Download Molecular imaging agents for SPECT (and SPECT/CT)

Eur J Nucl Med Mol Imaging
DOI 10.1007/s00259-013-2643-0
REVIEW ARTICLE
Molecular imaging agents for SPECT (and SPECT/CT)
Gopinath Gnanasegaran & James R. Ballinger
Received: 11 November 2013 / Accepted: 12 November 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract The development of hybrid single photon emission
computed tomography/computed tomography (SPECT/CT)
cameras has increased the diagnostic value of many existing
single photon radiopharmaceuticals. Precise anatomical localization of lesions greatly increases diagnostic confidence in
bone imaging of the extremities, infection imaging, sentinel
lymph node localization, and imaging in other areas. Accurate
anatomical localization is particularly important prior to surgery, especially involving the parathyroid glands and sentinel
lymph node procedures. SPECT/CT plays a role in characterization of lesions, particularly in bone scintigraphy and
radioiodine imaging of metastatic thyroid cancer. In the development of novel tracers, SPECT/CT is particularly important in monitoring response to therapies that do not result in an
early change in lesion size. Preclinical SPECT/CT devices,
which actually have spatial resolution superior to PET/CT
devices, have become essential in characterization of the
biodistribution and tissue kinetics of novel tracers, allowing
coregistration of serial studies within the same animals, which
serves both to reduce biological variability and reduce the
number of animals required. In conclusion, SPECT/CT increases the utility of existing radiopharmaceuticals and plays a
pivotal role in the evaluation of novel tracers.
Keywords Single photon emission computed tomography .
Computed tomography . SPECT/CT . Radiopharmaceutical .
Preclinical imaging
G. Gnanasegaran : J. R. Ballinger (*)
Department of Nuclear Medicine, Guy’s and St Thomas’ NHS
Foundation Trust, Great Maze Pond, London SE1 9RT, UK
e-mail: [email protected]
J. R. Ballinger
Division of Imaging Sciences and Biomedical Engineering, King’s
College London, Westminster Bridge Road, London SE1 7EH, UK
Introduction
The development of hybrid SPECT/CT cameras has been an
important advance in traditional nuclear medicine, much as
PET/CT broadened the indications and acceptance of PET.
However, there is one difference in that planar gamma camera
imaging remains an important modality, whereas PET/CT has
virtually replaced stand-alone PET.
The availability of SPECT/CT has increased the diagnostic
value of many existing single photon radiopharmaceuticals,
some of which were on the verge of withdrawal from the
market but have been given new life by SPECT/CT. Other
papers in this special issue of the European Journal of
Nuclear Medicine and Molecular Imaging address various
clinical areas in great detail. We begin by briefly reviewing
the contribution of SPECT/CT to existing radiopharmaceuticals, then we discuss the role of clinical and preclinical
SPECT/CT in the development of novel tracers.
Clinical role of SPECT/CT
The combined functional and structural information provided
by SPECT/CT has been shown to influence patient management in many cases. The clinical role of SPECT/CT can be
divided into four areas: anatomical localization of a lesion for
diagnostic purposes, localization as a guide to surgery, multimodal characterization of a lesion, and CT-based attenuation
correction for quantification, with the last of these being
covered by Bailey et al. in this special issue in more detail [1].
Localization for diagnosis
Accurate localization of increased tracer uptake, especially
while imaging the bone extremities such as the wrist,
foot and ankle, is often challenging in planar radionuclide
Eur J Nucl Med Mol Imaging
99m
Tc-diphosphonate bone imaging due to the complex
grouping of bony articulations in a small area [2]. In general,
SPECT/CT is particularly useful in wrist/hand and foot/ankle
pathology, especially after intervention/surgery, when metallic
artefacts may limit imaging with MRI [2]. Further, SPECT/CT
is useful in making a more specific diagnosis [2] (Fig. 1). In
patients with low back pain, bone SPECT with 99mTcdiphosphonates is useful for diagnosing facet joint arthropathy
in the spine, but the addition of CT makes it more useful in
terms of accurately localizing the vertebral level.
Radionuclide infection imaging is a widely used procedure
involving radiolabelled leucocytes, 67Ga-citrate, radiolabelled
antigranulocyte antibodies and 99mTc-diphosphonates [3].
However, conventional radionuclide techniques struggle to
differentiate soft-tissue infection from osseous infection and
to define the extent of disease. SPECT/CT in infection imaging has been reported to lead to more accurate diagnosis and
precise localization [3–6] (Fig. 2). In patients with suspected
infection, Bar-Shalom et al. evaluated the role of SPECT/CT
as an adjunct to 67Ga-citrate or 111In-labelled white blood cell
imaging for the diagnosis and localization of infection [4]. In
their study, the results of conventional radionuclide scintigraphy (planar and SPECT) and SPECT/CT were concordant for
the diagnosis and location of infection in 50 % of their patients
Fig. 1 99mTc-MDP SPECT/CT
imaging in a patient with pain in
the right scaphoid 9 years after
injury. a, b On the two-phase
bone scan, there is low-grade
blood pool activity with intense
focal uptake of tracer in the right
scaphoid bone which on the CT
component of the study (d)
corresponds to a fracture through
the waist of the scaphoid which
has partial bridging. c–e The scan
findings are in keeping with
pseudoarthrosis at the site of a
partially united fracture through
the waist of the right scaphoid
(41/82) and, encouragingly, SPECT/CT was found to be beneficial in determining the precise anatomical location of infection in 85 % (35/41) of their discordant studies [4].
Furthermore, in a site-based analysis, conventional scintigraphy and SPECT/CT showed concordant results for the diagnosis and localization of infection in 50 % (49/98) of sites, and
SPECT/CT was able to provide precise anatomical location of
44 % (43/98) of infectious sites which had been equivocal or
erroneous on conventional scintigraphy [4]. Filippi et al. evaluated SPECT/CT for 99mTc-HMPAO-labelled leucocyte imaging in patients with diabetic foot infection and reported a
change in the interpretation of the planar and SPECT images
in 10 of 19 suspected sites (53 %) [5].
