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MOLECULAR BIOLOGY PROBLEMS
OF DRUG DESIGN AND MECHANISM
OF DRUG ACTION
18F-FDG AND OTHER LABELED GLUCOSE DERIVATIVES
FOR USE IN RADIONUCLIDE DIAGNOSIS
OF ONCOLOGICAL DISEASES (REVIEW)
V. M. Petriev,1V. K. Tishchenko,1and R. N. Krasikova2,3
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 50, No. 4, pp. 3 – 14, April, 2016.
Original article submitted October 28, 2014.
This review addresses progress in the radionuclide diagnosis of oncological diseases using
radiopharmaceutical preparations (RPP) based on labeled glucose derivatives. Most attention is paid to
2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG), a glucose analog labeled with fluorine-18 (T1/2 = 110 min) and
the only radiotracer for glycolysis, which is used in 90% of clinical studies using positron emission tomogra-
phy (PET). We describe approaches to the synthesis of 18F-FDG and state-of-the-art automated technologies
allowing tens of clinical doses of RPP for PET investigations of patients to be prepared. The main areas of use
of PET with 18F-FDG in the diagnosis of various tumors are discussed, as is the potential for using glucose de-
rivatives with other radionuclides (68Ga, 123I, 99mTc, 188Re) as tracers for use in PET and SPECT diagnosis.
Keywords: 2-[18F]Fluoro-2-deoxy-D-glucose, 18F-FDG, radiopharmaceutical preparations, radiotracers,
oncological diagnosis, positron emission tomography, PET, single-photon emission computed tomography,
SPECT, planar scintigraphy, PS, labeled glucose derivatives.
The early diagnosis of malignant tumors plays a leading
role in selecting treatment tactics and the prognosis for sur-
vival of oncological patients. This task is widely approached
using radionuclide diagnosis (nuclear medicine) - planar
scintigraphy (PS), single-photon emission computed tomog-
raphy (SPECT), and positron emission tomography (PET).
These methods are based on in vivo studies of the distribu-
tion of compounds labeled with radioactive isotopes
(radiotracers, radiopharmaceutical preparations (RPP)) using
external detector systems; these differ in terms of the type
and nuclear physics properties of the radionuclides used, the
methods of detecting their radiation and processing the data,
and the set of radiotracers available [1]. This allows informa-
tion to be obtained on impairments to physiological and bio-
chemical processes at the molecular level and provides for
detection of functional changes in organs and tissues before
the onset of clinical signs of disease. SPECT and PET meth-
ods are currently used in combination with topographical an-
atomical radiological diagnostic methods such as computed
tomography (CT) and magnetic resonance imaging (MRI).
These latter are have high resolution and provide clear imag-
ing of morphological changes to organs and tissues and the
structure and size of tumor neoplasms, though they do not
provide any information on functional changes, metabolic
impairments, or other processes typical of malignant cells.
The development of hybrid (multimodal) technologies com-
bining PET and CT to make a PET-CT scanner has signifi-
cantly widened the potentials of oncological diagnosis [2].
Pharmaceutical Chemistry Journal, Vol. 50, No. 4, July, 2016 (Russian Original Vol. 50, No. 4, April, 2016)
209
0091-150X/16/5004-0209 © 2016 Springer Science+Business Media New York
1Medical Radiology Scientific Center, Ministry of Health of the Russian
Federation, 4 Korolev Street, 249036 Obninsk, Kaluga Region, Russia;
e-mail: petriev@mrrc.obninsk.ru.
2N. P. Bekhterev Institute of the Human Brain, Russian Academy of Scien-
ces, 9 Pavlov Street, 197376 St. Petersburg, Russia; e-mail:
raisa@ihb.spb.ru.
3Faculty of Chemistry, St. Petersburg State University, 7-9 Universitet-
skaya Bank, 199034 St. Petersburg, Russia.
