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REVIEWS
Q J NUCL MED MOL IMAGING 2007;51:99-110
Nuclear medicine applications in molecular imaging:
2007 update
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F. G. BLANKENBERG 1, H. W. STRAUSS 2
This review examines several classes of radiolabeled
agents, including analogs localizing in somatostatin,
benzodiazepine and dopamine receptors; analogs of
progesterone and estrogen; and agents localizing in
lesions with hypoxia. It concludes the status of agents
advocated for detecting angiogenesis and inflammation. The current clinical status of these agents, and
their potential roles in diagnosis and treatment are discussed.
1Division
of Pediatric Radiology
F.G.B.-Department of Radiology
Lucile Salter Packard Children’s Hospital, Stanford, CA, USA
2Section of Nuclear Medicine
H.W.S.-Department of Radiology
Memorial Sloan Kettering Cancer Center, NY, USA
KEY WORDS: Tomography, emission-computed, single-photon
- Radiopharmaceuticals - Molecular imaging - Receptors.
Fusion imaging with
magnetic resonance imaging
and computed tomography
adionuclide detectors are exceptionally sensitive
to small amounts of radioactivity. Collimated single photon imaging systems typically provide sensitivities of 2-4 counts/s/mCi of technetium-99m in the
field of view, while positron emission tomography
(PET) full ring imaging systems typically have sensitivities of ~2-5 thousand counts/s/mCi of fluorine-18
in the field of view. These sensitivities can be used to
detect nanomolar concentrations of tracer.1, 2 The high
sensitivity permits mapping of metabolism, perfusion,
receptor expression, and dynamic imaging of compartments, pools and spaces. Although these systems
Supported in part by NIH Grant # EB000898.
Address reprint requests to: F. G. Blankenberg, M.D., 725 Welch Road
Palo Alto, CA 94304 USA. E-mail: [email protected]
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are sensitive, they lack the anatomic resolution of
ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI). Combining single
photon emission computed tomography (SPECT) and
PET with CT and MRI to make hybrid PET/CT,3, 4
SPECT/CT,5-7 and PET/MRI 8, 9 scanners provides
images containing both functional and anatomic information in co-registered fusion images (Figure 1),10 to
define a specific physiologic parameter in a clearly
defined anatomic location. Hybrid units have several
distinct advantages: the systems provide non-image
based spatial co-registration of the multimodal image
data, assuming the patient remains motionless between
studies; the CT data allows attenuation correction of
PET or SPECT data; the combined PET-CT facilitates
biopsy of lesions visible on radionuclide scans, that
cannot be appreciated on CT (as often observed in
malignant peritoneal disease from gynecological cancers).11 A number of recent investigations have successfully used fusion imaging performed directly with
dual modality units for preoperative localization of
tumor, detection of recurrent disease, tumor staging,
and the prediction of tumor response.12-16 In all stud-
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The somatostatins
Somatostatin is a peptide hormone that inhibits cell
proliferation. Proliferating cells in some tumors express
somatostatin receptors. Five different somatostatin
receptors, SSTR-1 through SSTR-5,27 have been identified. SSTR-3 activation leads to target cell apoptosis
while the other four inhibit growth by cell-cycle
arrest.28 The marked somatostatin receptor (mostly
SSTR-2) density, found in breast carcinoma, lymphoma
and neuroendocrine tumors, permits clinical SPECT
imaging of primary and metastatic tumor with currently available radiolabeled somatostatin analogs
namely, [111In]D-Phe-DTPA-octreotide (Octreoscan,
which primarily recognizes SSTR-2) 29, 30 and [99mTc]
depreotide (Neotect, which primarily recognizes SSTR3).31 Reports describe the use of these agents for the
detection of malignant lung nodules,32, 33 bronchial
carcinoids,34 paragangliomas of the head and neck,35
primary and metastatic insulinoma,36 ectopic Cushing’s
syndromes,37 metastatic iodine negative thyroid carcinoma,38 predicting the endocrine response of
metastatic breast carcinoma,39 as well as pathologic
lymphocytic processes, such as lymphoma,40 Graves’
opthalmopathy,41, 42 granulomatous disease,43 cardiac
allograft rejection,44 and the formation of unstable
(vulnerable) atherosclerotic plaques, in which T-lymphocytes accumulate and overexpress the SSTR-2
receptor.45 When [111In]D-Phe-DTPA-octreotide was
imaged with hybrid SPECT/CT scanners, preoperative localization of abdominal neuroendocrine tumors
improved significantly compared to SPECT alone.