Localization of sentinel lymph nodes (SLN) in patients with
breast cancer and melanomas by planar lymphoscintigraphy
using 99mTc-labelled nanocolloids is well-accepted [7].
However, the major limitations include failure to detect SLNs
and false-positive radiotracer uptake on planar scans [7–14].
Several studies have shown the usefulness of SPECT/CT with
99m
Tc-radiocolloid in not only breast cancer and melanoma but
also in head/neck malignancies, prostate cancer and
gynaecological malignancies [7–14]. In SLN localization,
SPECT/CT with 99mTc-radiocolloid may improve the accuracy
of preoperative anatomical localization, detect hot lymph
Eur J Nucl Med Mol Imaging
the evaluation of 169 lesions in 81 patients with NET,
In-pentetreotide SPECT/CT was found to have a significantly greater diagnostic accuracy than SPECT in both a
patient-based analysis (93 % vs. 79 %, respectively) and a
lesion-based analysis (96 % vs. 81 %, respectively) [19].
Overall, 111In-pentetreotide SPECT/CT was significantly
more accurate for lesion localization than was SPECT (95 %
vs. 46 %, respectively). In a study in 54 patients with NET,
111
In-pentetreotide SPECT/CT provided additional information in 46 % of the patients, anatomical localization improved
in 37 % and tracer uptake considered as possible disease was
excluded as physiological uptake in 9 %. 111In-Pentetreotide
SPECT/CT altered the management in 26 % of the patients,
changing the diagnostic strategy in 15 % and the treatment
strategy in 11 % [20]. In general, there are fewer equivocal
results/interpretation with SPECT/CT than with SPECT
imaging alone in patients with NET. However, in the
future SPECT/CT imaging of NET tumours will face competition from PET/CT with 68Ga-DOTA peptides and/or
18
F-fluorodopa [21].
Although 111In-capromab pendetide (Prostascint) has been
on the market since 1997 in the US, interpretation of SPECT
images was plagued by the lack of anatomical markers and
inability to distinguish between pathological and physiological accumulation [22]. In the first study to combine SPECT
and CT imaging with 111In-capromab, 46 % (74/161) of the
sites interpreted as positive on SPECT alone turned out to be
negative when examined by SPECT/CT [20]. More recent
studies have confirmed the added value of CT in interpretation
of 111In-capromab SPECT images, to the point that pretreatment 111In-capromab SPECT/CT has been shown to predict
biochemical disease-free survival and disease-specific survival in primary prostate cancer and to be useful for defining
biological target volumes for intensity modulated radiotherapy [23]. This is a clear example of SPECT/CT extending the
scope of use of an existing radiopharmaceutical.
111
Fig. 2 111In-labelled WBC SPECT/CT in a patient with previous left
quadriceps tendon repair with ongoing sinus; query left patella osteomyelitis. a There is a focal area of increased tracer uptake seen in the region
of the left lower thigh on the whole body scan. b–d On SPECT/CT
images the uptake is localized to soft-tissue uptake in the quadriceps
femoral tendon. The scan findings are consistent with soft-tissue infection
at the quadriceps femoral tendon which will correspond with the ongoing
sinus problem. There is no evidence of patellar osteomyelitis
nodes missed by conventional planar imaging, and exclude
non-nodal false-positive sites of increased uptake [7–10]
(Fig. 3).
Radionuclide scintigraphy and therapy with 123I/131I is
used in the treatment and follow-up of patients with differentiated thyroid cancer [15]. Radioiodine SPECT/CT has been
reported to be useful in accurate localization of sites of pathological uptake such as metastasis or remnant/residual thyroid
[15–17].
There are several studies evaluating the role of radiolabelled
somatostatin analogues in imaging neuroendocrine tumours
(NET) which have shown that the addition of SPECT/CT to
conventional planar scintigraphy and SPECT, as well providing incremental value for lesion localization and characterization, increases diagnostic confidence, and has a positive
clinical impact on the management of NET [18–20]. In
Localization for surgery
99m
Tc-Sestamibi SPECT/CT has proved to be a useful technique for preoperative localization of parathyroid adenomas,
especially at ectopic sites and in patients with a history of
previous neck surgery/interventions [24, 25]. However, the
role 99mTc-sestamibi SPECT/CT in the routine investigation
of eutopic sites is debatable [26, 27]. SLN radiocolloid imaging is performed in patients with melanoma, breast cancer and
other malignancies such as vulval, penile, and prostate cancer
[7–14]. Often, intraoperative SLN detection using the gamma
probe can be challenging. In general, approximately 95 % of
the injected activity may remain at the injection site, and SLN
close to the injection site can be missed, both on planar images
and when using hand-held gamma ray detection probes.
Further, the SLN and second echelon nodes may not be
Eur J Nucl Med Mol Imaging
Fig. 3 99mTc-Nanocolloid SPECT/CT imaging in a patient with squamous cell carcinoma of the left lateral border of the tongue. 99mTcnanocolloid was injected around the left lateral tongue border. a, b On
the planar images and SPECT images two focal areas of increased tracer
uptake are seen on the left side of the neck. c On the fused SPECT/CT
scan, the increased tracer uptake close to the injection site on the planar
images localizes to a level 2a lymph node, and one lower to a level 3
lymph node
accurately differentiated using intraoperative gamma probes.
99m
Tc-Radiocolloid SPECT/CT improves the accuracy of preoperative anatomical localization of these nodes to help in
planning the surgical approach [9, 13, 18]. Further, a few
centres have reported the use of concomitant radionuclide
and fluorescence-guided SLN biopsy using indocyanine green
99m
Tc-nanocolloid, in which SPECT/CT is used for anatomical localization [9, 14].
result of upstaging or downstaging disease using radioiodine
SPECT/CT [17].
To summarize the role of SPECT/CT with current clinical
tracers, SPECT/CT adds incremental value to conventional
radionuclide planar and SPECT imaging studies by improving
lesion detection, localization and characterization, which
translates into better diagnostic confidence, sensitivity and
specificity (Table 1). These factors are essential components
for optimal management of both oncological and nononcological patients. Examples of radiopharmaceuticals for
which diagnostic utility has been enhanced by SPECT/CT
are presented in Table 2.
