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Vol. 5 • Issue 3 • 2011•3
THE NEWSLETTER OF THE SNM CENTER FOR MOLECULAR IMAGING INNOVATION AND TRANSLATION
Molecular Magnetic ResonanceINImaging
THIS ISSUE
FDA
Moves
Forward
on
Imaging
of the Kidney
LitBriefs
2
Amyloid in the Brain
ney, molecular imaging will play a role in
Importance of imaging in
biomarker
discovery advances
to detect in
early
seen tremendous
thedevelderenal diagnosishe past several years have
T
opment of CKD.
Kidney diseases
affect a large
velopment
of newportion
radiopharmaceuticals
for molecular imaging with
Severe CKD is characterized by reof the population worldwide. Of all chronic
positron emission tomography (PET). Despite the large number of
diseases, chronic kidney disease (CKD) and duced glomerular filtration rate (GFR), inpre-clinical
and early
clinical
studiesa in
the literature,
however,
dicating
failure
of the kidney
to suffionly
cientend-stage renal failure
are strikingly
comdissolved
solutes
mon. Chronic kidney disease of clinical ly excrete or reabsorb
Continued on page 2. See FDA.in
stage 3 or higher affects about 11 percent of the blood. Thus the total GFR is a stanadults over 65, and stages 1-4 affect about dard clinical measurement in patients with
13 percent of the population over 20 (1). suspected CKD or liver disease. Elevated
Several factors contribute to the prevalence serum creatinine, a derivative of liver creof renal disease, including genetic, envi- atinine, is another routine blood biomarker
ronmental and dietary conditions, and the for CKD. Both of these clinical biomarkers
presence of autoimmune disease. CKD has are highly insensitive to early development
a strong correlation with the development of CKD such as polycystic kidney disease,
of cardiovascular and heart disease. Unfor- diabetic nephropathy, and nephrotic synolecular
imaging
of silent
various
composcavenging
of insudated
lipid, oversee
their
because
of a combination
of comtunately,
CKD is
clinically
at its
early drome,
nents ofAsatherosclerotic
transformation
to foam
cells or mediate
cell
increases
in glomerular
filtration
stages.
early detectionplaques
of CKDhas
can been
lead pensatory
proposed,
and proofpatient
of principle
has been
death
(1).
uninvolved
nephrons and because of
to
greatly improved
outcomes
with in
demonstrated
in isexperimental
of variations
Molecular
targets
have also
included
in the
background
of blood
cretreatment,
there
a vital needmodels
for novel
disease
(1). These
preclinical
studiesprobes
have atinine.
events that
arevariations
associated
or conseThese
arewith
exacerbated
by
and
sensitive
molecular
diagnostic
predominantly
targeted
quentand
to kidney
inflammation,
such as producdisease, confounding
clin(2).
Since the early
onsetplaque
of CKDinflammacan start liver
tion with
premise
that theinextent
of ical
tion measurements
of cytokines and
metalloproteinases.
of renal
disease in these
with
a focalthe
lesion
or pathology
the kidinflammation would determine the vulner- Although these experimental molecular
ability of the plaque to rupture. Plaque in- imaging studies have offered significant
flammation has been detected by targeting promise, translational data in the clinical
alterations in monocytes that facilitate their setting has just started to emerge. Clinical
migration to the neointima, ensure efficient studies of molecular targeting are the major
Clinical Feasibility of Molecular
Imaging of Plaque Inflammation
in Atherosclerosis
M
TheMolecular
likelihood that atherosclerotic
plaques
result in acute vascular
Imaging
in will
Surgery
events ishile
intimately
associated
with thehas
morphologic
traits ofonthe
the nuclear
imaging community
traditionally focused
the plaque
development
W
of radiopharmaceuticals for diagnostic gamma scintigraphy, positron emission
andtomography
the extent(PET),
of inflammation.
and single photon emission computer tomography (SPECT) imag-
ing, a new imaging modality may bring molecular imaging into surgery and surgical pathology.