DOI 10.1007/s11094-016-1425-y
Multimodal technologies are also used in SPECT, though
PET has better sensitivity, resolution, and other properties
than SPECT [3]. The use of short-lived cyclotron radionuc-
lides in PET generates the unique capacity of the method:
positron decay is accompanied by the formation of two
high-energy gamma annihilation photons (0.511 MeV) emit-
ted at an angle of 180° and which are easily detected using
external detectors operating in a coincidence regime without
the need for lead collimators. An undoubted advantage of
PET is that the shortest-lived PET radionuclides (15O,
T1/2 = 2.04 min; 13N, T1/2 = 9.96 min; 11C, T1/2 = 20.4 min) ae
isotopes of vitally important biological elements. Incorpora-
tion of these isotopes into the structures of various molecules
has no effect on their biochemical properties or metabolism,
providing PET with exclusively high biospecificity. The
fourth radionuclide, 18F, is not an organogenic element, but is
regarded as an “ideal” PET radionuclide because of its rela-
tively long delay halflife (110 min) and other nuclear physics
properties.
Over a period of more than 30 years, the development of
PET has included production of a whole series of RPP with
different mechanisms of involvement in metabolic and other
processes associated with tumor malignancy (glycolysis,
amino acid transport, proliferation, apoptosis, angiogenesis,
hypoxia, expression of particular receptor types, etc.) at the
molecular level. Nonetheless, the main RPP for PET, used in
more than 90% of all investigations, was and remains an
18F-labeled fluorinated glucose analog – 2-[18F]fluoro-2-deo-
xy-D-glucose (18F-FDG). PET studies using 18F-FDG allow
regional glucose consumption rates to be measured - a prop-
erty which cannot be obtained by any other method.
Oncological diagnosis is the main area of use of 18F-FDG; in
addition, this radiotracer is used in cardiology [4, 5] for im-
aging myocardial viability, in neurological investigations of
patients with Alzheimer’s disease and other forms of demen-
tia, patients with epilepsy [6, 7], and in basic research into
age-related metabolic impairments, and others. In addition to
the unique properties of 18F-FDG as a radiotracer for
glycolysis, an enormous role in its wide utilization is also
played by the development of highly productive methods for
synthesis and automation, which allow tens of clinical doses
of RPP to be made in a single run. Considering the relatively
long halflife of 18F, new technologies provide for the deliv-
ery of 18F-FDG to PET facilities or radionuclide diagnosis
departments lacking expensive radiochemical equipment.
As 18F production in a medical cyclotron is quite expen-
sive (and leads to high costs for clinical doses of 18F-FDG
[8]), recent years have seen development of the potential for
210 V. M. Petriev et al.
Fast
18
18
18
F-FDG
OOH
F
18
OH
OH
OH OOH
F
18
OH
OH
OP
O
O
O
O
OH
F
18
OH
OH
OH
2-
1. Glut1, Glut2
2. Hexokinase
Glucose phosphatase
Slow
FDG-6-phosphate
Glucose phosphate
isomerase
Fluorodeoxyfructose
Fig. 1. Scheme for “blocking” of 18FäFDG metabolism in cells [11].
TABLE 1. Nuclear Physics Properties of Radionuclides Used for Preparing Labeled Glucose Derivatives.
Radionuclide T1/2 EC Emission energy, MeV Preparation method*) Use
18F 110 min b+96.9 % EC 3.1 % g0.511 Cyclotron, 18O(p, n)18F PET
11Ñ 20.4 min b+99.8 % EC 0.2 % g0.511 Cyclotron 14N(p, a)11CPET
68Ga 68 min b+89.1 % EC 10.9 % g0.511 Generator 68Ge (288 days) PET
99mTc 6.02 h IT g0.140 (89 %) Generator 99Mo (6 days) PS, SPECT
using other PET radionuclides as radioactive labels, particu-
larly 68Ga – generator isotopes which can be produced with-
out a cyclotron. Alternatives to PET are the cheaper PS and
SPECT diagnostic methods. The main problem in develop-
ing RPP for measurement of glycolytic activity in tissues
(like 18F-FDG) is that these methods use metal isotopes or
123I as the radionuclide, introduction of which into molecules
inevitably affects their metabolism and requires detailed
study. Investigations using technetium-99m (99mTc) have re-
ceived the most development, because of the exclusive role
of this generator radionuclide (99mTc) in more than 90% of
all PS and SPECT investigations. Similar developments have
also been achieved with the generator radionuclide rhe-
nium-188 (188Re, a chemical analog of technetium) with
unique nuclear physics properties: because of the high en-
ergy of its b–particles, 188Re has potential as a radiothera-
peutic nuclide; its distribution in the body and uptake into tu-
mors can be detected using a gamma camera because the
emission spectrum includes a quite intense gline at
0.155 MeV (Table 1). The radionuclides 99mTc/188Re form an
isotope pair for cancer theranostics – a new, rapidly advanc-
ing area of medicine combining diagnosis and treatment [9].