Characterization of lesions
Radionuclide planar bone scintigraphy with 99m Tcdiphosphonates is highly sensitive for detecting bone metastases but its specificity is relatively variable for accurate
differentiation of benign and malignant bone disease [2].
The addition of SPECT imaging has improved diagnostic
accuracy to a certain extent, but is still inadequate for
confirming or excluding metastases with a high degree of
confidence [28–31]. The additional value of SPECT/CT compared with SPECT alone in differentiating benign and malignant bone lesions on 99mTc-diphosphonate bone scintigraphy
has been shown in several studies and most of the papers agree
that SPECT/CT is useful for the assessment of indeterminate
lesions noted on both planar and SPECT imaging [28–31].
The consensus is that 99mTc-diphosphonate SPECT/CT improves diagnostic confidence in making a definitive diagnosis
in most patients (Fig. 4).
Radioiodine SPECT/CT is also useful in differentiating
pathological from physiological tracer uptake [15]. Overall,
radioiodine SPECT/CT has been reported to improve detection and accurate localization of lymph node metastases and
distant metastases, compared with conventional whole-body
imaging [16]. Further, Schmidt et al. have reported management changes in approximately one-quarter of patients as a
Development of novel tracers
The development of novel tracers generally involves a sequence of chemical and biological validations. Once the
targeting and labelling chemistry have been worked out,
the potential tracer is evaluated in an in vitro binding
system. Only after that has been established is it ethical to
evaluate localization and biodistribution in animal models.
Biodistribution studies have traditionally involved the killing
of groups of animals at a limited number of time-points after
injection, removal of specific organs, and measurement of
their radioactive content in a gamma counter. However, the
information obtained is limited by the number of time-points,
requires relatively large numbers of animals, and introduces
variability since, for example, every experimental tumour will
not be the same size. Moreover, transgenic animals can be
extremely expensive. Thus, imaging techniques would allow
serial studies in the same animal, improving reproducibility
and reducing the number of animals required [32].
Eur J Nucl Med Mol Imaging
Table 1 Contribution of SPECT/CT to interpretation of clinical radionuclide images
Contribution
Example
Reference
Anatomical localization of
a lesion for diagnostic
purposes
Anatomical localization as
a guide to surgery
99m
[2]
Tc-Diphosphonates in
wrist/hand and foot/ankle
pathology
99m
Tc-Sestamibi for
preoperative localization
of parathyroid adenomas,
especially at ectopic sites
Multimodal characterization 131I-Iodide for detection and
accurate localization of
of a lesion
lymph node metastases and
distant metastases
Attenuation correction
CT component
improves accuracy of
quantification
Fig. 4 99mTc-MDP SPECT/CT imaging in a patient with breast cancer
with back pain, worse at night; query bone metastasis. a On the wholebody bone scan, there is a focal area of increased tracer uptake seen in the
T8 vertebra, which corresponds to a sclerotic lesion at this site on the CT
component (c). b–d The appearance of the scans is consistent with a
solitary T8 vertebral metastasis. On the whole-body bone scan, the lowgrade increased tracer uptake in the upper thoracic spine is suggestive of
degenerative disease
Gamma cameras have been used to image research animals
for many years, but there has always been uncertainty about
the exact anatomical localization of sites of radiotracer accumulation. With SPECT, even in relatively large animals such
as monkeys, the precise localization of brain regions has
proven difficult in our experience. Dedicated preclinical
SPECT devices were introduced about a decade ago, offering
submillimetre resolution with advances in detector and collimator design [32]. Indeed, resolution is sufficient to allow
discrimination of regions within the mouse brain or heart.
Very quickly CT was incorporated into the devices, further
reducing the uncertainty about the anatomical localization
of radioactivity on the SPECT images [32]. SPECT/CT allows
differentiation of pathological and physiological accumulation,
[24]
[16]
[1]
particularly in the organs of excretion, and is important for
coregistration of serial studies within the same animals, making best use of the reduction in biological variability.
With clinical equipment, the spatial resolution of SPECT is
typically inferior to that of PET. However, the same does not
hold true with preclinical equipment where SPECT can
achieve higher spatial resolution than PET. Moreover,
SPECT allows simultaneous imaging of multiple tracers with
different gamma energies, which is not possible with PET
where all radionuclides are detected via 511 keV annihilation
photons. Also, most positron-emitting radionuclides have
very short half-lives, making studies technically challenging.
The easier availability and longer half-lives of most commonly used gamma-emitting radionuclides of medical interest
allows longer experiments to be carried out. Thus, preclinical
SPECT/CT has become of interest to the pharmaceutical
industry as well as to radiopharmaceutical researchers [32].
We review a number of examples of novel tracers under
development which will lead to improvements in current
diagnostic targets or allow exploitation of new targets.
Angiogenesis
Reduction in angiogenesis is another early indicator of the
effectiveness of novel therapies, particularly those which do
not immediately result in a reduction in tumour size. Most
angiogenesis markers have used the integrin αvβ3 binding
sequence Arg-Gly-Asp (RGD). As reviewed recently by
Gaertner et al. [33], 99mTc-maraciclatide (NC100692) has
been used in clinical trials [34] but development of other
RGD tracers continues, in particular to evaluate the role of
multimers in enhancing accumulation in tumours. The recent
clinical study by Zhao et al. provides evidence of the wisdom
of this approach [35]. They used a high-affinity RGD dimer
Eur J Nucl Med Mol Imaging
Table 2 Examples of current radiopharmaceuticals used with
SPECT/CT
Contribution of SPECT/CT
Application
Radiopharmaceutical
Anatomical localization of a lesion
for diagnostic purposes
Bone imaging
Inflammation imaging
Inflammation imaging
99m
Anatomical localization as a guide to
surgery
Multimodal characterization of a
lesion
with PEG to fine-tune the pharmacokinetics and a Hynic
group for attachment of 99mTc. The utility of this tracer for
monitoring the response to antiantiogenic therapy has recently
been demonstrated in a mouse model of glioma [36].
