Imaging angiogenesis
Lawrence W Dobrucki and Albert J Sinusas
Angiogenesis represents the formation of new capillaries by
cellular outgrowth from existing microvessels and plays a
critical role in the response to ischemia associated with
peripheral arterial disease and myocardial infarction. Imaging
of angiogenesis would be valuable in risk stratification of
patients with arterial occlusive disease. The progress in
noninvasive imaging strategies to assess angiogenesis has
been made possible with the availability of many technological
advances, which include dedicated hybrid SPECT-CT and
PET-CT systems and agents targeted at molecular markers of
the angiogenic process, involving both receptor–probe
interactions and reporter gene technology. These novel
targeted approaches for imaging angiogenesis will
complement standard imaging of physiological parameters and
will play a crucial role for evaluation of therapeutic interventions
to promote angiogenesis.
Addresses
Animal Research Laboratories, Section of Cardiovascular Medicine,
Department of Internal Medicine, Yale University School of Medicine,
PO Box 208017, 3FMP, New Haven, CT 06520-8017, USA
Corresponding author: Sinusas, Albert J (albert.sinusas@yale.edu)
Current Opinion in Biotechnology 2007, 18:90–96
This review comes from a themed issue on
Analytical biotechnology
Edited by Joseph C Wu and Jagat Narula
Available online 19th January 2007
0958-1669/$ – see front matter
# 2007 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.copbio.2007.01.005
Introduction
Angiogenesis, defined as the formation of new capillaries
by cellular outgrowth from existing microvessels into
avascular tissue, is an underlying process in many human
diseases including cancer, congestive heart failure, ather-
osclerotic plaque, and peripheral artery disease. This
process in turn can be enhanced or impaired in different
pathological states such as diabetes, resulting in blinding
ocular disorders or lower limb ulceration and amputation,
respectively.
The ability to selectively target and image neovascular-
ization is an attractive strategy that represents a novel
approach to noninvasively monitor angiogenesis and to
assess the efficacy of therapies directed at modulation of
the angiogenic process. This review presents the authors’
Current Opinion in Biotechnology 2007, 18:90–96
view on some of the most relevant imaging strategies
to assess angiogenesis and includes a brief overview of
both current technological advances and applications to
evaluate myocardial and peripheral angiogenesis.
Noninvasive imaging modalities to assess
angiogenesis
The recent progress in new molecular imaging tech-
niques would have been impossible without significant
advances in imaging technology and instrumentation.
Several imaging modalities are currently used or under
development; however, only a few are ideally suited for
molecular imaging of biological processes in vivo. Table 1
presents selected operational parameters for different
imaging modalities and the potential advantages and
disadvantages for targeted imaging of angiogenesis.
X-ray computed tomography (CT) and ultrasound
approaches provide primarily anatomical information at
high spatial resolution; however, these techniques suffer
from the lack of readily available targeted probes.
Recently, efforts have focused on the development of
ultrasound probes to monitor biochemical processes
including angiogenesis at a molecular level [1–4]; how-
ever, these probes tend to remain intravascular and might
have limited sensitivity. Magnetic resonance (MR) ima-
ging is another popular imaging modality that offers
superior spatial resolution and penetration depth and
provides both anatomical and functional information.
Despite lack of widely available MR-compatible molecu-
lar probes and relatively low sensitivity, novel strategies
can be employed to overcome these limitations, which
include MR signal amplification using nanoparticles.
A limited number of studies have employed highly para-
magnetic nanoparticles to track angiogenesis by targeting
avb3 integrins [5,6], which are activated during the
initiation of the angiogenic process.
Imaging modalities such as optical imaging that provide
non-anatomical information have recently gained substan-
tial interest for tracking gene expression in vivo due to the
superior sensitivity of this technology. ATP-dependent
bioluminescence is based on the conversion of luciferin
to photon-emitting oxyluciferin. Visible photons are then
detected and quantified with charge-coupled device
(CCD) cameras. By contrast, fluorescence imaging is based
on the use of green (GFP) or red (RFP) fluorescent proteins
that emit visible photons in response to excitation by an
external energy source. The versatility of optical imaging
has been demonstrated by numerous studies; however, this
approach involves planar imaging of subcutaneous struc-
tures owing to the very low penetration depth, attenuation
www.sciencedirect.com
 Imaging angiogenesis Dobrucki and Sinusas 91

Table 1

Selected operational parameters for different imaging modalities and their potential advantages and disadvantages.

