda, MD.)
May 2010
Increased FDG uptake can be seen
in infectious/inflammatory conditions
since FDG-PET does not target a molecular process that is specific for neoplasia but rather uses the relative
increase in glucose metabolism of neoplastic cells over normal parenchymal
cells. The main limitation of using
FDG in inflammation imaging, thus, is
its lack of specificity. In fact, FDG
uptake of benign tumors, inflammatory
processes and malignant neoplasms
can sometimes overlap.151-153
To improve differentiation between
neoplastic and infectious/inflammatory
processes, multiple molecular imaging
targets of infection/inflammation have
been evaluated mostly in animals, with
few human applications at this point.
Examples of human applications include the use of monoclonal antigranulocyte antibodies, such 99mTc-fanolesomab
(NeutroSpec®, Palatin Technologies,
Cranbury, NJ), which binds the CD15
antigen expressed on neutrophils.154-158
Antibody fragments are slightly more
popular due to lower immunogenicity
and faster clearance, such as 99mTclabelled sulesomab (LeukoScan®,
Immunomedics Inc., Morris Plains, NJ)
which was found to be as accurate as
white blood cell scanning in osteomyelitis
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FIGURE 8. 124I-FIAU PET-CT scan of a patient with suspected infected left hip prosthesis.
Axial fused PET and CT image of the left femur at the distal end of the prosthesis shows
increased radiopharmaceutical uptake. Surgery documented an MRSA infection.
and soft-tissue infections159,160 as well
as prosthetic joint infections.161,162
Radiolabeled antibiotics, on the other
hand, have been used to directly target
bacteria, rather than reactive cells. The
best known is probably 99mTcciprofloxacin (Infecton®, DRAXIMAGE, Kirkland, Quebec, Canada)163,164
which has been evaluated in a multitude of infectious entities such as acute
cholecystitis,165 spinal infections,166
and abdominal infections.167
Recently, 124I-FIAU168,169 PET-CT
has been found to be useful in imaging
musculoskeletal bacterial infections.170
In that study, the substrate specificity
difference between bacterial TK and
the major human TK was exploited to
develop a new imaging technique that
can detect the presence of viable bacteria (Figure 8).170
Neuroimaging and
neurodegeneration
FIGURE 9. PET images of a 67-year-old healthy control (HC) subject (left) and a 79-year-old
Alzheimerʼs disease (AD) patient (right). The left column shows lack of PIB retention in the entire
gray matter of the HC subject (top left) and normal FDG uptake (bottom left). The right column
shows high PIB retention in the frontal and temporoparietal cortices of the AD patient (top right)
and a typical pattern of FDG hypometabolism present in the temporoparietal cortex (arrows; bottom right) along with preserved metabolic rate in the frontal cortex. (Annals of Neurology, Vol. 55,
No. 3, 2004, 306–319. ©2004; reprinted with permission of John Wiley & Sons , Inc.)
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Alzheimer’s dementia (AD) is the
most common cause of dementia and
earlier diagnosis is sought for more
accurate prognosis and education of the
patients and their families. Several
gene therapy trials are attempting to
halt or even reverse progression of
AD.171-175 In AD, decreased FDG
uptake is seen, reflective of regional
impairment of cerebral glucose metabolism, mostly in neocortical association
areas, whereas primary visual areas, the
sensorimotor cortex, basal ganglia, and
cerebellum are relatively well preserved.176 FDG-PET abnormalities
however are not pathognomonic of AD.
Alternative molecular imaging targets
are sought for higher specificity. The
most intuitive targets are the pathologic
associates of AD, namely neurofibrillary tangles (NFTs) and amyloid
plaques (APs). Novel PET and SPECT
ligands for NFTs and APs are under
investigation, most of which are
derived from known histologic staining
agents used in AD such as DDNP,177-179
thioflavins S and T180-185, and
stilbenes.178,186-188
Perhaps the best known amyloid ligand
currently is the 11C-labeled Pittsburgh
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compound B (PIB). The development
of this compound from the initial investigations in mouse models of AD189-191
to the first applications in humans was
extraordinarily fast (Figure 9).192-195 In
the earliest studies, AD patients
showed increased retention of PIB in
association cortex areas known to contain large amounts of amyloid deposits
in AD, compared with controls.192
However, “cognitively normal” controls with higher-than-normal PIB
uptake were noted,196-199 raising the
possibility of those subjects being predisposed to develop AD. If this is
proven in prospective larger studies,
PIB could potentially be a useful diagnostic tool for detection of disease prior
to the onset of symptoms, which can
help maximize the benefits of therapy.
However, PIB suffers from the short
physical half-life of 11C such that 18F
amyloid-binding derivatives are
actively being pursued. Other ligands
investigated as AP and NFT markers
include 18F-FDDNP,200,201 6-iodo-2-(4’dimethylamino) phenyl-imidazo[1,2a]pyridine (IMPY) derivatives,202,203
and 11C-SB-13.204-205
Conclusion
In summary, molecular imaging is
undergoing constant change and is
rapidly expanding. It spans all current
life sciences and is being utilized at the
frontiers of modern research. For the
clinical radiologist, the future will bring
application of molecular imaging techniques into the standard diagnostic
workflow. Radiology will continue to
be enhanced as knowledge from molecular biology, genomics and proteomics,
neuroscience and molecular physiology
continues to be integrated into imaging
research and, eventually, practice.
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