Moreover, 111In-labelled RGD has been coupled with a fluorescent dye to produce a hybrid tracer which will allow visualization of tumour margins during surgery as well as the
detection of distant metastases [37]. However, SPECT/CT will
face challenges from PET/CT, in which 18F fluciclatide and
18
F-galacto-RGD have already been widely used in patients
[33, 38, 39].
Apoptosis
Detection of apoptosis is an important goal in the assessment
of the effectiveness of novel therapies. While the ideal agent
for clinical use has not yet been identified, a variety of tracers
have been evaluated preclinically. Annexin V was the original
targeting agent, binding to phosphatidyl serine exposed at an
early stage of apoptosis, but 99mTc-Hynic-annexin V does not
have ideal biological properties [40]. Engineered variants of
annexin V have been developed which incorporate a 99mTc
binding domain or a His-tag for labelling with 99mTctricarbonyl, thus improving specific targeting and reducing
renal accumulation [40, 41]. Another protein, the C2A domain
of synaptotagmin I, has also been shown to bind to apoptotic
cells [42]. Both of these classes of compounds are relatively
large proteins which suffer the disadvantage of slow kinetics
and high activity in the abdomen. It does not appear that
gamma-emitting analogues of the malonate or isatin small
molecules developed for PET imaging have been evaluated
[43, 44]. However, recently a caspase-3-binding peptide
consisting of a Phe-Gly-Cys 99mTc chelation sequence and
Asp-Glu-Val-Asp targeting sequence has shown promising
results [45]. It is not yet clear whether SPECT/CT or PET/
CT will predominate in the future for imaging apoptosis.
SLN localization
Thyroid cancer imaging
Neuroendocrine tumour
localization
Prostate cancer detection
Parathyroid gland localization
SLN localization
Bone imaging
Thyroid cancer imaging
Tc-Medronate
In-Labelled white blood cells
99m
Tc-Labelled white blood
cells
99m
Tc-Nanocolloid
131
I-Iodine
111
In-Pentetreotide
111
111
In-Capromab
Tc-Sestamibi
99m
Tc-Nanocolloid
99m
Tc-Medronate
131
I-Iodine
99m
Chemokine receptor 4 expression
The chemokine receptor 4 (CXCR4) is overexpressed in a
variety of cancers including cancer of the breast, prostate and
ovary. Its expression in mammary ductal carcinoma in situ has
been studied by Buckle et al. using an 111In-labelled peptide
antagonist Ac-TZ140011 [46]. Early images (1 h after injection) showed that the peptide is delivered to both CSCR4expressing and non-expressing tumours (which is also similar
for angiogenesis, as noted above) but the peptide is only
retained (24 h after injection) in the CXCR4-expressing tumours as shown by serial SPECT/CT imaging [46]. Another
group has labelled a non-peptide small-molecule antagonist
AMD3100 with 99mTc and studied its biodistribution in
athymic mice bearing human prostate cancer xenografts
[47]. Tumours were visible over 2 h on SPECT imaging.
Moreover, activity could be displaced from the tumours and
other CXCR4-rich tissues by preinjection of an excess dose of
unlabelled AMD3100 [47].
A recent review offers the opinion that PET/CT is more
promising than SPECT/CT for imaging CXCR4 expression in
patients, but fluorescent, paramagnetic and hybrid agents are
also under development [48].
Epidermal growth factor receptor in breast cancer
Members of the human epidermal growth factor (EGF) receptor family including HER2 and EGFR are overexpressed in
many solid tumours including breast cancer. In particular,
HER2/EGFR heterodimers are associated with a more aggressive tumour phenotype. Recently, a group from the University
of Toronto has prepared a bispecific radioimmunoconjugate
which is capable of binding to this heterodimer [49]. To prepare
the bispecific agent, Fab fragments of trastuzumab (Herceptin)
were coupled to human EGF using a polyethylene glycol
linker, then a DTPA chelator was added for radiolabelling with
Eur J Nucl Med Mol Imaging
111
In. In athymic mice bearing HER+/EGFR+ xenografts, accumulation of the radioimmunoconjugate seen on SPECT/CT
imaging was maximal at 24–48 h and could be blocked by
pretreatment with unlabelled trastuzumab Fab or EGF [49].
Folate receptor overexpression
Folate is involved in many biosynthetic processes including
nucleotide precursors of DNA. Rapidly dividing cells, including many cancers, consume higher amounts of folate. The
folate receptor (transporter) is overexpressed on the surface
of some epithelial tumours including ovarian (95 %) and lung
(75 %) cancer [50]. Thus, folate receptor overexpression is an
attractive target for selective delivery of chemotherapeutics
and toxins. However, only patients who overexpress the receptor will benefit from these novel treatments so a “companion diagnostic” imaging agent is required for patient selection.
That is what is being carried out in clinical trials of etarfolatide
(EC20, FolateScan) prior to treatment with vintafolide
(EC145), which consists of vinblastine coupled to a folate
targeting moiety [51].
However, the use of folate targeting is complicated by
accumulation of radiofolate in normal tissues, particularly
the kidneys. Thus, pharmacological intervention is required
to allow delivery of a sufficient fraction of the administered
activity to the tumour. In the etarfolatide trials, folic acid is
administered immediately before the tracer. A group at the
Paul Scherrer Institute has been evaluating alternative means
of achieving this, including the antifolate pemetrexed combined with thymidine as an antidote to the potential toxicity of
pemetrexed, a chemotherapeutic agent in its own right
[52–54]. Although trials of this combination have been promising, it remains to be seen whether the degree of protection of
normal tissues is sufficient to allow therapy with folatecoupled alpha or beta particle-emitting radionuclides without
unacceptable radiotoxicity to the kidneys.
Although PET agents are under development for imaging
the folate receptor, etarfolatide for SPECT/CT is the most
advanced agent, being already under review for licensing by
the European Medicines Agency as a theranostic together with
vintafolide.