Modality Resolution spatial temporal Penetration Sensitivity Advantages Disadvantages

depth (mol/l)
11 12
PET 10 s to minutes No limitation 10 –10 Very high sensitivity Fundamentally limited
High throughput spatial resolution
11
C, 18F imaging Lack of anatomical
Attenuation correction information
Expensive
10 11
SPECT 0.5–1.5 mm Minutes No limitation 10 –10 High sensitivity Attenuation-associated
High resolution accuracy limit
Multiple isotope imaging Size of reporter probes
Availability of tracers and
Instruments
15 17
Optical: 3–5 mm Seconds to 1–2 mm 10 –10 Superior sensitivity Very low penetration
bioluminescence minutes depth
Optical: 2–3 mm Seconds to <1 mm 10 9–10 12
Lack of anatomical
fluorescence minutes information
MRI 25–100 mm Minutes to No limitation 10 3–10 5
Superior spatial resolution Lack of targeted
hours Anatomical imaging probes
Expensive
CT 25–200 mm Minutes No limitation – Superior spatial resolution Use of X-radiation
Anatomical imaging Lack of targeted
probes
Ultrasound 50–500 mm Seconds to mm–cm – Availability Lack of targeted
minutes Anatomical imaging probes
Low penetration depth

of low energy photons, and lack of widely available tomo-
graphic instruments.
The nuclear imaging techniques based on positron emis-
sion tomography (PET) or single-photon emission com-
puted tomography (SPECT) offer favorable sensitivity
and resolution for in vivo tomographic imaging. Based
on the limited (nanograms) amount of a molecular
probe needed to obtain a detectable signal, and on the
large number of radioactive atoms per unit mass, it is
quite feasible to perform molecular imaging with trace
amounts of radiolabeled compounds that will not cause a
pharmacological or biological effect [7]. Both PET and
SPECT have advantages and disadvantages based on the
underlying physical and chemical differences, thus the
choice of method should be based on the availability of a
molecular probe and accessibility to SPECT or PET
instrumentation. The major fundamental limitation of
SPECT is the attenuation of low-energy photons by body
tissue and less established approaches for attenuation
correction, making SPECT less quantitative than PET.
Although PET permits more accurate attenuation correc-
tion, this approach has a functional limitation related to
spatial resolution. The variable movement of positrons
before annihilation, and the deviation of the generated
511 keV photons from the exact 1808 angular separation,
can limit the resolution. Many PET radiotracers have a
short half-life, which allows for repetitive imaging. By
contrast, SPECT has the potential for simultaneous
imaging of multiple readily available isotopes (99mTc,
111
In, 125I, 123I, etc.) and allows for easy validation of the
radiotracer retention and biodistribution using gamma-
well counting of tissue specimens.
Although, both PET and SPECT imaging enables a
relative precise localization of radiotracer retention, these
approaches do not provide true anatomical information.
To overcome this limitation, hybrid systems have been
introduced including SPECT-CT and PET-CT. The CT
component of these systems is used to relate tracer signal
with anatomical landmarks and to create attenuation
maps to correct for non-uniform attenuation.
Until quite recently, all commercially available PET or
SPECT scanners were designed primarily for human use.
With increasing interest from basic science investigators
in targeted molecular imaging, dedicated small animal
imaging systems have been designed. Several groups of
investigators successfully constructed microPET systems
with the spatial resolution and sensitivity sufficient to
delineate tracer uptake in small animals [8–12], which led
to the construction of commercially available scanners
[11]. Unfortunately, as mentioned before, PET technol-
ogy suffers from a fundamental limitation of spatial
resolution (Table 1) and the higher expense of the
microPET systems. Recent effort has been invested in