This improvement caused a change of surgical or
radiotherapeutic management in 28% of patients studied.46
Somatostatin analogues can also be used as a carrier for targeted radionuclide therapy to treat neuroendocrine tumors expressing SSTR-2 and STTR-5
receptors.47 For therapy, a β-emitting nuclide, such
as yttrium-90 (90Y), is used in place of the γ emitter
111In.48 Using the same peptide platform for diagnostic lesion localization, dose-planning and therapy
allows more precise calculation of tumor dose, as
well as the dose to bone marrow and kidneys. The
high concentration of somatostatin peptides in the
renal cortex is a major factor limiting the administered dose for tumor therapy. There are several strategies to reduce the renal uptake of somatostatin
analogs, including preloading with infusions of amino
acids (such as lysine), succinylated gelatin,49, 50 and
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Figure 1.—FDG PET/CT scan of a 51 year old man with stage IV
Hodgkins disease. The coronal PET (A), transaxial through the lesion
in the right axilla (B), CT at the same level as the transaxial PET (C),
and the transaxial fusion image (D) depicting the anatomic correlation of the enlarged node seen on CT with the metabolic focus seen
on the transaxial PET.
ies, the fusion of cross-sectional image data with
radionuclide images resulted in improved detection of
tumor that lead to changes in patient staging, prognosis, or therapeutic management. Misregistration of
data, caused by respiratory or cardiac motion, remains
significant challenges for these hybrid imaging techniques.
Oncology has been the major focus of fusion imaging with fluorodeoxyglucose (FDG) PET/CT for the
past 5 years. Applications of combined imaging
include: radioiodine studies in patients with metastatic thyroid cancer 17 (to distinguish osseous lesions
from uptake in nodes and soft tissue), somatostatin
and meta-iodo-benzylguanidine imaging 18, 19 (to precisely localize uptake in bowel, nodes, adrenal glands
and liver), bone scans in patients suspected of metastatic disease,20 programmed cell death with radiolabeled-annexin V,21 tissue hypoxia with misonidazole
and 2-nitroimadazole analogs.22 In addition to oncologic applications, hybrid imaging provides detailed
information about brain pathophysiology with labeled
neurotransmitter analogs,23 provides opportunities to
study the mechanisms of inflammation,24 the progression of angiogenesis,25 and the distribution of βamyloid in Alzheimer’s disease.26 We discuss these
and other radiotracers below.
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recently the use of angiotensin converting enzyme
inhibitors. Work is ongoing to see which of these
approaches will be best suited to the clinic.
The SSTR-2 receptor gene has also been successfully
used as a molecular reporter of the incorporation and
expression of DNA constructs in vivo.51, 52 As somatostatin analogues have proven safe and effective in
humans, it is possible that cells genetically engineered
to express the SSTR-2 receptor in vitro or via viral or
other in vivo vector could be in the near future noninvasively detected and monitored with SPECT/CT.