Hypoxia
Tumours which are hypoxic are less sensitive to radiation therapy and other treatments, and hypoxia tends to select a more
aggressive phenotype. However, there are no structural or clinical predictors of the extent of hypoxia in a particular tumour.
Moreover, hypoxia tends to be heterogeneous both spatially and
temporally. Imaging of hypoxia has traditionally involved either
nitroimidazole or bioreductive targeting, but clinically this is
mainly the domain of PET/CT rather than SPECT/CT [55].
However, a novel alternative approach has been suggested
recently that utilizes hypoxia-inducible factor 1α (HIF-1α)
which has previously been used as an in vitro marker for
hypoxia [56]. The oxygen-dependent degradation domain of
HIF-1α was fused with the protein transduction domain and
with streptavidin which will then react with radiolabelled biotin.
Using preclinical SPECT coregistered with CT and MRI images, intratumoral heterogeneity in localization was visualized.
Hypoxia imaging is a prime example of the need for hybrid
imaging, since both functional and structural measurements are
required to calculate the hypoxic fraction of a tumour – the
fractional volume of the tumour in which the tissue oxygen
concentration is below a particular threshold value.
Prostate-specific membrane antigen
Prostate specific membrane antigen (PSMA) is a cell surface
antigen which is expressed at a basal level in prostate cells, but
its expression increases progressively in higher grade tumours, metastatic disease, and hormone-refractory disease.
Urea-based small-molecule ligands which bind to PSMA
are being developed for SPECT/CT and PET/CT imaging
and for molecular radiotherapy. Building on the success of
123 131
I/ I-labelled compounds (diagnostic/therapeutic), chemists at Molecular Insight Pharmaceuticals have developed
99m
Tc/186/188Re-labelled analogues [57]. The Glu-urea-Glu
pharmacophore has turned out to be relatively forgiving, and
the second Glu can readily be conjugated or replaced with
Lys derivatives containing tridentate chelating moieties for
99m
Tc-tricarbonyl. All but one of the analogues tested has
shown low nanomolar affinity for PSMA. Currently, one of
these compounds, 99mTc-MIP-1404, is under evaluation in an
international phase 2 study in men scheduled for radical
prostatectomy at high risk of lymph node involvement [58].
However, SPECT/CT will face difficult competition from the
68
Ga-labelled ureas developed for PET/CT [58].
Bone imaging
Although the 99mTc-labelled diphosphonates have been used
for many years for bone imaging, and constitute the most
widely used class of radiopharmaceuticals internationally,
they are not optimal because the diphosphonate acts as both
chelator and targeting group. Moreover, each role may compromise the other. Several research groups are developing
bifunctional agents in which the diphosphonate targeting
group is coupled to a chelator, separating the two functions
[59, 60]. Preclinical SPECT/CT has been essential in characterizing the in vivo behaviour of these tracers.
Torres et al. used alendronate, a clinically approved
diphosphonate with high affinity for hydroxyapatite, coupled
via the sidechain to a dipicolylamine group which serves as a
chelator for 99mTc tricarbonyl [60]. The resulting complex is a
single, chemically defined species, unlike current 99mTc-
Eur J Nucl Med Mol Imaging
diphosphonates, and shows excellent bone localization with
good clearance from nontarget tissues (Fig. 5). Moreover, the
same technology can be used to prepare a stable 188Re complex for palliative treatment of bone metastases [60]. Indeed,
this theranostic application of bifunctional bone-seeking
agents will be important if they are to compete with 18Ffluoride PET/CT bone imaging [61].
Perspectives
The addition of hybrid CT improves confidence in spatial
localization of the radioactive signal, accurate sizing of lesions, anatomically relevant placement of regions of interest,
and precise repositioning for serial studies. The studies described above included examples of these properties. Buckle
et al. used CT to determine experimental tumour volumes and
stratify mice into early, intermediate or late stages of tumour
development for analysis of SPECT images [46]. Serial studies have been performed over 24 h [46] or even 72 h [49] with
CT being used for repositioning, allowing the time of peak
accumulation to be determined following a single injection of
a radiotracer with a half-life that is sufficiently long. Serial
studies in the same animals with repeat administration of
radiotracer have been performed over 18 days in a therapeutic
study [36]. SPECT/CT is important for localization of radioactivity in the xenograft and metastases, but also in the organs
of excretion which can be affected by coadministered drugs
[52]. Excised tissues can be imaged with SPECT/CT ex vivo
and the images superimposed on the in vivo images in order to
study the influence of respiratory motion, scatter, and
counting statistics [56]. However, preclinical SPECT/CT can
require injection of relatively large quantities of radiotracer
(e.g. 50 MBq) in order that the acquisition times are not
unreasonably long; this may result in slight quantitative differences from low activity biodistribution (tissue counting)
studies, in part due to specific activity effects [47, 56].
Despite PET being the current flavour of the month, there is
a continuing need to develop tracers for SPECT, as elegantly
argued by Mariani et al. [62]. The worldwide installed equipment base for SPECT is much greater than that for PET. The
longer half-lives of many of the radionuclides used for SPECT
make them much more convenient to supply compared to the
short-lived PET radionuclides which often rely on a nearby
cyclotron. The average cost of PET radiopharmaceuticals is
about ten times greater than those for SPECT, although the
difference may not be as great for newer agents. It is uncertain
whether PET will be economically viable in some parts of the
world.
Table 3 Examples of novel radiopharmaceuticals being developed for
SPECT/CT
Application
Radiopharmaceutical
Reference
Angiogenesis
99m
Tc-Maraciclatide
Tc-3P-RGD2
111
In-MSAP-RGD
[34]
[35]
[37]
99m
Tc(CO)3-His-annexin A5
C2AcH-[99mTc(CO)3]
99m
Tc-(Me)FGCDEVD
111
In-DTPA-Ac-TZ14011
99m
Tc-AMD3100
111
In-DTPA-Fab-PEG24-EGF
[41]
[42]
[45]
[46]
[47]
[49]
99m
Tc-Etarfolatide
In-DOTA-folate
123/125
I-IPOS
99m
Tc-MIP1404
[51]
[53]
[56]
[57]
99m
[60]
99m
Apoptosis
Chemokine receptor 3
expression
Fig. 5 SPECT (colour)/CT (greyscale) image of an adult Balb/C mouse
acquired 4 h after intravenous injection of 99mTc(CO)3-DPA-alendronate.