We consider here the abilities and limitations of PET in-
vestigations with 18F-FDG in the radionuclide diagnosis of
tumors and the potential for using other glucose derivatives
using iodine and various metal isotopes (Table 1) as the ra-
dioactive label in PET and SPECT diagnosis and, perhaps,
radiotherapy. In addition, this review also describes methods
of preparing and automating 18F-FDG synthesis to provide
this radionuclide for clinical PET investigations.
Metabolism of 18F-Based Radiotracers
Interest in the use of 18F-labeled RPP arises from the nu-
clear physics properties of this radionuclide, which are al-
most idea for PET investigations. 18F is an essentially pure
positron emitter. Because of the low energy of the emitted
positrons (maximum b+energy 0.63 MeV) and, conse-
quently, its very short track length in cells (2.4 mm), 18F
gives PET images with the best spatial resolution. The sim-
ple and convenient method for preparing the radionuclide us-
ing the nuclear reaction 18O(p, n)18F, occurring on irradiation
of an aqueous target in a cyclotron with medium-energy pro-
tons, makes 18F particularly attractive for routine production
of RPP. In more modern cyclotron models, simultaneous ir-
radiation of two targets for 2 h at a beam current of 80 mA
produces up to 25 Ci of 18F [10]. The relatively long (com-
pared with other cyclotron-produced PET radionuclides)
halflife of 18F allows complex radiochemical RPP syntheses
to be performed quite far away from clinics lacking their
own cyclotron or radiochemical facilities. The number of
PET cameras in service is now much greater than the number
of installed cyclotrons, such that 18F-labeled RPP is in great
demand by clinicians.
It should be noted that 18F is not an organogenic element.
Fluorine can substitute for hydrogen atoms or hydroxyl
groups with small van der Waals radii in various molecules,
causing minimal structural alterations. However, the metabo-
lism of fluorinated labeled derivatives is significantly differ-
ent from that of the starting substrates. This at first sight un-
favorable factor is used with good effect in the PET concept
of “blocked” or “captured” metabolism, as described in de-
tail in [11] (Fig. 1). Like glucose, on entry from the blood
into a cell, 18F-FDG is phosphorylated by hexokinase,
though the metabolism process ends at this point. 18F-FDG
remains in the cell as 18F-FDG-6-phosphate, which does not
undergo glycolysis because of the presence of the fluorine
atom in the molecule and the low concentration of the en-
zyme glucose-6-phosphatase in tumor cells. Some tumors
provide exceptions (for example, highly differentiated hepa-
tocellular carcinomas) and have high intracellular phospha-
tase concentrations, thus allowing dephosphorylation of
18F-FDG-6-phosphate and its excretion via the liver [12].
Malignant tumors are characterized by more active
glycolysis, due to increased levels of glucose-transporting
proteins (glucose transporters Glut1 and Glut2) [13 – 15]
and, to a greater extent, increases in hexokinase activity in
the neoplasm [15 – 17]. This is the basis of PET investiga-
tions with 18F-FDG in tumor diagnostics, the informative-
ness and value of which in contemporary oncological diag-
nosis is difficult to overstate. The distribution of 18F-FDG in
the body tissues is described in the framework of a simple
pharmacokinetic model. Thus, PET data from investigations
using 18F-FDG are quite straightforward to interpret.
18F-FDG and Other Labeled Glucose Derivative 211
O
H
AcO
AcO
AcO
H
OTf
H
H
OAc
O
H
OH
OH
OH
H
H
F
18
H
OH
1) [18F]KF/K222 or [ 18 F]TBAF
AcN, 100°C
2) OH
–
or H
+
Fig. 2. Scheme of the nucleophilic synthesis of 18F-FDG; OTf – the triflate leaving group; OAc – the acetate protecting group; AcN –
acetonitrile.
