A new PET probe, (18)F-tetrafluoroborate, for the sodium/iodide symporter: possible impacts on nuclear medicine.
ABSTRACT As early as 1915, it was found that iodide is required in the thyroid gland for the production of thyroid hormones. Since then, radioiodines have been used as tracers in thyroid function tests and as agents for the treatment of hyperthyroidism and benign thyroid diseases. Furthermore, knowledge of the importance of the role played by iodine transport in thyroid cancer cells provides the rationale for the use of radioiodines to diagnose and treat thyroid cancer (1, 2). In fact, the clinical utilization of radioiodines led to the birth of nuclear medicine. Today, it is known that the iodide pump is a sodium/iodide symporter (NIS), an intrinsic membrane protein of the thyroid gland follicular cells (3, 4), and that the NIS-catalysed accumulation of iodide in cells from the interstitium is achieved against its transmembrane electrochemical gradient, which is maintained by sodium-potassium adenosine triphosphatase. The identification of the human NIS (hNIS) gene created many new diagnostic and therapeutic opportunities, and in particular, researchers are currently investigating the use of hNIS as a reporter gene for gene therapy and molecular and genomic imaging (5).
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ABSTRACT: Conventional methods for radiolabelling biomolecules such as proteins and peptides with fluorine-18 for PET imaging rely on carbon-fluorine bond formation and are complex and inefficient. Several non-carbon elements form strong bonds (i.e. with high bond enthalpy) with fluorine, but with lower activation energy for their formation compared to carbon-fluorine bonds, whilst preserving a relatively high kinetic stability. In particular, by incorporating boron-, aluminium- and silicon-containing prosthetic groups into biomolecules, promising results have recently been achieved in the radiolabelling with F-18-fluoride under mild aqueous conditions, affording a level of convenience, efficiency and specific activity potentially superior to those offered by conventional C-F bond formation methods. The promise already shown by these early studies heralds a new branch of bioconjugate radiochemistry involving a wider range of "fluoridephilic" elements for synthesis of PET molecular imaging agents.Dalton Transactions 06/2011; 40(23):6196-205. · 3.81 Impact Factor
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ABSTRACT: Preclinical and clinical tomographic imaging systems increasingly are being utilized for non-invasive imaging of reporter gene products to reveal the distribution of molecular therapeutics within living subjects. Reporter gene and probe combinations can be employed to monitor vectors for gene, viral, and cell-based therapies. There are several reporter systems available; however, those employing radionuclides for positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) offer the highest sensitivity and the greatest promise for deep tissue imaging in humans. Within the category of radionuclide reporters, the thyroidal sodium iodide symporter (NIS) has emerged as one of the most promising for preclinical and translational research. NIS has been incorporated into a remarkable variety of viral and non-viral vectors in which its functionality is conveniently determined by in vitro iodide uptake assays prior to live animal imaging. This review on the NIS reporter will focus on 1) differences between endogenous NIS and heterologously-expressed NIS, 2) qualitative or comparative use of NIS as an imaging reporter in preclinical and translational gene therapy, oncolytic viral therapy, and cell trafficking research, and 3) use of NIS as an absolute quantitative reporter.Current Gene Therapy 02/2012; 12(1):33-47. · 5.32 Impact Factor
A new PET probe,18F-tetrafluoroborate,
for the sodium/iodide symporter: possible impacts
on nuclear medicine
Hyewon Youn & Jae Min Jeong & June-Key Chung
Received: 6 August 2010 /Accepted: 11 August 2010 /Published online: 7 September 2010
# Springer-Verlag 2010
As early as 1915, it was found that iodide is required in the
thyroid gland for the production of thyroid hormones. Since
then, radioiodines have been used as tracers in thyroid
function tests and as agents for the treatment of hyperthy-
roidism and benign thyroid diseases. Furthermore, knowl-
edge of the importance of the role played by iodine
transport in thyroid cancer cells provides the rationale for
the use of radioiodines to diagnose and treat thyroid cancer
(1, 2). In fact, the clinical utilization of radioiodines led to
the birth of nuclear medicine.
Today, it is known that the iodide pump is a sodium/iodide
symporter (NIS), an intrinsic membrane protein of the thyroid
gland follicular cells (3, 4), and that the NIS-catalysed
accumulation of iodide in cells from the interstitium is
achieved against its transmembrane electrochemical gradient,
which is maintained by sodium-potassium adenosine tri-
phosphatase. The identification of the human NIS (hNIS)
gene created many new diagnostic and therapeutic opportu-
nities, and in particular, researchers are currently investigat-
ing the use of hNIS as a reporter gene for gene therapy and
molecular and genomic imaging (5).