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Dopamine transporter and D2 dopamine receptor
imaging
The presynaptic dopamine transporter (DAT) and
the postsynaptic D2 receptor are two of the most
extensively studied neurotransmitter-receptor systems
in the CNS.62, 63 Several disease states, including
depression, the antipsychotic drug induced negative
syndrome of schizophrenia, Parkinson’s disease, and
extrapyramidal Parkinson-plus neurodegenerative
syndromes are characterized by focal or regional
decreases in DAT and D2 receptor binding.64-67 Opiates
and Parkinson’s disease both effect the DAT system
with decreased uptake on SPECT images recorded
with [123I]β-CIT, a cocaine analog with a binding constant of 1.6 nM for the DAT and [123I]FP-CIT, a tracer
that has been successful at documenting the accelerated presynaptic dopaminergic degeneration found
in Parkinson’s patients.68 Diseases characterized by
abnormal increases in D2 receptor binding potential
include attention deficit-hyperactivity disorder, mania
and schizophrenia. Iodine-123-iodo-benzamide or
[123I]iodolisuride are also useful for SPECT. Lisuride, an
ergolene derivative used in the treatment of
Parkinson’s disease, k=0.27 nM, is similar to 76 Br-bromolisuride used for PET. These studies all show excellent correlations of D2 binding potential with neuropsychiatric function and may have an immediate
benefit in the diagnosis and treatment of the depression that occurs in over 1/3 of patients undergoing
anti-psychotic treatment for schizophrenia.69, 70
One fascinating area of clinical research is the specific identification of abnormalities of the dopaminergic
system in patients with substance abuse.71, 72 Patients
abusing cocaine, methamphetamine, methylenedioxymethaphetamine, alcohol, opiates, tobacco, marijuana, and inhalants all appeared to be associated
with abnormalities of the brain dopamine system, the
primary force behind the reward center in humans.
Dopamine producing cell bodies are located in the
midbrain within the substantia nigra and the ventral
tegmental area with projections to the striatal area,
that is known as the reward center, the nucleus accumbens. All abused substances, despite different mechanisms of action, increase synaptic levels of dopamine.
Chronic substance abusers have stimulant-induced
highs associated with increases in brain dopamine,
but abnormally low numbers of dopamine D2 receptors at rest as measured by the PET radioligand
[11C]raclopride.73-75 Carbon-11-raclopride is a radio-
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Gamma-aminobutyric acid A-benzodiazepine receptor agonists
Gamma-aminobutyric acid (GABA) is the most
abundant inhibitory transmitter in the central nervous
system (CNS).53 This neurotransmitter is distributed
within GABAergic neurons throughout the brain.
When GABA inhibitory activity exceeds that of excitatory inputs (mainly glutaminergic) sedation, amnesia and ataxia appear. Benzodiazepines work by
potentiating the effects of GABA on the chloride ion
channel of GABAA-benzodiazepine receptor complex.
Benzodiazepine derivatives [11C]flumazenil for PET
and [123I]iomazenil for SPECT, that primarily image
the peripheral (as opposed to central) benzodiazepine
receptors, are commercially available and have been
applied to the neuroimaging of a variety of neurologic disorders including, anxiety and temporal lobe
epilepsy, characterized in part by decreases in GABAA
receptors within the brain.54-56 In addition, reductions
in temporal-mesial uptake of [123I]iomazenil can be
found in regions that are structurally intact by MRI in
patients with medically refractory temporal lobe
epilepsy.57 It is now recommended that presurgical
studies with [123I]iomazenil (SPECT) or [11C]flumazenil
(PET) be performed as part of routine imaging along
with MRI.
Iomazenil also binds selectively to activated
microglial cells (brain macrophages). These cells have
no significant binding of tracer in their quiescent state.