A plethora
of review.
preclinical studies havetion
shown
utility
of molecularly
targeted,
focus of the
following
and the
labeled
lipoproteins
to trace
their
near-infrared
fluorescence
imaging
agents
for
intraoperative
detection
of
cancer-positive
We have referred to some of the early destination in the inflammatory cells in
lymph
nodes
in headattempts
and neck,
breast,
and prostate
as well
as inthe
delineation
of
molecular
imaging
that
labeled
plaquescancers,
(1). Even
though
incorporatumor
margins.
Indeed,
several
groups
have
developed
and
demonstrated
the
feasibility
white blood cells to follow their localiza- tion of radiolabeled components in the
of peptide and antibody-based targeting agents that are dual-labeled for non-invasive PET
Continued on page 5. See Surgery.
patients. There are several
promising
MI in
the News blood
4
biomarkers of kidney disease in preclinical
to number
Sponsor of re5
and clinical trials, but aSNM
large
nal diseases are detected
early
only through
New RECIST
Guidelines
6
biopsy.
7
Journal and
Imaging techniques inMI general,
molecular imaging techniques
in particuMI Calendar
8
lar, are just recently being applied to problems in diagnosis and detection of CKD.
plaque
may not
have been
adequate,
these
The most
prevalent
imaging
technolostudies
created
sound
the
gies applied
to aimage
thefoundation
kidney areforx-ray
development
of imaging(CT),
strategies
of the
computed tomography
ultrasound
future.
imaging, and magnetic resonance imaging (MRI). Positron emission tomography
Pathologic
Basis of Inflammation
(PET) and single-photon
emission tomogImaging
raphy (SPECT) techniques for renal imagplaques
have
typically
large
ing Vulnerable
are important,
though
targeted
molecunecrotic
cores
that are
are relatively
covered by
thin
filar imaging
probes
new.
Each
brous
capsimaging
(2). Many
foam cells
seen
of these
modalities
has are
distinct
around
the and
necrotic
cores. There
extenadvantages
disadvantages
in issensitivsive
inflammation
within the
fibrous caps;
ity, resolution,
contrast
formation,
level
the
more macrophages,
the Athinner
cap.
of invasiveness,
and cost.
furtherthemajor
Migration
of monocytes
to the
consideration
in the future
rolesubintimal
of these
layers of the plaque is associated with deContinuedfor
on page
2. See Kidney MRI
velopment of receptors
chemoattractant
factors, such as monocyte chemotactic protein-1 (MCP-1); adhesion molecules, such as
vascular cell adhesion molecule-1 (VCAM-1)
(1); and expression of scavenger receptors,
IN THIS ISSUE
including SRAI/II, CD68 and FcRIII.
In addition
upregulation
of various
New to
Editor
for Molecular
Imaging sur5
face receptors, foam cells in the neointima
release numerous cytokines, Tech
suchCorner
as inter6
leukin-1, tumor necrosis factor-� and MCP1 (3). Activated macrophages also release
Industry Partners
Circle Meeting
7
metalloproteinases
and other
proteolytic
enzymes, such as cathepsins, which lead to
degradation of the matrix, thinning
of the fiMI in the News
7
brous cap and positive outward remodeling
of the vessel wall. Cell death
is commonly
New Board
Members ob8
Amyloid in the Brain
Continued on page 2. See Plaque.
CMIIT Awards
8
Kidney MRI. Continued from page 1.
techniques is how readily the developed probes can receive regulatory approval for clinical use. This ease of regulatory approval can
in fact drive the focus of technology development in specific modalities, apart from any advantages or disadvantages in diagnostic
ability. To its advantage, the combination of PET or SPECT detection with other imaging modalities will make it possible to coregister detected agents with high-resolution anatomical images.
The challenge for MR based molecular imaging is that new agents
are typically independent of previously approved compounds and
are therefore subject to lengthy toxicity and distribution studies
prior to clinical trial. However, there are several examples of sensitive MRI contrast agents, particularly in the area of MRI-based cell
tracking, that are being currently investigated in clinical trials (3).