Various negative ions, like ClO4−, ReO4−, TcO4−, I−,
SCN−, ClO3−and Br−, are transported by NIS (6), and thus,
radiolabelled forms of these agents can be used for thyroid
and NIS imaging. The apparent common denominator of
these substrates is that they are monovalent anions with a
size close to that of iodide. Tetrafluoroborate (TFB) is a
fluorine-containing ion that interacts with NIS (7), and
Anbar et al. (8) reported that radiolabelled TFB has the
potential for thyroid imaging, because it specifically
accumulates in the thyroid and inhibits iodide uptake by
the thyroid. It is hydrolytically stable under physiological
conditions, is not significantly metabolized and has low
For more than 65 years, radioiodines like131I,123I and
125I have been used as probes for NIS (2). However, the
half-lives of gamma-emitting radioiodines are longer than
those required for imaging, and thus, absorbed radiation
doses are unnecessarily high. The resolution and sensitivity
of positron emission tomography (PET) are significantly
better than those of gamma camera images and single
photon emission computed tomography (SPECT), and
better quantifications of the absolute amounts of a tracer
in small regions are also possible by PET.
The first choice for a PET NIS imaging agent should be
124I, which can be produced by a cyclotron.
positron emitter with a half-life of 4.18 days, which is
appropriate for dosimetric calculation of131I. However, its
positron emission rate is only 23% and it emits several
high-energy gamma photons with energy values of 603
(61%), 723 (10%) and 1,691 keV (10%), and these high
emissions result in high radiation doses and relatively poor
image quality as compared with
production requires a special solid
accelerated proton beam (9), and this type of system is
unavailable in the majority of cyclotron centres.
124I is a
124Te target and an
H. Youn:J. M. Jeong:J.-K. Chung (*)
Department of Nuclear Medicine, Seoul National University
College of Medicine,
101 Daehang-Ro, Jongno-Gu,
Seoul, Korea 110-744
H. Youn:J. M. Jeong:J.-K. Chung
Laboratory of Molecular Imaging and Therapy, Cancer Research
Institute, Seoul National University College of Medicine,
H. Youn:J. M. Jeong:J.-K. Chung
Institute of Radiation Medicine, Medical Research Center,
Seoul National University,
Eur J Nucl Med Mol Imaging (2010) 37:2105–2107
18F is the most widely used radionuclide for PET and is
available from almost all cyclotrons.18F can be produced
by irradiating18O-water with an accelerated proton beam
and has a half-life of 110 min, which is appropriate for
short-term imaging. Accordingly, the idea of developing an
18F-labelled NIS imaging agent is still very much alive.
In a study published in this issue of EJNMMI,
Jauregui-Osoro et al. (10) found that TFB had been used
as a substrate for NIS and labelled it with
isotope exchange method under acidic conditions at 120°C
for 10 min. The procedure was simple but specific activities
were low, though labelling, purification and quality control
procedures were straightforward. The precursor TFB is
commercially available at a low price, and the labelled18F-
TFB is easily purified using sequential treatment through a
silver ion-loaded cation exchange column and two alumina
columns. Quality control can be performed by alumina
thin-layer chromatography using a methanol mobile phase.
Although the reported specific activity of18F-TFB was
about 1 GBq/μmol, which is much lower than18F-labelled
radiopharmaceuticals used for receptor imaging, high
thyroid uptakes and excellent images were obtained in the
experimental mice. This high uptake is explained by the
fact that negative ion uptake by NIS has much greater
capacity than uptakes by receptor binding. Generally,
receptor binding agents require specific activities of higher
than 30 GBq/μmol for PET. A preliminary biological
assessment of18F-TFB showed that it is similar to99mTc-
pertechnetate and that it justifies evaluation in humans.
The main advantages of124I PET imaging are its high
resolution and the dosimetric information provided. Be-
cause131I is the mainstay of therapy for thyroid cancer, and
because treatment success or failure depends on the degree
of iodine uptake by tumour cells,124I PET imaging will
increasingly act as a indicator of this treatment. Absolute
124I accumulation in residual cancer tissues can be obtained
from PET/CT images, and radiation doses can be calculat-
ed, although recovery correction is mandatory for124I PET
quantifications (12). Freudenberg et al. (13) reported that
compared to an empirical fixed dose protocol,
dosimetry findings changed management in 25% of
patients. PET dosimetry could provide useful routine
procedures for radioiodine therapy in advanced differenti-
ated thyroid cancer and might allow safer or more effective
radioiodine dose and earlier multimodal interventions than
standard empirical protocols. In addition, PET can be used
for dosimetric calculation in patients with Graves’ disease
and autonomously functioning nodule (11).