The image is a maximum intensity projection from a 30-min acquisition
on a NanoSPECT/CT system (Bioscan Inc). There is high accumulation
of 99mTc in the skeleton, particularly the joints, and good clearance from
other tissues (courtesy of Dr. R. Torres and Prof. P. Blower, Division of
Imaging Sciences and Biomedical Engineering, King’s College London)
Epidermal growth factor
receptor
Folate receptor
111
Hypoxia
Prostate-specific
membrane antigen
Bone imaging
Tc(CO)3-DPA-alendronate
Eur J Nucl Med Mol Imaging
Summary
SPECT/CT has become the state of the art technique for
in vivo evaluation of novel gamma-emitting radiotracers
(Table 3). Preclinical SPECT offers submillimetre resolution,
accurate quantification and reasonable acquisition times,
while taking advantage of the properties of gamma emitters—longer half-lives than most positron emitters, easier
accessibility and the potential for simultaneous imaging of
more than one radionuclide using different energy windows.
In the clinic, SPECT/CT is revolutionizing radionuclide imaging by its incremental value providing accurate localization,
diagnosis, characterization and surgical guidance. Further,
SPECT/CT improves specificity and diagnostic confidence,
which may reduce the number of equivocal reports. Overall,
SPECT/CT is spectacular, especially in orthopaedic indications, and should be considered the standard modality with
equivalent status to PET/CT.
Acknowledgments The authors acknowledge financial support from
the Department of Health via the National Institute for Health Research
(NIHR) comprehensive Biomedical Research Centre award to Guy’s & St
Thomas’ NHS Foundation Trust in partnership with King’s College
London and King’s College Hospital NHS Foundation Trust. We would
also like to thank Dr. R. Torres and Prof. P. Blower, Division of Imaging
Sciences and Biomedical Engineering, King’s College London, for providing the preclinical SPECT/CT image.
Conflicts of interest The authors declare that they have no conflict of
interest.
References
1. Bailey DL, Willowson KP. Quantitative SPECT/CT: SPECT joins
PET as a quantitative imaging modality. Eur J Nucl Med Mol
Imaging. 2013. doi:10.1007/s00259-013-2542-4.
2. Gnanasegaran G, Barwick T, Adamson K, Mohan H, Sharp D,
Fogelman I. Multislice SPECT/CT in benign and malignant bone
disease: when the ordinary turns into the extraordinary. Semin Nucl
Med. 2009;39:431–42.
3. Navalkissoor S, Nowosinska E, Gnanasegaran G, Buscombe JR.
Single-photon emission computed tomography-computed tomography in imaging infection. Nucl Med Commun. 2013;34:283–90.
4. Bar-Shalom R, Yefremov N, Guralnik L, Keidar Z, Engel A, Nitecki
S, et al. SPECT/CT using 67Ga and 111In-labeled leukocyte scintigraphy for diagnosis of infection. J Nucl Med. 2006;47:587–94.
5. Filippi L, Uccioli L, Giurato L, Schillaci O. Diabetic foot infection:
usefulness of SPECT/CT for 99mTc-HMPAO-labeled leukocyte imaging. J Nucl Med. 2009;50:1042–6.
6. Erba PA, Conti U, Lazzeri E, Sollini M, Doria R, De Tommasi SM,
et al. Added value of 99mTc-HMPAO-labeled leukocyte SPECT/CT
in the characterization and management of patients with infectious
endocarditis. J Nucl Med. 2012;53:1235–43.
7. Wagner T, Buscombe J, Gnanasegaran G, Navalkissoor S. SPECT/
CT in sentinel node imaging. Nucl Med Commun. 2013;34:191–202.
8. Kraft O, Havel M. Localisation of sentinel lymph nodes in patients
with melanomas by planar lymphoscintigraphic and hybrid SPECT/
CT imaging. Nucl Med Rev Cent East Eur. 2012;15:101–7.
9. Olmos RA, Vidal-Sicart S, Nieweg OE. SPECT-CT and real-time
intraoperative imaging: new tools for sentinel node localization and
radioguided surgery? Eur J Nucl Med Mol Imaging. 2009;36:1–5.
10. van der Ploeg IM, Olmos RA, Kroon BB, Rutgers EJ, Nieweg OE.
The hidden sentinel node and SPECT/CT in breast cancer patients.
Eur J Nucl Med Mol Imaging. 2009;36:6–11.
11. Lerman H, Metser U, Lievshitz G, Sperber F, Shneebaum S, EvenSapir E. Lymphoscintigraphic sentinel node identification in patients
with breast cancer: the role of SPECT-CT. Eur J Nucl Med Mol
Imaging. 2006;33:329–37.
12. Kraft O, Havel M. Detection of sentinel lymph nodes in gynecologic
tumours by planar scintigraphy and SPECT/CT. Mol Imaging
Radionucl Ther. 2012;21:47–55.
13. Vermeeren L, Klop WM, van den Brekel MW, Balm AJ, Nieweg OE,
Valdés Olmos RA. Sentinel node detection in head and neck malignancies: innovations in radioguided surgery. J Oncol. 2009;2009:
681746.
14. van den Berg NS, Brouwer OR, Klop WM, Karakullukcu B, Zuur
CL, Tan IB, et al. Concomitant radio- and fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral
cavity using ICG-99mTc-nanocolloid. Eur J Nucl Med Mol
Imaging. 2012;39:1128–36.
15. Barwick TD, Dhawan RT, Lewington V. Role of SPECT/CT in
differentiated thyroid cancer. Nucl Med Commun. 2012;33:787–98.