Methods of preparing [18F]FDG
18F-FDG was first prepared in the mid-1970s at the
Brookhaven National Laboratory, USA [18]. The synthesis
consisted of reaction of electrophilic radiofluorination using
18F-labeled acetylhypofluorite, while the radionuclide was
prepared by the nuclear reaction 20Ne(d, a)18F in a gaseous
cyclotron target. Fluorination of 3,4,6-tri-O-acetyl-D-glu-
cose yielded 3,4,6-tri-O-acetyl-2-deoxy-2-[18F]fluoro-D-glu-
copyranosyl fluoride, hydrolysis of which in acid conditions
formed 18F-FDG. The radiochemical yield of the reaction and
the radiochemical purity of the product compound were
24 ±3 and 98% respectively. Despite the high levels of up-
take of 18F-FDG in tumor tissues demonstrated in the earliest
studies, this radiotracer has not found wide use because of
the very complex and difficult synthesis method, run essen-
tially by hand using standard chemical glassware.
In 1986, a German group [19] developed a nucleophilic
method for preparing 18F-FDG which, because of its high
radiochemical yield and operator simplicity is ideal for syn-
thesizing radiotracer for routine PET investigations. The re-
action proposed in this work – nucleophilic substitution of
the triflate group in the 1,3,4,6-tetra-O-acetyl-2-O-trifluoro-
methanesulfonyl-b-D-mannopyranose (mannose triflate)
molecule in the presence of interphase catalysts – Kryptofix
(K2.2.2) or tetrabutylammonium (TBA) carbonate, forming
activation complexes with [18F]fluoride [K/K2.2.2]+F–or
[18F]TBAF – runs stereospecifically with a conversion of the
configuration (Walden inversion) (Fig. 2). The second stage
of the synthesis is “release” of the protective groups, after
which the end product is purified by solid-phase extraction
on single-use cartridges. This method, often called the
Hamacher method, is used with minor modifications in all
current 18F-FDG synthesis modules.
In the first variant, removal of acetyl groups is by acid
hydrolysis at a temperature of 130°C. Alkaline hydrolysis
was found to be more convenient for automation, as it does
not require stringent conditions and runs easily and quickly
at room temperature, including in on-line regimes with sin-
gle-use cartridges [20]. Alkaline hydrolysis is also used in
18F-FDG synthesis at the Institute of the Human Brain, Rus-
sian Academy of Sciences, St. Petersburg (IHB RAS) [21].
18F-FDG synthesis has been presented in many studies; a
general monograph was prepared under the auspices of the
IAEA, and this is available free of cost [22].
The isotopically labeled (“pure”) glucose analog
[11C]-2-deoxy-D-glucose is of particular interest for studies
of the pharmacokinetics of labeled glucose analogs. How-
ever, in view of the short halflife of carbon-11 and the com-
plicated radiochemical synthesis, this radiotracer has not
been employed in routine PET investigations, but is used in
scientific studies, including those determining the constant of
elimination in a three-compartment model of 18F-FDG me-
tabolism.
Automated 18F-FDG synthesis
As already noted, developments in automated synthesis
have played an enormous role in the use of 18FäFDG, en-
abling preparation of tens of clinical doses of radiotracer per
synthesis run. In PET radiochemistry, automated processes
constitute a key element from the point of view of radiation
safety, as the activity of radionuclides emanating from the
target reach tens of Ci in the case of fluorine-18 and 1 – 3 Ci
for the radionuclides prepared in gaseous form (11C, 15O).
The need for automation is also dictated by current GMP re-
quirements, addressing the stepwise automated control of
preparation for synthesis and all stages of synthesis as one of
the main factors assuring the quality of the RPP prepared. In
addition, a stable radiochemical product yield and its com-
plete compliance with quality control parameters are impor-
tant for routine clinical investigations, these being achieved
using automated methods.
212 V. M. Petriev et al.
O
O
NH
OH NO
O
H
N
OH
HO
HO 18F
[18F]-FDG
80oC, 30 min
Arg-Arg-Pro-Tyr-Ile-Leu-OH
Glu-Arg-Arg-Pro-Tyr-Ile-Leu-OH
Arg-Arg-Pro-Tyr-Ile-Leu-OH
Glu-Arg-Arg-Pro-Tyr-Ile-Leu-OH
Glu-Arg-Arg-Pro-Tyr-Ile-Leu-OH
Glu-Arg-Arg-Pro-Tyr-Ile-Leu-OH
Arg-Arg-Pro-Tyr-Ile-Leu-OH
HN
2
Peptide
Peptide
Peptide
Fig. 3. Introduction of 18F label into peptide molecules via formation of [18F]FDG [77].