www.sciencedirect.com Current Opinion in Biotechnology 2007, 18:90–96

92 Analytical biotechnology

developing microSPECT systems as a lower cost alterna-
tive to microPET. Commercial hybrid microSPECT-CT
systems are now available from multiple vendors. For
most of these systems pinhole collimation is employed to
achieve adequate spatial resolution (<1 mm). For some
applications, the low sensitivity associated with pinhole-
collimation of microSPECT instruments is a limiting
factor; therefore, recent efforts have been devoted toward
the construction and evaluation of multipinhole collima-
tors or coded aperture plates. The multiple pinhole
approach is an extension of conventional single pinhole
collimation. Multiple pinholes (>5) are arranged in such a
way that the resulting image is partially overlapped. This
approach requires novel reconstruction algorithms
[13,14], although it increases the sensitivity of the system
with little degradation of resolution. Commercial
multiple pinhole microSPECT systems are currently
available. Coded aperture imaging offers a higher sensi-
tivity alternative approach that is based on multiple pin-
holes arranged in the form of a mathematically encoded
mask pattern [15,16]. The resulting image is a set of
overlapped pinhole projection images that requires post-
processing ‘decoding’, which yields a clear image of the
object. This technology still remains in development
phase, however, theoretically it will permit high-resol-
ution imaging with preserved count statistics and high
signal-to-noise ratio.
scintigraphic tracers for hypoxia imaging. The action of
these agents is based on the selective trapping of reduced
nitroimidazoles within hypoxic cells. Experimental stu-
dies have shown the potential of the positron-emitting
18
F-labeled misonidazole [19,20] and 99mTc-labeled
nitroimidazoles [21–24] to detect hypoxic tissue.
Hypoxic events trigger the activation of matrix metallo-
proteinases (MMPs) to degrade the extracellular matrix
(ECM; Figure 1b). A clear cause-effect relationship
between MMPs and angiogenesis has been demonstrated
in experimental animal models. Although MMPs are
implicated in an early angiogenic response, most of the
imaging studies were done in animal models of myo-
cardial [25,26] and vascular remodeling and lesion devel-
opment [27,28], where MMPs play a key role. Following
activation of MMPs, the angiogenic sprouting is initiated
by vascular endothelial growth factor (VEGF) and modu-
lated by interactions between the ECM and adhesion
molecules such as integrins (Figure 1c). Angiogenesis is
modulated by several local and circulating angiogenic
factors including VEGF, angiopoietins (Ang-1 and Ang-
2), and basic fibroblast growth factor (bFGF). VEGF and
integrins (particularly avb3 integrin) have been identified
as favorable targets for imaging angiogenesis, and inves-
tigators have focused on the development of probes for
these specific targets.

Imaging angiogenesis
Figure 1
The major consequence of angiogenesis is restoration of
perfusion and oxygenation of ischemic tissue; therefore,
the angiogenic process can be assessed by the evaluation
of standard physiologic parameters such as regional myo-
cardial perfusion, function, and metabolism. Although
preclinical animal studies have demonstrated the benefit
of angiogenic therapy, recent clinical trials focused on the
stimulation of myocardial or peripheral angiogenesis by
the local delivery of growth factors were somewhat dis-
appointing, showing no clear benefit over placebo in
patients with severe ischemia [17,18]. Most of these
studies evaluated angiogenesis using standard clinical
endpoints or by looking for a physiological improvement
(i.e. improvement in perfusion). These approaches may
have insufficient sensitivity to detect a therapeutic benefit.
Indeed, there is a need for the development of noninvasive
imaging strategies for the direct noninvasive evaluation of
molecular events associated with angiogenesis, including
local proliferation and migration of vascular smooth muscle
and endothelial cells as well as participation of blood-
derived macrophages and circulating stem cells.