16. Maruoka Y, Abe K, Baba S, Isoda T, Sawamoto H, Tanabe Y, et al.
Incremental diagnostic value of SPECT/CT with 131I scintigraphy
after radioiodine therapy in patients with well-differentiated thyroid
carcinoma. Radiology. 2012;265:902–9.
17. Schmidt D, Szikszai A, Linke R, Bautz W, Kuwert T. Impact of 131I
SPECT/spiral CT on nodal staging of differentiated thyroid carcinoma at the first radioablation. J Nucl Med. 2009;50:18–23.
18. Lu SJ, Gnanasegaran G, Buscombe J, Navalkissoor S. Single photon
emission computed tomography/computed tomography in the evaluation of neuroendocrine tumours: a review of the literature. Nucl Med
Commun. 2013;34:98–107.
19. Perri M, Erba P, Volterrani D, Lazzeri E, Boni G, Grosso M, et al.
Octreo-SPECT/CT imaging for accurate detection and localization of
suspected neuroendocrine tumors. Q J Nucl Med Mol Imaging.
2008;52:323–33.
20. Castaldi P, Rufini V, Treglia G, Bruno I, Perotti G, Stifano G, et al.
Impact of 111In-DTPA-octreotide SPECT/CT fusion images in the
management of neuroendocrine tumours. Radiol Med. 2008;113:
1056–67.
21. Geijer H, Breimer LH. Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis. Eur J
Nucl Med Mol Imaging. 2013;40:1770–80.
22. Schettino CJ, Kramer EL, Noz ME, Taneja S, Padmanabhan P, Lepor
H. Impact of fusion of indium-111 capromab pendetide volume data
sets with those from MRI or CT in patients with recurrent prostate
cancer. AJR Am J Roentgenol. 2004;183:519–24.
23. Ellis RJ, Kaminsky DA, Zhou EH, Fu P, Chen WD, Brelin A, et al.
Ten-year outcomes: the clinical utility of single photon emission
computed tomography/computed tomography capromab pendetide
(Prostascint) in a cohort diagnosed with localized prostate cancer. Int
J Radiat Oncol Biol Phys. 2011;81:29–34.
24. Papathanassiou D, Flament JB, Pochart JM, Patey M, Marty H, Liehn
JC, et al. SPECT/CT in localization of parathyroid adenoma or
hyperplasia in patients with previous neck surgery. Clin Nucl Med.
2008;33:394–7.
25. Krausz Y, Bettman L, Guralnik L, Yosilevsky G, Keidar Z, BarShalom R, et al. Technetium-99m-MIBI SPECT/CT in primary hyperparathyroidism. World J Surg. 2006;30:76–83.
26. Gayed IW, Kim EE, Broussard WF, Evans D, Lee J, Broemeling LD,
et al. The value of 99mTc-sestamibi SPECT/CT over conventional
SPECT in the evaluation of parathyroid adenomas or hyperplasia. J
Nucl Med. 2005;46:248–52.
Eur J Nucl Med Mol Imaging
27. Dasgupta DJ, Navalkissoor S, Ganatra R, Buscombe J. The role of
single-photon emission computed tomography/computed tomography in localizing parathyroid adenoma. Nucl Med Commun.
2013;34:621–6.
28. Sharma P, Dhull VS, Reddy RM, Bal C, Thulkar S, Malhotra A, et al.
Hybrid SPECT-CT for characterizing isolated vertebral lesions observed by bone scintigraphy: comparison with planar scintigraphy,
SPECT, and CT. Diagn Interv Radiol. 2013;19:33–40.
29. Hirschmann MT, Davda K, Rasch H, Arnold MP, Friederich NF.
Clinical value of combined single photon emission computerized
tomography and conventional computer tomography (SPECT/CT)
in sports medicine. Sports Med Arthrosc. 2011;19:174–81.
30. Ndlovu X, George R, Ellmann A, Warwick J. Should SPECT-CT
replace SPECT for the evaluation of equivocal bone scan lesions in
patients with underlying malignancies? Nucl Med Commun.
2010;31:659–65.
31. Zhao Z, Li L, Li F, Zhao L. Single photon emission computed
tomography/spiral computed tomography fusion imaging for the
diagnosis of bone metastasis in patients with known cancer. Skelet
Radiol. 2010;39:147–53.
32. Franc BL, Acton PD, Mari C, Hasegawa BH. Small-animal SPECT
and SPECT/CT: important tools for preclinical investigation. J Nucl
Med. 2008;49:1651–63.
33. Gaertner FC, Kessler H, Wester HJ, Schwaiger M, Beer AJ.
Radiolabelled RGD peptides for imaging and therapy. Eur J Nucl
Med Mol Imaging. 2012;39 Suppl 1:S126–38.
34. Axelsson R, Bach-Gansmo T, Castell-Conesa J, McParland BJ. An
open-label, multicenter, phase 2a study to assess the feasibility of
imaging metastases in late-stage cancer patients with the alpha v beta
3-selective angiogenesis imaging agent 99mTc-NC100692. Acta
Radiol. 2010;51:40–6.
35. Zhao D, Jin X, Li F, Liang J, Lin Y. Integrin αvβ3 imaging of
radioactive iodine-refractory thyroid cancer using 99mTc-3PRGD2.
J Nucl Med. 2012;53:1872–7.
36. Ji S, Zhou Y, Voorbach MJ, Shao G, Zhang Y, Fox GB, et al.
Monitoring tumor response to linifanib therapy with SPECT/CT
using the integrin αvβ3-targeted radiotracer 99mTc-3P-RGD2. J
Pharmacol Exp Ther. 2013;346:251–8.
37. Bunschoten A, Buckle T, Visser NL, Kuil J, Yuan H, Josephson L,
et al. Multimodal interventional molecular imaging of tumor margins
and distant metastases by targeting αvβ3 integrin. Chembiochem.
2012;13:1039–45.
38. Tomasi G, Kenny L, Mauri F, Turkheimer F, Aboagye EO.
Quantification of receptor-ligand binding with [18F]fluciclatide in
metastatic breast cancer patients. Eur J Nucl Med Mol Imaging.