At the initial stage of development of PET, 18F-FDG was
produced using home-made semiautomated remote-control
module or, somewhat later, manufactured systems. In 1990,
the entry of PET into wide use in clinical diagnostics led to
the need multidose 18F-FDG synthesis to support the simulta-
neous operation of multiple PET scanners within PET cen-
ters or for delivery of RPP to close-by clinics. In parallel
with the development of highly productive targets for
radionuclide synthesis, leading medical PET cyclotron man-
ufacturing firms are actively involved in creating automated
synthesis modules, which can be divided into two groups: 1)
classical static systems which are loaded with reagents for
each synthesis, with subsequent washing of all lines prior to
the next synthesis, and 2) cassette-type modules in which the
reagents are placed in a single-use sterile cassette (disposable
kits). Static systems include TRACERlab FxFDG (GE
Healthcare), CPCU, Chemistry Process Control Unit (CTI,
Knoxville, Tennessee, USA), EBCO/Jaltech FDG synthesis
module (EBCO, Canada), and Explora FDG 4 (Siemens).
Examples of cassette-type modules (sometimes called “black
boxes”) are GE FASTlab (GE Healthcare), SYNTHERA
(IBA Molecular Imaging, Belgium), and BIOSCAN
FDG-Plus synthesizer (BIOSCAN Inc., USA). The use of
cassette modules such as GE FASTlab (GE Healthcare) al-
lows tens of clinical doses of 18FäFDG to be prepared in a
single synthesis run lasting 14 min, including preparation
time. The features and capacities of various synthesis mod-
ules are described in detail in reviews [24, 25].
Many PET centers have made their own developments in
automation. Thus, studies at the, Institute of the Human
Brain, Russian Academy of Sciences, St. Petersburg have de-
veloped a state-of-the-art automated static-type module for
preparation of 18F-FDG using an original computer program
and inexpensive commercially available and easily substi-
tuted components [26]. The radiochemical yield of 18F-FDG,
without correction for radioactive decay, was greater than
60%, which is a productivity level comparable with those of
the best exemplars of non-Russian modules.
Methodological Aspects of PET Investigations
with 18F-FDG in Oncological Diagnosis
The grounds for using labeled glucose derivatives to de-
termine the stage or extent of malignant tumors were laid
down more than 80 years ago in reports by Warburg [27], in
which in vitro studies of induced and spontaneous tumors in
humans and animals first revealed the positive correlation
between tumor stage and the rate of glycolysis. Decreases in
tumor differentiation and acceleration of tumor growth were
shown to be accompanied by increases in glucose utilization.
A predominance of anaerobic metabolism over the more effi-
cient oxidative was accompanied by a high rate of glucose
utilization at tumor growth stages 3 – 4 as compared with
stages 1 – 2 and an increase in the glucose-6-phosphate con-
centration, which could lead to an increase in the quantity of
2-deoxyglucose-6-phosphate at the later stages of the tumor
process, in accordance with Sokoloff’s kinetic model [28].
The different rates of anaerobic glycolysis in benign and ma-
lignant tumors allow this agent to be used in the differential
diagnosis of malignant tumors of different nosological forms
and locations, with identification of regional spread, detec-
tion of distant metastases, and evaluation of treatment effi-
cacy in oncological patients.
18F-FDG and Other Labeled Glucose Derivative 213
Fig. 4. Scheme for the synthesis of [18F]-FDG-folate.
Interpretation of data from clinical PET investigations
using 18F-FDG is enormously important. Despite the fact that
the absolute rate of glucose metabolism can be determined
using 18F-FDG (in ml/min/100 g of brain matter), identifica-
tion of the corresponding constants for the three-compart-
ment pharmacokinetic model requires a dynamic scanning
regime, which greatly increases the duration and complexity
of the PET investigation procedure and its associated data
processing. Most PET centers therefore use one or another
semi-quantitative evaluation, including calculation of the in-
dex of RPP uptake as the ratio of the accumulated 18F-FDG
concentration in tumors and the reference region. Applica-
tion of this and other semi-quantitative approaches to PET
diagnosis of cerebral tumors has been described in detail in
[3], in review [29], and other reports. The simple and very
rapid approach consisting of visual evaluation, based on vi-
sual determination of the pathological focus as a
hypometabolic (“cold” spot) or hypermetabolic (“hot spot”)
focus or indistinguishable from surrounding tissue is suffi-
ciently effective in determining tumor malignancy and/or
prognoses.