In the setting of ischemia due to either obstructive

coronary artery disease or peripheral arterial disease there
is a decrease in perfusion and an increase in hypoxia
(Figure 1a). These physiological changes can be assessed
with routine SPECT or PET perfusion imaging. More
recently, radiolabeled nitroimidazoles have been used as
Possible molecular targets for the molecular imaging of angiogenesis. (a)
The obstruction of flow causes a decrease in perfusion and distal
hypoxia. (b) Hypoxic events trigger the activation of matrix
metalloproteinases (MMPs) that degrade the vascular wall followed by
(c) activation of VEGF and adhesion molecules such as integrins
associated with endothelial cell proliferation and migration.

Current Opinion in Biotechnology 2007, 18:90–96 www.sciencedirect.com

 Imaging angiogenesis Dobrucki and Sinusas 93

Recent studies using VEGF121 as a targeting ligand
labeled with 111In have proved the feasibility of targeted
SPECT imaging in a rabbit model of peripheral angio-
genesis [29]. Others have demonstrated the use of
64
Cu-labeled VEGF121 for microPET imaging of VEGF
receptor expression in angiogenic vessels of mouse tumors
in vivo [30]. Reporter gene technology has been employed
by Wagner et al. [31] to identify successful adenoviral
transfer and subsequent expression of VEGF121 in porcine
myocardium. The same group successfully co-registered
CT images enhancing PET-determined biologic data by
defining morphology and contractile function of myo-
cardium. Such identification of VEGF receptors could
provide a tool to select the sites for local delivery of
angiogenic factors or therapeutic gene vectors.
Regulatory peptides represent another group of ligands
for targeting angiogenesis. Numerous studies have been
initiated to track angiogenesis using avb3 integrin as a
target [18]. These studies initially involved the use of

Figure 2

Targeted imaging of peripheral angiogenesis in murine model of hindlimb ischemia. (a) In vivo avb3-targeted planar pinhole images of control mice
and mice at variable time points after femoral occlusion were obtained following injection of 99mTc-NC100692. ‘Hot spots’ reflective of avb3
activation were shown in the ischemic hindlimb distal to the occlusion on days 3 and 7 and decreased on day 14. (b) Imaging analysis
provided quantification of the radiotracer ischemic-to-nonischemic retention ratio, which was confirmed by gamma-well counting of the ratio
of radiotracer activity in ischemic to nonischemic contralateral hindlimb (c). (Figure reprinted from [32] with permission.)

www.sciencedirect.com Current Opinion in Biotechnology 2007, 18:90–96

94 Analytical biotechnology

anti-avb3 antibody; however, owing to slow clearance and
low sensitivity this approach has been abandoned. Animal
studies with RGD (Arg-Gly-Asp)-containing peptides or
peptidomimetics that target integrins have demonstrated
that this approach can be used to successfully track
angiogenesis in vivo [32,33]. An 111In-labeled quino-
lone, which binds to avb3 integrin, was used for both
in vitro and in vivo imaging of myocardial angiogenesis in
canine and rodent models of myocardial angiogenesis
[33]. Others have used 123I-labeled RGD peptide for
targeted imaging of peripheral angiogenesis in a murine
model of hindlimb ischemia [34]. Shortly after this initial
report, Hua and coworkers demonstrated the potential of
99m
Tc-labeled RGD peptide (NC100692, GE Health-
care, UK) for targeted imaging of angiogenesis in a
murine model of peripheral angiogenesis using high-
resolution pinhole planar and microSPECT imaging
(Figure 2) [32,35]. These investigators used the same
approach to assess myocardial angiogenesis (Figure 3) in
mice lacking the gene for MMP-9 [36]. Others have
demonstrated 18F-galacto-RGD PET imaging to assess
tumor angiogenesis in patients [31] or the use of a 99mTc-
labeled derivative for SPECT imaging of integrin acti-
vation [37]. To complement the strengths of two imaging
modalities and to further improve the retention of avb3
radioligands, Liu et al. [38] recently developed multi-
meric (composed of several identical subunits) cyclic
RGD-peptide constructs with bifunctional chelators to
incorporate 99mTc or 64Cu for SPECT and PET imaging,
respectively. These multimeric RGD peptides showed