Endogenous MRI contrast techniques to
measure renal function
2
MRI is a highly flexible imaging technology that uses radiofrequency (RF) electromagnetic pulses to detect and spatially localize
magnetic nuclei and the local magnetic environment of the nuclei
in three dimensions. Most commonly in clinical scanners, water
1
H nuclei are detected because of their high natural abundance. A
major advantage of MRI as compared to other imaging modalities
is its ability to provide rich soft-tissue contrast, even in the absence
of a contrast agent. These contrast mechanisms can be exploited
to generate an unprecedented, noninvasive view of renal function.
As an example, functional MRI is an important imaging technique
that takes advantage of a change in hemoglobin from the diamagnetic to paramagnetic state when it is converted from oxygenated
to deoxygenated form. This so-called blood-oxygenation level dependent (BOLD) contrast has been used to understand tubule dysfunction due to changes in oxygen extraction throughout the kidney (4). Renal functional imaging (5), is now being developed to
extract quantitative information about renal blood flow. Renal perfusion can also be assessed by noninvasive arterial spin labeling,
whereby blood is labeled by an RF pulse and tracked dynamically
as it moves into the kidney. This can be used to generate quantitative maps of local renal tissue perfusion (6). Another example of
an endogenous MRI technique that has been applied to study renal
function is diffusion-weighted MRI (DWI) (7, 8). In DWI, applied
magnetic field gradients are used to sensitize the MRI signal to the
random motion of water inside the tissue. Because water diffuses
throughout the cellular and extracellular microstructure during
the MRI scan, DWI provides an indirect view of the tissue microenvironment. The source of changes in apparent diffusion coefficient
(ADC), as measured by MRI, with changes in tissue microstructure
is an active area of investigation in the kidney and other organs.
Importantly, ADC may be correlated with glomerular filtration rate
(9). DWI has been further developed to assess allograft viability
after transplantation (10).
Passive MRI contrast agents
Paramagnetic ions, typically lanthanides and transition metals, have long been used as MRI contrast agents because of their
effect on the MR relaxation times of the surrounding water. FDA
www.molecularimagingcenter.org/ mi
approved MRI contrast agents include both gadolinium chelates
(e.g. Gd-dota, Gd-dtpa, Gd-do3a) and iron oxides. These approved agents include small molecules and larger macromolecules,
each with a unique biodistribution and clearance. Other macromolecular agents are in clinical trials or preclinical research, and
are developed specifically to reduce interstitial diffusion while allowing for glomerular filtration, as described in the literature (11).
Contrast-enhanced MRI techniques are being developed to measure glomerular filtration rate to eventually provide an accurate
imaging surrogate or replacement for standard GFR measurement
techniques (12). To date, all clinically approved contrast agents for
MRI are “passive” rather than targeted, and are typically used by
either nonspecific uptake into tissues with disrupted vasculature
or through measurements of dynamic changes in the uptake or
excretion rates. Because imaging agents of small molecular weight,
such as the lanthanide chelates, are typically rapidly excreted and
freely diffusing, the rate of excretion can be used as an indicator
of glomerular function. However, the lack of molecular specificity of these agents may be a disadvantage from the standpoint of
identifying specific aspects of renal dysfunction. These issues are
shared by freely diffusible iodinated tracers. Paramagnetic MRI
contrast agents are typically detected by T1-weighting the MRI
pulse sequence. T1 is a measured relaxation time that is shortened
by the presence of the contrast agent. Fast T1- weighted sequences
can provide dynamic measurements of separate phases of contrast
agent excretion and can be used in conjunction with mathematical
modeling to map agent pharmacokinetics (13 14).
Targeted MRI contrast agents
In addition to the clinically approved agents, there is a wide
range of innovative, targeted molecular imaging probes for preclinical MRI (16, 17). Many are available commercially and can
be bought pre-functionalized for ready attachment to targeting
ligands, antibody fragments, fluorophores or specific chemical
functional groups. Compared to other techniques, MRI is relatively
insensitive to the presence of the contrast agents. For example,
typical PET/SPECT agents are detected in pM-fM concentrations.