Microglial cells make up 1 out of 10 cells in the normal brain. Activated microglial cells are abundant in
the entorhinal, temporoparietal, and cingulate cortex
of patients with Alzheimer’s presenile dementia and
multiple sclerosis, suggesting that these diseases can
be readily imaged, quantified, and serially followed
with [123I]iomazenil SPECT or [11C]flumazenil PET imaging.58-61
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pharmaceutical that binds to the postsynaptic D2/3
receptors and, therefore, is an indirect indicator of
endogenous concentrations of dopamine. This effect
coupled to decreases in dopamine release in response
to chemical stimuli leads to the compulsive drug seeking behavior in chronic substance abusers and is an
active area of neuropsychiatric investigation.76
The nitroimidazoles are chemically reduced when
they enter tissues. In the presence of adequate tissue
oxygen levels, the molecule is re-oxidized, remains soluble, and diffuses out of the tissue.85, 86 If the oxygen
tension in the cell is low, further reduction occurs,
the molecule becomes insoluble and is trapped in
the tissue. Misonidazole analogs have been labeled
with 18F for PET imaging and 2-nitroimadazole analogs
have been labeled with 123I and 99mTc for SPECT imaging of hypoxia. These agents have demonstrated
increased uptake in hypoxic and low flow ischemic
myocardium and brain as well as in tumors.87-92
Technetium-99m labeled HL91 and BRU 59-21 as well
as 18F-labeled fluoromisonidazole ([18F]FMISO) have
been recently been used to study temporal changes in
tumor hypoxia in patients undergoing radiation and
chemotherapy for primary and recurrent squamous
head and neck carcinoma.93-95 Hypoxia may become
more important as PET/CT imaging is gaining importance in radiation treatment planning. FDG PET/CT
identifies areas of metabolically active tissue within the
tumor volume. This information is used to define the
areas to ‘boost’ with intensity modulated radiation
therapy (IMRT). Mapping the distribution of hypoxia
in tumors offers additional information to integrate
into the IMRT radiation therapy plan.96
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Estrogen and progesterone
Selection of therapy in breast cancer is influenced
by the expression of estrogen receptors by the tumor
cells. In the absence of imaging, receptor status is
determined by multiple biopsies of the primary tumor
and regional lymph nodes.77 Both 18F estrogen
analogs 78 and iodinated compounds have been synthesized for imaging.79 An iodinated estrogen analog,
123-labeled cis-11β-methoxy-17α-iodovinyl estradiol
(Z-[123I]MIVE) has proven successful as a predictor of
tamoxifen therapy in a recent study of breast cancer
patients in which all patients with faint baseline uptake
or mixed or no estrogen receptor (ER) blockade after
tamoxifen showed progressive disease, while patients
with clear baseline uptake and complete ER blockade
after tamoxifen had a significantly longer progression-free interval.80 Progesterone receptor SPECT imaging with a progesterone analog, Z-[123I]IPG2, may also
be possible in the near future.81
Hypoxia
Most tissues require a sufficient level of oxygen to
maintain function. To facilitate the maintenance of
adequate oxygen supplies, there are oxygen sensors82,
83 that initially respond to low oxygen levels by complex signaling for vascular dilatation (typically by
nitric oxide mediated responses). When this is insufficient, hypoxic tissues produce a number of growth
factors that stimulate the growth of new capillaries,
including vascular endothelial growth factor (VEGF).84
Neoplasms are often hypoxic due to their relatively
unstructured cellular proliferation, and lack of well
developed arteries. Lack of oxygen in these lesions
leads to the production of substantial amounts of
angiogenic factors, which ultimately results in the
neovascularity associated with neoplasia. One
approach to treating tumors interferes with hypoxia
generated angiogenic signaling.
Decreased oxygen tension in tissues can be imaged
with radiolabeled agents, such as the nitroimidazoles.
102
Imaging of the αvβ3 integrin and vascular endothelial
growth factor receptors
The integrins, a family of heterodimeric endothelial
cell membrane proteins, serve as adhesion receptors
for extracellular matrix proteins that contain exposed
arginine, glycine, and, aspartate (single letter coding
RGD) amino acid sequences.97 These include laminin,
fibronectin, collagens, and vitronectin that help form
blood vessels. The most abundant integrin expressed
on the surface of proliferating endothelial cells is the
αvβ3 receptor.98 In the adult human the αvβ3 integrin
has a limited tissue distribution. It is not expressed on
quiescent epithelial cells and appears at minimal levels on smooth muscle cells.99 In contrast, both activated
endothelial cells in tumor capillaries,100 and some
tumor cells101 express high levels of αvβ3.
The cyclic pentapeptide cyclo (-Arg-Gly-Asp-DPhe-Val-) has been identified as a potent (Kd <10
nmol/L) inhibitor of αvβ3 integrin binding to extracellular matrix proteins.102 Modifications of this peptide at position 4 or 5 have allowed radiolabeling with
iodine for SPECT and 18F for PET imaging.103, 104
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Contrast between tumor and normal tissues (especially liver) has been since improved by addition of
sugar to the amino acids of the peptide.105-107
Radiolabeled RGD-peptides have been recently used
to image αvβ3 expression in tumor prior to administration of αvβ3 antagonists, such as EMD-121974 to
allow selection of patients entering clinical trials.