Figure 3

Targeted imaging of angiogenesis in murine model of myocardial infarction. (a) Representative in vivo dual isotope 201Tl and 99mTc-
NC100692 microSPECT/CT images are shown for wild-type and MMP-9-null mice. MicroSPECT short axis images are co-registered with
microCT images and demonstrate the 99mTc-NC100692 uptake in areas of angiogenesis (red) associated with a 201Tl perfusion defect (green)
and CT anatomy (grayscale). The areas boxed in white in the images on the left are enlarged in the images on the right. Uptake of the avb3-targeted
radiotracer is seen within the anteriolateral infarct (white solid arrow). 99mTc-NC100692 activity is also seen in the liver. (b) By well counting, the
relative uptake of the 99mTc-labeled avb3 peptide NC100692 was found to be higher in MMP-9 null mice (n = 7), compared with wild type mice
(n = 10), in the infarct region (0–40% non-ischemic region). This observation suggests augmentation of the angiogenic process. *p < 0.05 for
wild-type versus MMP-9 null. (Figure reprinted from [36] with permission.)

Current Opinion in Biotechnology 2007, 18:90–96 www.sciencedirect.com


increased binding affinities in vitro and improved tracer
accumulation compared with the monomeric compounds,
proposing their use in imaging of myocardial or peripheral
angiogenesis [39].
More recently, the novel RGD pharmacophore NC-
100717 was derived from a phage display library and was
reported to be a potent and selective binder of both avb3
and avb5 integrins [40]. From NC-100717 several con-
jugates were derived that allow for applications spanning
several imaging modalities, such as fluorescence (Cy5.5),
PET (18F or 68Ga), and SPECT (99mTc) imaging.
Other markers of angiogenic endothelium and their ligands
have been identified by phage display experiments. The
NGR (Asn-Gly-Arg) peptide motif has a threefold higher
efficacy for the detection of angiogenic vessels than RGD
peptide. The vascular target for NGR has been identified
as CD13, a membrane-bound glycoprotein, which is
expressed on new, but not quiescent, vessels. Preliminary
studies using fluorescent quantum dots labeled with NGR
peptide demonstrated specific binding to myocardial endo-
thelium in angiogenic areas [41].
Conclusions
The angiogenic process is a crucial component of the
natural response to ischemic injury. The non-invasive
evaluation of the physiological consequences of ischemic
injury and angiogenesis remain important; however,
direct molecular imaging of angiogenesis can be used
in both preclinical development and clinical applications
as discussed. The future of targeted imaging of angiogen-
esis rests on both the development of targeted biologic
markers, reporter gene techniques to evaluate gene
therapy, and novel imaging instrumentation. Despite a
clear future of targeted imaging of these molecular and
physiological processes associated with angiogenesis, the
scientific community should be aware that excitement
derived from scientific curiosity can lack a practical focus.
Development of ideal new strategies to assess angiogen-
esis and the translation of these imaging approaches to
patients can only be accomplished through close collab-
oration of multidisciplinary teams with a wide range of
expertise. Novel targeted imaging strategies complement
standard imaging of physiological parameters and such