In addition to visual assessment of images, various meth-
ods are used to normalize levels of RPP uptake, for example,
a standardized uptake value (SUV). This parameter is calcu-
lated by correcting the concentration of radioactivity in the
tumor for the RPP dose given and the patient’s weight
[30 – 32] and is widely used for assessing tumors in
whole-body PET investigations. It was previously thought
that the threshold value of this parameter, 2.5, could discrim-
inate between malignant and benign neoplasms, i.e., spots
with higher uptake levels should be evaluated as malignant
and those with lower uptake are taken as benign [33]. How-
ever, the value of this parameter is now doubted by most in-
vestigators. Foci of inflammation with high uptake levels and
metastases with SUV of around 1.0 are often encountered
[34]. This parameter is therefore now used mainly for evalu-
ating treatment efficacy [35].
Pharmacokinetic studies with 18F-FDG in healthy mice
have shown that the compound is quickly taken up by the
kidneys, liver, lungs, and small intestine and is then rapidly
eliminated from these organs [36]. On the other hand, the
18FäFDG contents in the brain (2 – 3%/organ) and heart
(3 – 4%/organ) remained unaltered for 2 h. The substance is
eliminated mainly via the kidneys: 16% of the activity given
is excreted in 1 h [36]. Analysis of the biological behavior of
18F-FDG in rats with AH109A ascites hepatoma demon-
strated that the compound is taken up mainly by tumor tissue
(up to 2.65%/g), heart, intestine, and brain. 18F-FDG is rap-
idly eliminated from the blood, promoting high numerical tu-
mor/blood content ratios (22.1) at 60 min [37].
A significant drawback of this compound is its ability to
accumulate not only in tumor cells, but also in inflammatory
cells such as granulocytes, macrophages, and leukocytes
[38]. In normal conditions, significant quantities of 18F-FDG
are taken up by the intestine, urinary bladder, muscle tissue,
and brown fatty tissue [39, 40].
Potential of PET with 18F-FDG in Oncological Diagnosis
PET investigations with 18F-FDG have opened up new
possibilities for in vivo differentiation of malignant and be-
nign neoplasms, for identification of the spread of the tumor
process (tumor growth staging), detecting recurrences and
distant metastases after treatment, differentiating areas of ne-
crosis and metastases, and planning antitumor treatment and
monitoring its efficacy, etc. [41]. The capacities of PET with
18F-FDG and other potential radiotracers have been dis-
cussed in Russian monographs [3, 42]. PET is currently per-
formed simultaneously with CT investigations using com-
bined PET-CT scanners [43, 44]. Overall, use of PET/CT de-
creases the number of false positive results associated with
the physiological uptake of glucose by brown fatty tissue,
muscles, lymphoid tissue, and the intestine [40, 45, 46].
Diagnosis of lung cancer. Data reported in [47] indicate
that the sensitivity and specificity of 18F-FDG PET in the di-
agnosis of non small cell lung cancer are 96% and 80% re-
spectively. It is of fundamental importance that PET provides
reductions in the number of invasive procedures required for
staging tumors [48].
The accuracy of diagnostic investigations increases with
repeat PET investigations some hours after i.v. administra-
tion of 18F-FDG, as radiotracer uptake by tumors increases
with time [49, 50].
False negative results can be produced by neoplasms of
size less than 5 mm, low tumor metabolic activity, and
hyperglycemia [50].
Diagnosis of breast cancer. In the diagnosis of breast
cancer (CaBr), the most important direction for the use of
18F-FDG is in evaluating the spread of the process, where
PET is more effective than other medical imaging methods.
The sensitivity of PET in the diagnosis of primary CaBr foci
is 20 – 100% and the specificity is 65 – 100% [51, 52]. The
sensitivity of this investigation is very dependent on the size
of the primary neoplasm. For tumors of size less than 5 mm,
the sensitivity of PET with 18F-FDG has been found to be no
214 V. M. Petriev et al.
Fig. 5. Structural formula of 68Ga-DOTA-2-deoxy-D-glucose
(68Ga-DOTA-DG) [84].
more than 53%, while for lesions of size greater than 20 mm,
sensitivity increases to 92% [53]. Tumors of up to 5 mm can
be diagnosed successfully by positron emission mammogra-
phy (PEM) with 18F-FDG. Numerous studies have demon-
strated that the specificity of PET reaches 91 – 100%, which
is greater than obtained with mammography [54].