These peptides in the near future will be used to
assess the effectiveness of αvβ3 integrin blockade by
specific doses of other αvβ3 antagonists. This approach
will permit optimization of dose for a specific patient
and tumor type.
Sites of neoangiogenesis may be imaged with a
number of tracers. Maschauer et al.108 demonstrated an
82% increase in FDG uptake in vascular endothelial
cells stimulated with VEGF, a potent pro-angiogenic
growth factor. This relationship has been borne out by
several clinical studies in which FDG uptake positively correlated with VEGF expression.109 Specific
growth factor receptors at sites of neoangiogenesis
may also be imaged using several radiolabeled forms
of VEGF.110-112 Although these radiolabeled VEGF
analogs localize, the random localization of the radiolabel chelates (such as HYNIC) on the VEGF molecule, may have a significant effect on the biodistribution of the labeled molecule. A new recombinant
VEGF combining two 3-112 aa fragments of VEGF121
into a single-chain (sc) protein expressed with N-terminal 15-aa cysteine-containing Cys-tag (scVEGF) was
developed to allow reproducible site-specific labeling
for SPECT, PET, and fluorescent imaging via facile
malemide based chemistry.113 sc-VEGF also has the
advantage of extreme heat stability and can withstand
90 °C up to 10 min that maybe helpful for the chelation of metal isotopes such as 177Lu, 90Y, and 64Cu;
and has no pro-angiogenic potential as this domain
has been removed from the recombinant protein.
Another isoform of VEGF, VEGF165 labeled with 123I for
SPECT, has also proven successful for the imaging of
tumor in 9 patients with pancreatic carcinoma.114
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very high concentrations in the placenta and lower
concentrations in endothelial cells, kidney, myocardium, skeletal muscle, skin, red cells, platelets and
monocytes. Although the precise physiologic function of annexin is uncertain, the protein has several
well studied functions, including: inhibition of coagulation (annexin was originally discovered because of
its ability to trap calcium [i.e. “annex” calcium] and prevent clotting); inhibition of phospholipase A2, an
enzyme responsible for the release of arachidonic
acid from the cell membranea component of the
inflammatory process; and inhibition of protein kinase
C, a system responsible for intracellular signaling.
The binding of annexin V to sites of phosphatidylserine (PS) expression in vivo has been found
to be extremely complex and difficult to model. While
annexin V is a relatively large protein (about half the
molecular weight of albumin) it was shown early on
that the protein can be internalized at sites of ischemic
injury both in the heart and brain and cross the intact
blood brain barrier.128 The mechanism of annexin V
uptake into PS expressing cells appears to be via a
newly described energy dependent form of pinocytosis.129
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Imaging of apoptosis
While many tracers are being developed as imaging agents for apoptosis 115-126 radiolabeled annexin V
so far is the only radiopharmaceutical that has been
studied extensively in animals and in humans.127
Annexin V (MW ⊕36 000) is an endogenous human
protein that is widely distributed intracellularly, with
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Positron emission tomography
and single photon emission
computed tomography imaging
with radiolabeled annexin V
Annexin has been radiolabeled with 125I, 124I, 18F,
and 68Ga. An array of human imaging studies has
been performed with recombinant human annexin
V. Two clinical trials were performed with the first
form of radiolabeled annexin V, [99mTc]N2S2-rh annexin, the same formulation used in an unrelated clot
detection trial.130 The first study was designed to detect
graft rejection in heart transplant recipients by Narula
et al.131 that studied 18 cardiac allograft recipients. In
the second trial, Belhocine et al.132 studied the
increased uptake of tracer with in days after the start
of chemotherapy in 15 cancer patients in late stages
small cell and non-small cell lung cancers.
To reduce the complexity of preparing the radiolabeled material, alternative labeling approaches were
sought and hydrazino nicotinamide (HYNIC) was
selected as the coupling molecule.133 The whole labeling procedure has been reduced to a standardized
two-vial kit that can be ready for patient use within 30
99mTc
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min of receiving 20-30 mCi of sterile [99mTc]pertechnetate from a local radiopharmacy or generator.