hybrid approaches are likely to play an important role for
both diagnostic and prognostic purposes as well as for
evaluation of therapeutic interventions.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
 of special interest
 of outstanding interest
1. Blankenberg FG: Molecular imaging: the latest generation
of contrast agents and tissue characterization techniques.
J Cell Biochem 2003, 90:443-453.
www.sciencedirect.com
Imaging angiogenesis Dobrucki and Sinusas 95
2. Dayton PA, Pearson D, Clark J, Simon S, Schumann PA, Zutshi R,
Matsunaga TO, Ferrara KW: Ultrasonic analysis of peptide- and
antibody-targeted microbubble contrast agents for molecular
imaging of alphavbeta3-expressing cells. Mol Imaging 2004,
3:125-134.
3. Leong-Poi H, Christiansen J, Heppner P, Lewis CW, Klibanov AL,
Kaul S, Lindner JR: Assessment of endogenous and therapeutic
arteriogenesis by contrast ultrasound molecular imaging of
integrin expression. Circulation 2005, 111:3248-3254.
4. Leong-Poi H, Christiansen J, Klibanov AL, Kaul S, Lindner JR:
Noninvasive assessment of angiogenesis by ultrasound and
microbubbles targeted to alpha(v)-integrins. Circulation 2003,
107:455-460.
5. Winter PM, Caruthers SD, Kassner A, Harris TD, Chinen LK,
Allen JS, Lacy EK, Zhang H, Robertson JD, Wickline SA et al.:
Molecular imaging of angiogenesis in nascent Vx-2 rabbit
tumors using a novel alpha(nu)beta3-targeted nanoparticle
and 1.5 tesla magnetic resonance imaging. Cancer Res 2003,
63:5838-5843.
6. Winter PM, Morawski AM, Caruthers SD, Fuhrhop RW, Zhang H,
Williams TA, Allen JS, Lacy EK, Robertson JD, Lanza GM et al.:
Molecular imaging of angiogenesis in early-stage
atherosclerosis with alpha(v)beta3-integrin-targeted
nanoparticles. Circulation 2003, 108:2270-2274.
7. Blankenberg FG, Strauss HW: Nuclear medicine applications in
molecular imaging. J Magn Reson Imaging 2002, 16:352-361.
8. Chatziioannou A, Tai YC, Doshi N, Cherry SR: Detector
development for microPET II: a 1 microl resolution PET scanner
for small animal imaging. Phys Med Biol 2001, 46:2899-2910.
9. Chatziioannou AF, Cherry SR, Shao Y, Silverman RW, Meadors K,
Farguhar TH, Pedarsani M, Phelps ME: Performance evaluation
of microPET: a high-resolution lutetium oxyorthosilicate PET
scanner for animal imaging. J Nucl Med 1999, 40:1164-1175.
10. Knoess C, Siegel S, Smith A, Newport D, Richerzhagen N,
Winkeler A, Jacobs A, Goble RN, Graf R, Wienhard K et al.:
Performance evaluation of the microPET R4 PET scanner for
rodents. Eur J Nucl Med Mol Imaging 2003, 30:737-747.
11. Tai C, Chatziioannou A, Siegel S, Young J, Newport D, Goble RN,
Nutt RE, Cherry SR et al.: Performance evaluation of the
microPET P4: a PET system dedicated to animal imaging.
Phys Med Biol 2001, 46:1845-1862.
12. Yang Y, Tai YC, Siegel S, newport DF, Bai B, Li Q, Leahy RM,
Cherry SR: Optimization and performance evaluation of
the microPET II scanner for in vivo small-animal imaging.
Phys Med Biol 2004, 49:2527-2545.
13. Liu Y-H, Rangarajan A, Gagnon D, Themen M, Sinusas AJ,
Wackers FJT, Zubal IG: A novel geometry for SPECT imaging
associated with the EM-type blind deconvolution method.
IEEE Trans Nucl Sci 1998, 45:2095-2101.
14. Meng LJ, Clinthorne NH: A modified uniform Cramer-Rao
bound for multiple pinhole aperture design. IEEE Trans Nucl Sci
2004, 23:896-902.
15. Schellingerhout D, Accorsi R, Mahmood U, Idoine J, Lanza RC,