In contrast, many MRI contrast agents are detected in ~uM-mM
concentrations. This problem is being overcome through the development of high-relaxivity agents, more sensitive acquisition
strategies, and novel hyperpolarized agents with nuclear polarization 1,000-fold greater than traditional imaging agents (18).
Many of these probes are being used to assess excretion rates and
dynamic changes in renal function. Novel paramagnetic chemical
exchange saturation transfer agents (PARACEST) have been developed with specific off-resonance frequency spectra so that individual agents can be distinguished. Recently, PARACEST imaging was
used to detect TmDOTA-4AmC(-) accumulation and clearance in
the mouse kidney (19). Paramagnetic agents sensitive to renal pH
have also been synthesized (20).
Targeted contrast agents have been developed for molecular
MRI of the kidney. These targeted agents are typically paramagnetic or superparamagnetic contrast agents with a binding moiety
Continued on page 3. See Kidney MRI.
Kidney MRI. Continued from page 2.
Figure 1: 3D gradient-echo MRI of perfused rat kidneys before (left) and after
(right) the intravenous injection of cationic ferritin nanoparticles. The superparamagnetic nanoparticles accumulate in individual renal glomeruli through the
glomerular endothelial fenestrations and allow for whole-kidney measurements of
nephron endowment.
on the agent surface. When the agents are intravenously injected
they are targeted to the glomerulus or must pass through the glomerulus and bind to the tubule. For example, 13-nm nanoparticle
contrast agents can be targeted specifically to the glomerular basement membrane because they pass through ~80 nm fenestrations
in the glomerular endothelium. We have recently demonstrated
that cationic ferritin, a 13 nm superparamagnetic nanoparticle, accumulates in the glomerular basement membrane due to electrostatic binding to anionic proteoglycans. The accumulation of these
nanoparticles allows each glomerulus and nephron to be detected
with MRI (21). We have recently used this technique to measure
whole-kidney nephron endowment (22), as shown in Figure 1.
The in vivo application of these techniques will rely on advanced
image processing in order to overcome inherent limitations in
resolution, as well as the development of a fuller understanding
of binding kinetics of cationic nanoparticles as they attach to the
glomerulus.
Kidney transplants are commonly required for patients with
end-stage renal disease. The causes of transplant rejection are
poorly defined and are under active investigation. There is a vital
need to assess the structure and function of transplanted kidneys
before and after they are surgically implanted, both to ensure sufficient function to provide glomerular filtration and to quickly detect the early onset of rejection. As an example, macrophage infiltration has been identifed during transplant rejection by detecting
macrophages labeled with an MRI-detectable contrast agent (23).
Furthermore, there is a need for noninvasive techniques to study
the mechanisms of transplant rejection in large preclinical studies and in patient populations. Cellular imaging techniques have
also been used to detect inflammation and macrophage infiltration
during development of renal disease (24, 25).
Assessment of renal function is crucial to understanding the
metabolism and excretion of new therapeutic agents. Preclinical
toxicity screening is a major, costly requirement for regulatory approval of new compounds, and a majority of kidney screens are
performed by histological assessment and blood markers. Noninvasive molecular imaging could play a major role in accurate,
Figure 2: Example 3D (left) and corresponding 2D (right) SPECT/CT images of a
mouse four hours after the retroorbital injection of a high molecular weight dextran
targeted to the renal glomeruli. The retention of this agent within the renal cortex
is highly specific and its uptake primarily depends upon glomerular number and
volume within the kidney.
rapid, inexpensive measurements of toxicology and pharmacodynamics (26) and represents an opportunity to develop both functional MRI techniques and novel molecular probes to assess renal
viability.
Regulatory approval of new MRI contrast agents is relatively
slow compared to new compounds conjugated to radioligands.