It might be possible to use18F-TFB as a detector for
functioning cancer tissues. However, it is questionable to
use18F-TFB for dosimetry, because it has some problems,
such as the pharmacokinetic and pharmacodynamic differ-
ences between it and radioiodines. Although18F-TFB can
18F using an
be taken up by NIS, its transportation rate differs from that
of iodide. Furthermore, it cannot be incorporated into
thyroglobulin for the synthesis of thyroid hormones like
iodide. Thus, a compensatory calculation method should be
applied for simulating radioiodine uptake, and comparative
studies with other NIS imaging agents, such as99mTc,123I
and131I, are required.
Immunostaining using hNIS antibodies was found to
produce positive results in only a few malignant papillary
or follicular thyroid cells (14), but the presence of this small
amount of NIS determines the effectiveness of radioiodine
therapy in residual thyroid cancer. We evaluated the
outcomes of radioiodine therapy in 22 patients with
recurrent lesions and found that 80% of patients positive
by NIS immunostaining responded to therapy, whereas only
33.3% of patients negative for NIS did so (15). Thyroid
cancer tissues expressing NIS take up more radioiodines
and respond better to the therapy, which strongly suggests
management. It may be important for staging thyroid
cancer before thyroidectomy and for detecting recurrence/
metastases during follow-up.
Reporter imaging of NIS using a gamma camera is easier
for radioiodines and
camera is available in most nuclear medicine departments
(5). The use of NIS for reporter imaging allows the
noninvasive and repeated visualization of NIS-expressing
cells in living animals, and these images even provide the
locations, durations and magnitudes of NIS gene expression
in cells and information on the migration and differentiation
of NIS-expressing cells. The most commonly used NIS
reporter imaging system is a cis-promoter/NIS system. This
type of system can be based on endogenous or exogenous
NIS gene expression controlled by specific promoters, and
thus, increased radioiodine uptake for such a system
represents the increased activity of a particular promoter.
Furthermore, this strategy can be applied to NIS radionu-
clide therapy by killing NIS-expressing cells (16).
Most conventional PET imaging reporter genes, such as
HSV-tk and D2R, require the synthesis of complicated
substrates, but NIS has the advantage of a wide range of
available substrates. Radioiodines and99mTc have been used
as NIS imaging substrates, and more powerful therapeutic
nuclides with shorter half-lives, such as188Re and211At, can
also be used for NIS radiotherapy. However, the routinely
available PET agents still have been highly requested for
small animal PET imaging. Despite the advantage of wide
substrate availability of NIS, no specific cost-effective PET
agent with a lower imaging dose has been developed.
18F-TFB has demonstrated the capability to overcome
the limitations of the small animal PET imaging of NIS
(10). The use of labelled TFB has considerable promise
because it shows high stability, low metabolic potential and
18F-TFB NIS imaging is important for patient
99mTc, because a suitable gamma
2106Eur J Nucl Med Mol Imaging (2010) 37:2105–2107
low toxicity (rat LD50=550 mg/kg s.c.). The low positron
energy (633 keV) and the high positron yield (96.7%) of
18F reduce possible radiation damage to animals and
provide sufficient positrons to maintain image quality.
Although Jauregui-Osoro et al. (10) did not demonstrate
transport of the TFB ion into cells by NIS or direct binding
to NIS, their PET images and biodistribution studies
indicated that the specific activity of18F-TFB for NIS was
sufficient in small animal imaging.
In conclusion, the development of
possibility of inducing a big impact on the diagnosis and
treatment of thyroid disorders, especially thyroid carcinoma.
18F-TFB can be used for the sensitive imaging method to
detect metastatic cancer before thyroidectomy and residual
cancer after operation. In addition, it can be used in making
decisions about radioiodine therapy and prediction of therapy
result in individual tumour lesions. For the dosimetric
calculations should be established following pharmacokinet-
ic and pharmacodynamic studies.18F-TFB has several merits
for small animal PET imaging of the NIS reporter gene.
However, it is still necessary to develop an improved method
to obtain higher specific activity of18F-TFB.
18F-TFB has a
131I therapy, compensatory
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