Weissleder R: Coded aperture nuclear scintigraphy: a novel
small animal imaging technique. Mol Imaging 2002, 1:344-353.
16. Tsui BMW: Initial development and evaluation of multi-pinhole
image acquisition and reconstruction methods for small
animal SPECT. J Nucl Med 2004, 45(Suppl.):156P.
17. Dobrucki LW, Sinusas AJ: Cardiovascular molecular imaging.
Semin Nucl Med 2005, 35:73-81.
18. Sinusas AJ: Imaging of angiogenesis. J Nucl Cardiol 2004,
 11:617-633.
Comprehensive review on biology of angiogenesis and imaging strategies
to assess the angiogenic process in vivo. Recent clinical trials to promote
angiogenesis in myocardial and peripheral arterial diseases are discussed.
19. Martin GV, Caldwell JH, Graham MM, Grierson JR, Kroll K,
Cowan MJ, Lewellen TK, Rasey JS, Casciari JJ, Krohn KA:
Noninvasive detection of hypoxic myocardium using
fluorine-18-fluoromisonidazole and positron emission
tomography. J Nucl Med 1992, 33:2202-2208.
Current Opinion in Biotechnology 2007, 18:90–96
96 Analytical biotechnology
20. Shelton ME, Dence CS, Hwang DR, Welch MJ, Bergmann SR:
Myocardial kinetics of fluorine-18 misonidazole: a marker of
hypoxic myocardium. J Nucl Med 1989, 30:351-358.
21. Rumsey WL, Patel B, Kuczynski B, Hood C, Linder E, Nunn A,
Strauss HW: Comparison of two novel technetium agents
for imaging ischemic myocardium. Circulation 1995, 92:181.
22. Rumsey WL, Kuczynski B, Patel B, Bauer A, Narra RK,
Eaton SM, Nunn AD, Strauss HW: SPECT imaging of ischemic
myocardium using a technetium-99m-nitroimidazole ligand.
J Nucl Med 1995, 36:1445-1450.
23. Shi CQ, Sinusas AJ, Dione DP, Singer MJ, Young LH,
Heller EN, Rinker BD, Wackers FJ, Zaret BL: Technetium-99m-
nitroimidazole (BMS181321): a positive imaging agent
for detecting myocardial ischemia. J Nucl Med 1995,
36:1078-1086.
24. Sinusas AJ: The potential for myocardial imaging with hypoxia
markers. Semin Nucl Med 1999, 29:330-338.
25. Su H, Spinale FG, Dobrucki LW, Song J, Hua J, Sweterlitsch S,
Dione DP, Cavaliere P, Chow C, Bourke BN et al.: Non-invasive
targeted imaging of matrix metalloproteinase activation in a
murine model of post-infarct remodeling. Circulation 2005,
112:3157-3167.
26. Su H, Spinale F, Dobrucki L, Chow C, Sweterlitsch S, Hu X,
Bourke B, Cavaliere P, Hua J, Azure M: Evaluation of
myocardial matrix metalloproteinase (MMP) mediated
post-MI remodeling with a novel radiolabeled MMP inhibitor.
J Nucl Cardiol 2004, 11:S20.
27. Kopka K, Breyholz HJ, Wagner S, Law MP, Riemann B, Schroer S,
Trub M, Guilbert B, Levkau B, Schober O et al.: Synthesis and
preliminary biological evaluation of new radioiodinated MMP
inhibitors for imaging MMP activity in vivo. Nucl Med Biol 2004,
31:257-267.
28. Schafers M, Riemann B, Kopka K, Breyholz HJ, Wagner S,
Schafers KP, Law MP, Schober O, Levkau B: Scintigraphic
imaging of matrix metalloproteinase activity in the arterial wall
in vivo. Circulation 2004, 109:2554-2559.
29. Lu E, Wagner WR, Schellenberger U, Abraham JA,
Klibanov AL, Woulfe SR, Csikari MM, Fischer D, Schreiner GF,
Brandenburger GH et al.: Targeted in vivo labeling of
receptors for vascular endothelial growth factor: approach to
identification of ischemic tissue. Circulation 2003, 108:97-103.
30. Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS,
 Rosenblum MG, Chen X: PET of vascular endothelial growth