Thus, PET/SPECT techniques are advantageous in that preclinical
studies can be rapidly translated to the clinic. The development of
novel radioactive agents for PET/SPECT imaging of kidney function
is a major area of research, as illustrated in Figure 2 (unpublished
figure, reproduced by permission from Drs. C. Chad Quarles and
Takamune Takahashi, Vanderbilt University Institute of Imaging
Science and the Vanderbilt O’Brien Kidney Disease Center). Here,
a high molecular weight dextran, tagged with 99mTc, is imaged
after it accumulates in the mouse glomerulus following retroorbital injection. Microscopic imaging of the optical analog to this
agent revealed that it is preferentially localized within the mesangium. Such an agent could potentially be used, both pre-clinically
and clinically, to quantitatively assess total nephron endowment in
vivo. A similar technique using high-molecular weight dendrimer
contrast agents has been used to specifically enhance the outer
stripe of the medulla (27). The modulation of contrast agent size
and surface charge may be an important way to provide specificity
of contrast agents to kidney structures, and may be a window into
localized function in these areas.
Conclusions
As the field of molecular MRI develops, a wide range of highly
sensitive agents will be available to investigate renal function, with
sensitivity to scientifically and clinically useful parameters such as
local pH, oxygenation, temperature, and metal ion content. Furthermore, the development of novel switchable agents such as
those being currently developed (28, 29), with on-off or one-way
contrast changes, will allow for detection levels on the order of
Continued on page 4. See Kidney MRI.
3
Kidney MRI. Continued from page 3.
those observed in PET/SPECT probes. Chemical and enzymatic
amplification techniques may be used to enhance the sensitivity
of MRI contrast agents. The outlook for MRI of the kidney will
depend to a large extent on the development of tools such as these
and an investment by both academic and industry partnerships
in moving these agents through regulatory approval. Nonetheless,
MRI holds a great deal of promise for highly sensitive measurement of renal function.
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11. Grenier N, P.M., and Hauger O Contrast agents for functional and cellular MRI of
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12. Grenier, N. et al. Measurement of glomerular filtration rate with magnetic
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13. Pedersen, M. et al. Quantitation of differential renal blood flow and renal function using dynamci contrast-enhanced MRI in rats. Magn Reson Med 51, 510-517
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14. Mandry, D. et al. Renal functional contrast-enhanced magnetic resonance
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imaging contrast agents. Methods Mol Med 124, 7-400 (2006).
17. Artemov, D., Bhujwalla, Z. & Bulte, J. Magnetic resonance imaging of cell surface receptors using targeted contrast agents. Curr Pharm Biotechnol 10, 485-494
(2004).
18. Viale, A. & Aime, S. Current concepts on hyperpolarized molecules in MRI. Curr
Opin Chem Biol 14, 90-96 (2010).
19. Vinogradov, E. et al. MRI detection of paramagnetic chemical exchange effects
in mice kidneys in vivo. Magn Reson Med 58, 650-655 (2007).
20. Raghunand, N., Howison, C., Sherry, A., Zhang, S. & Gillies, R. Renal and
systemic pH imaging by contrast-enhanced MRI. Magn Reson Med 49, 249-257
(2003).21. Bennett, K.M. et al. MRI of the basement membrane using charged
nanoparticles as contrast agents. Magn Reson Med 60, 564-574 (2008).
22. Beeman, S.C. et al. Measuring glomerular number and size in perfused kidneys
using MRI. Am J Physiol Renal Physiol 300, 1260-1266 (2011).
23. Zhang, Y., Dodd, S., Hendrich, K., Williams, M. & Ho, C. Magnetic resonance
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27. Kobayashi, H. et al. Renal tubular damage detected by dynamic micro-MRI with
a dendrimer-based magnetic resonance contrast agent. Kidney Int 61, 1980-1985
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28. Jastrzebska, B. et al. New enzyme-activated solubility-switchable contrast
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By Kevin M. Bennett, PhD, School of Biological and Health Systems Engineering,
Arizona State University
SNM 2010-2011 president, Dominique Delbeke, MD, PhD, presented (L to R) Todd E.
Peterson, PhD, Carolyn J. Anderson, PhD, and Henry F. VanBrocklin, PhD, as well as
Peter S. Conti, MD, PhD and Michael D. Devous, PhD (not pictured) with awards at
the SNM President’s Reception for championing the SNM Bench to Bedside campaign,
which concluded in June.
www.molecularimagingcenter.org/ mi