2011;38:2186–97.
39. Beer AJ, Niemeyer M, Carlsen J, Sarbia M, Nährig J, Watzlowik P,
et al. Patterns of αvβ3 expression in primary and metastatic human
breast cancer as shown by 18F-galacto-RGD PET. J Nucl Med.
2008;49:255–9.
40. Tait JF, Smith C, Blankenberg FG. Structural requirements for in vivo
detection of cell death with 99mTc-annexin V. J Nucl Med. 2005;46:
807–15.
41. Vangestel C, Van de Wiele C, Van Damme N, Staelens S, Pauwels P,
Reutelingsperger CP, et al. 99mTc-(CO)3 His-annexin A5 microSPECT demonstrates increased cell death by irinotecan during the
vascular normalization window caused by bevacizumab. J Nucl Med.
2011;52:1786–94.
42. Tavaré R, Torres Martin De Rosales R, Blower PJ, Mullen
GE. Efficient site-specific radiolabeling of a modified C2A
domain of synaptotagmin I with [99mTc(CO)3]+: a new radiopharmaceutical for imaging cell death. Bioconjug Chem. 2009;20:
2071–81.
43. Allen AM, Ben-Ami M, Reshef A, Steinmetz A, Kundel Y, Inbar E,
et al. Assessment of response of brain metastases to radiotherapy by
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
PET imaging of apoptosis with 18F-ML-10. Eur J Nucl Med Mol
Imaging. 2012;39:1400–8.
Challapalli A, Kenny LM, Hallett WA, Kozlowski K, Tomasi G,
Gudi M, et al. 18F-ICMT-11, a caspase-3-specific PET tracer for
apoptosis: biodistribution and radiation dosimetry. J Nucl Med.
2013;54:1551–6.
Bohn P, Mouchard F, Rouvet J, de Boisgrollier AC, Vera P. 99mTc(Me)FGCDEVD, a potential tracer for apoptosis detection. Bioorg
Med Chem Lett. 2013;23:1375–8.
Buckle T, van Berg NS, Kuil J, Bunschoten A, Oldenburg J,
Borowsky AD, et al. Non-invasive longitudinal imaging of tumor
progression using an 111indium labeled CXCR4 peptide antagonist.
Am J Nucl Med Mol Imaging. 2012;2:99–109.
Hartimath SV, Domanska UM, Walenkamp AM, Rudi AJOD, de
Vries EF. [99mTc]O2-AMD3100 as a SPECT tracer for CXCR4
receptor imaging. Nucl Med Biol. 2013;40:507–17.
Weiss ID, Jacobson O. Molecular imaging of chemokine receptor
CXCR4. Theranostics. 2013;3:76–84.
Razumienko E, Dryden L, Scollard D, Reilly RM. MicroSPECT/CT
imaging of co-expressed HER2 and EGFR on subcutaneous human
tumor xenografts in athymic mice using 111In-labeled bispecific
radioimmunoconjugates. Breast Cancer Res Treat. 2013;138:709–18.
Fisher RE, Siegel BA, Edell SL, Oyesiku NM, Morgenstern DE,
Messmann RA, et al. Exploratory study of 99mTc-EC20 imaging for
identifying patients with folate receptor-positive solid tumors. J Nucl
Med. 2008;49:899–906.
Edelman MJ, Harb WA, Pal SE, Boccia RV, Kraut MJ, Bonomi P,
et al. Multicenter trial of EC145 in advanced, folate-receptor positive
adenocarcinoma of the lung. J Thorac Oncol. 2012;7:1618–21.
Müller C, Forrer F, Schibli R, Krenning EP, de Jong M. SPECT study
of folate receptor-positive malignant and normal tissues in mice using
a novel 99mTc-radiofolate. J Nucl Med. 2008;49:310–7.
Müller C, Mindt TL, de Jong M, Schibli R. Evaluation of a novel
radiofolate in tumour-bearing mice: promising prospects for folatebased radionuclide therapy. Eur J Nucl Med Mol Imaging. 2009;36:
938–46.
Müller C, Reber J, Schlup C, Leamon CP, Schibli R. In vitro and
in vivo evaluation of an innocuous drug cocktail to improve the
quality of folic acid targeted nuclear imaging in preclinical research.
Mol Pharm. 2013;10:967–74.
Chia K, Fleming IN, Blower PJ. Hypoxia imaging with PET: which
tracers and why? Nucl Med Commun. 2012;33:217–22.
Fujii H, Yamaguchi M, Inoue K, Mutou Y, Ueda M, Saji H, et al. In
vivo visualization of heterogeneous intratumoral distribution of
hypoxia-inducible factor-1α activity by the fusion of highresolution SPECT and morphological imaging tests. J Biomed
Biotechnol. 2012;2012:262741.
Lu G, Maresca KP, Hillier SM, Zimmerman CN, Eckelman WC,
Joyal JL, et al. Synthesis and SAR of 99mTc/Re-labeled small
molecule prostate specific membrane antigen inhibitors with novel
polar chelates. Bioorg Med Chem Lett. 2013;23:1557–63.
Eder M, Eisenhut M, Babich J, Haberkorn U. PSMA as a target for
radiolabelled small molecules. Eur J Nucl Med Mol Imaging.
2013;40:819–23.
Ogawa K, Mukai T, Inoue Y, Ono M, Saji H. Development of a novel
99mTc-chelate-conjugated bisphosphonate with high affinity for
bone as a bone scintigraphic agent. J Nucl Med. 2006;47:2042–7.
Torres Martin de Rosales R, Finucane C, Mather SJ, Blower PJ.
Bifunctional bisphosphonate complexes for the diagnosis and therapy of bone metastases. Chem Commun. 2009;(32):4847–9.
Fogelman I, Blake GM, Cook GJ. The isotope bone scan: we can do
better. Eur J Nucl Med Mol Imaging. 2013;40:1139–40.
Mariani G, Bruselli L, Duatti A. Is PET always an advantage versus
planar and SPECT imaging? Eur J Nucl Med Mol Imaging. 2008;35:
1560–5.