factor receptor expression. J Nucl Med 2006, 47:2048-2056.
The authors visualize VEGF receptor expression in vivo to allow for clinical
translation of a VEGF121-based radiopharmaceutical for imaging tumor
angiogenesis and guiding antiangiogenic treatment.
31. Wagner B, Anton M, Nekolla SG, Reder S, Henke J, Seidl S,
 Hegenloh R, Miyagawa M, Haubner R, Schwaiger M, Bengel FM:
Noninvasive characterization of myocardial molecular
interventions by integrated positron emission tomography
Current Opinion in Biotechnology 2007, 18:90–96
and computed tomography. J Am Coll Cardiol 2006,
48:2107-2115.
The authors investigate the usefulness of integrated positron emission
tomography (PET) and computed tomography (CT) for in vivo character-
ization of an angiogenesis-directed molecular intervention.
32. Hua J, Dobrucki LW, Sadeghi MM, Zhang J, Bourke BN,
 Cavaliere P, Song J, Chow C, Jahanshad N, van Royen N et al.:
Noninvasive imaging of angiogenesis with a 99mTc-labeled
peptide targeted at alphavbeta3 integrin after murine hindlimb
ischemia. Circulation 2005, 111:3255-3260.
The authors demonstrate the use of a SPECT tracer targeted at av integrin
to assess spatial and temporal changes in peripheral angiogenesis in
murine model of hindlimb ischemia.
33. Meoli DF, Sadeghi MM, Krassilnikova S, Bourke BN,
Giordano FJ, Dione DP, Su H, Edwards DS, Lui S, Harris TD et al.:
Noninvasive imaging of myocardial angiogenesis following
experimental myocardial infarction. J Clin Invest 2004,
113:1684-1691.
34. Johnson L, Haubner R, Schofield L: Radiolabeled RGD peptide
to image angiogenesis in swine model of hibernating
myocardium. Circulation 2003, 108:IV-405.
35. Hua J, Bourke B, Song J, Dobrucki LW, Sinusas AJ: Non-invasive
detection of angiogenesis with a technetium-99m labeled
peptide targeted at avb3 integrin following hindlimb ischemia.
J Am Coll Cardiol 2004, 43:25A.
36. Lindsey ML, Escobar GP, Dobrucki LW, Goshorn DK, Bouges S,
Mingoia JT, McClister DM Jr, Su H, Gannon J, MacGillivray C
et al.: Matrix metalloproteinase-9 gene deletion facilitates
angiogenesis after myocardial infarction. Am J Physiol Heart
Circ Physiol 2006, 290:H232-H239.
37. Decristoforo C, Faintuch–Linkowski B, Rey A, von Guggenberg E,
Rupprich M, Hernandez–Gonzales I, Rodrigo T, Haubner R:
[(99m)Tc]HYNIC-RGD for imaging integrin alpha(v)beta(3)
expression. Nucl Med Biol 2006, 33:945-952.
38. Liu S: Radiolabeled multimeric cyclic RGD peptides as
integrin alphavbeta3 targeted radiotracers for tumor imaging.
Mol Pharm 2006, 3:472-487.
39. Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M,
Becker KF, Goebel M, Hein R, Wester HJ et al.: Noninvasive
visualization of the activated avb3 integrin in cancer patients
by positron emission tomography and [F-18]Galacto-RGD.
PLoS Med 2005, 2:244-252.
40. Indrevoll B, Kindberg GM, Solbakken M, Bjurgert E, Johansen JH,
Karlsen H, Mendizabal M, Cuthbertson A: NC-100717:
A versatile RGD peptide scaffold for angiogenesis imaging.
Bioorg Med Chem Lett 2006, 16:6190-6193.
41. Buehler A, van Zandvoort MA, Stelt BJ, Hackeng TM,
Schrans–Stassen BH, Bennaghmouch A, Hofstra L, Cleutjens JP,
Duijvestijn A, Smeets MB et al.: cNGR: a novel homing sequence
for CD13/APN targeted molecular imaging of murine cardiac
angiogenesis in vivo. Arterioscler Thromb Vasc Biol 2006,
26:2681-2687.
www.sciencedirect.com