Unfortunately, although [99mTc]HYNIC annexin V is
not concentrated in the liver or excreted in the bowel, it concentrates in the cortex of the kidney, limiting
visualization of any structures in this region.134 In spite
of this shortcoming, clinical trials tested the clinical utility of HYNIC-annexin V to determine the efficacy of
chemotherapy in patients with tumors,135-139 detect
apoptosis in areas of acute myocardial infarction,140, 141
define activity of rheumatoid arthritis (personal communication R. Hustinx and C. Beckers, Liege,
Belgium), ischemic preconditioning,142-144 identify vulnerable atherosclerotic plaque,145 acute stroke,146, 147
and Alzheimer’s dementia.148
There are alternative methods to radiolabel annexin V, including the use of self-chelating annexin V
mutants that have lower concentrations in the kidneys of rodents compared with HYNIC-annexin V.149
An alternative to random modification of annexin V
with bifunctional agents, such as HYNIC, is a selfchelating annexin V mutant, known as V-128.150, 151
Annexin V-128 is a fusion protein with an endogenous
Tc chelation site (Ala-Gly-Gly-Cys-Gly-His) added to
the N-terminus of annexin V, that can be rapidly
labeled with 99mTc using glucoheptonate as the
exchange reagent. This form of radiolabeled annexin V has major advantages over the HYNIC chelator
with regard to renal retention of 99mTc, with attendant
decreased abdominal background and renal radiation dose and because it is site specifically labeled
(as opposed to randomly modified) has at least twice
the in vivo uptake of other annexin V based tracers.
It will be helpful to quantify radiolabeled annexin
concentration before and after therapy in lesions.
Since PET has major advantages for quantitative imaging, several approaches to label annexin V with 18F
have been developed. Two laboratories have used
N-succinimidyl 4-fluorobenzoate 152, 153 to synthesize
[18F]annexin V. The fluorine-labeled agent has lower
uptake in the liver, spleen, and kidney compared to
HYNIC-annexin V.
tance.154-158 The These agents work by different mechanisms: radiolabeled phagocytes depend on chemotaxis to attract the cells to the lesion site; gallium
depends on the transfer of the metal transferrin complex into cells at the site of inflammation; while FDG
is concentrated in metabolically active cells, most likely macrophages, undergoing respiratory burst activation. When blood is incubated with FDG, it is possible to label white cells in vitro, likely due to the cells
activation in course of blood withdrawal into a syringe.
Trials in humans are ongoing.159, 160 Other investigational agents for imaging inflammation include: antigranulocytic antibodies and antibody fragments, nonspecific immunoglobulin G, liposomes, chemotactic
peptides, interleukins and chemokines. For each of
these agents reliable and efficient one-step with 99mTcor 123I-based labeling methods have been developed
and tested in humans.161 However, these agents have
the potential for unforeseen immunologic (usually a
mild drop in white blood cells [WBC] count due to
transient margination) or allergic responses. One of the
most promising of the anti-granulocyte antibody based
tracers, [99mTc]fanolesomab, an agent that binds to the
CD15 antigen expressed on the surface of neutrophils,
eosinophils, and lymphocytes was withdrawn from the
market in 2005 because of two cardiopulmonary
deaths occurring within 30 min after administration of
tracer.162
In general, it appears that liposomes, antibodies
against specific immune markers, nonspecific IgG,
and radiolabeled immune cells lack rapid background
clearance while the agents with relative fast pharmacokinetics (chemotactic peptides, interleukins) lack
high uptake in the target. The side effects of some of
the chemotactic peptides and interleukins (e.g. IL-1)
also need to be addressed by the use of lower doses
(<10 µg/kg of protein), such as has been done with
131I-labeled IL-8 a marker of acute inflammation163, 164
or the use of another less toxic member within a specific family of immune related proteins or peptides,
such as the substitution of IL-1 (either the α or β isoforms) with IL-1 receptor antagonist that has the same
affinity for IL-1 receptors but is lacking in biologic
activity.165 Despite the successful labeling of the IL-1
receptor antagonist with 123I, studies in humans have
so far been disappointing as the tracer appears to
localize non-specifically to regions of reactive edema in a similar fashion as polyclonal IgG.166
There are, however, notable exceptions to the rules
above including several agents that target the CXC-
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Imaging of inflammatory cells
A number of radiotracers have been proposed to
image inflammation, yet to date only white blood cell
scanning, 67Ga, and [18F]FDG have gained accep-
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receptor family (recognizing a chemokine characterized by 4 cysteines that form essential disulfide bonds),
particularly IL-2, platelet factor (PF4), IL-8, all of which
display remarkably efficient target uptake in combination with rapid background clearance. Both IL-2 167
and PF4 168 have a high affinity for monocytes and
may, therefore, be useful for imaging chronic inflammation, a process that is difficult to detect with the
granulocyte specific tracers, such as radiolabeled
leukocytes or neutrophil specific markers such as
leukotriene B4 (imaged with the antagonist,
DPC11870), NAP-2 and its variants (neutrophil activating petide-2), NCA-90 and NCA-95 (LeukoScan)
antibodies 169, 170 used for acute inflammation imaging.
The first of these agents is IL-2, a cytokine that is a
member of the interleukin family. IL-2 binds to the Th1
(T-helper 1) receptor expressed on surface of T-cells,
that are an integral part of the chronic lymphocytic
infiltrates seen in Crohn’s disease, celiac disease, type1 diabetes and autoimmune thyroiditis.171-173 IL-2 can
be readily radiolabeled with either 123I or 99mTc; however, 99mTc labeling has proven to be a complex procedure limiting its routine use in the clinic.174
IL-8 binds to neutrophils with nanomolar affinity and
has been successfully tested in human trials.175-177
Similar success has been found patients with acute
osteomyelitis using 99mTc-labeled anti-granulocyte Fab
antibody scintigraphy (LeukoScan).178 Despite the success of Leukoscan for imaging osteomyelitis and soft
tissue infection, such as acute appendicitis, caution
must be exercised as with this and other immune
tracers as it has not proven to be of use in other types
of inflammation such as with inflammatory bowel disease.179
Another major chemokine that can bind to monocytes and macrophages (Mφs) is monocyte chemoattractant peptide-1 (MCP-1), an endogenous human
peptide with isoforms weighing 9-12 kDa, that selectively binds to the CCR-2 receptor (a C-C based receptor) with a nanomolar affinity.180 MCP-1 has so far
been successful in the imaging of experimental atherosclerosis however no human trials have yet to be
conducted.181, 182
The latest generation of inflammatory markers selectively target the extracellular components of an infectious process and include a naturally occurring antimicrobial peptides, such as 99mTc-UBI 29-41
([99mTc]ubiquicidin 29-41), that target bacteria directly.183, 184 Another example is chitin, which is expressed
in the fungal cell wall, but is absent in mammalian and
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bacterial cells. Chitin can be detected with SPECT
using 123I-labeled chitinase: a marker that may prove
a great benefit in the work up and treatment of polymicrobial or opportunistic infections in immunocompromised hosts that lack sufficient numbers of leukocytes for standard WBC labeling techniques.185 The last
class of direct microbial labeling agents are radiolabeled antibiotic drugs, including [99mTc]ciprofloxacin
(and related fluoroquinolones) and ceftizoxmine, that
are now in clinical trials.186
The last major approach to the imaging of infection
is the targeting of the effects of inflammation on the
host’s cells and tissues. Acute inflammation is resolved
through the PS-specific recognition and clearance of
apoptotic granulocytes, cells that have outlived their
useful function.187, 188 Monocytes and Mφs also accelerate the apoptosis of bystander (unwanted) granulocytes at sites of inflammation.189 The degree of
macrophage infiltration and its associated granulocytic apoptotic response can, therefore be imaged
with radiolabeled annexin V.190 Annexin V also has the
advantage that it should be able to image all types of
inflammation including that seen in unstable atherosclerotic plaques and while non-specific with respect
to the exact type of infection it is far more robust and
versatile as compared with more specific immune
markers.191-193
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