Diagnosis of head and neck tumors. Tumors with a low
level of malignancy (low-grade tumors) are characterized by
decreased glucose metabolism, while highly malignant
(high-grade tumors) show hypermetabolism. The rate of
glycolysis in gliomas as determined by PET with 18F-FDG
provides a more precise reflection of the grade of malig-
nancy than MRI or CT scanning [93].
Despite the confirmed diagnostic significance of PET
with 18F-FDG in the diagnosis of brain neoplasms, long ex-
perience in the use of investigations has identified a whole
series of limitations for this radiotracer, associated with a
physiologically high level of glucose metabolism in the gray
matter of the brain and similarity with impairments to energy
metabolism in benign tumors and nontumor lesions [57]. As
18F-FDG is not a specific RPP for tumors, its utilization in
macrophages produced in abscesses or inflammatory foci
when infiltratory growth occurs can lead to false positive re-
sults [58].
In contrast to MRI scans, PET provides visualization of
radiation necrosis zones as areas of decreased metabolism
with 18F-FDG utilization rates which are lower than or com-
parable with those in the surrounding parenchyma, while re-
current tumors give clear hot spots with glucose utilization
rates greater than those in the adjacent unaltered tissue and
the contralateral side [59].
Diagnosis of thyroid neoplasms. In patients with differ-
entiated thyroid tumors, 18F-FDG can be used effectively for
detection of recurrences and the diagnosis of metastatic
lymph node and lung lesions with increased thyroglobulin
levels and negative whole-body scans using 131I [60]. The
sensitivity and specificity of this method in patients with in-
creased thyroglobulin levels were 88.5 – 95% and
25 – 84.7% respectively [61, 62].
Diagnosis of malignant abdominal tumors. In patients
with esophageal tumors, the use of PET with 18F-FDG is
most effective for staging. The sensitivity of this investiga-
tion for the diagnosis of regional and distant metastases is
45 – 78%, which is greater than for CT scanning [63].
18F-FDG has been indicated in the diagnosis of gastric
cancer for assessing the extent of the tumor process. The
main advantage of PET is that its sensitivity is greater than
that of CT scanning in the diagnosis of distant metastases
[64, 65].
PET with 18F-FDG is used with success for staging the
process in patients with colorectal cancer [66]. 18F-FDG is
more effective than CT scanning in terms of sensitivity for
the diagnosis of distant metastases, especially when there are
multiple metastases in the liver [67]. PET with 18F-FDG is
highly effective in the diagnosis of recurrences of colorectal
cancer independently of lesion site [68, 69].
The problem of the diagnosis of pancreatic cancer re-
mains relevant. PET with 18F-FDG can be used with success
in the complex diagnosis of cancer, especially for identifica-
tion of regional and distant metastases and for assessing
treatment efficacy [70]. The main problem is associated with
the nonspecific uptake of the agent in focal and diffuse pan-
creatitis. These pathologies are discriminated by using inter-
val investigations essentially 2 h after injection of agent,
when the level of 18F-FDG uptake into tumors generally in-
creases, while uptake into inflammatory foci decreases, as
well as by using dynamic PET investigations [71, 72].
The sensitivity of PET in the diagnosis of liver
metastases is significantly greater than that of CT, MRI, or
ultrasound scans [65]. PET can be used to evaluate the meta-
bolic activity of tumor tissue to obtain a differential diagno-
sis of malignant neoplasms and benign liver disease, particu-
larly focal nodular hyperplasia [73].
Diagnosis of malignant neoplasms of the urogenital
tract. 18F-FDG PET is rarely used in the diagnosis of malig-
nant neoplasms of the urogenital tract because of the high
physiological uptake of 18F-FDG in the kidneys and urinary
bladder in combination with the low metabolic activity of tu-
mors such as renal and prostate cancers [74]. The greatest
significance of PET with 18F-FDG in oncological urology is
in patients with testicular tumors for detection of reginal and
distant metastases [75, 76]. The sensitivity of the method for
diagnosing metastases of testicular tumors is greater than
that of CT scans [76].
Other Areas of the Use of Labeled Glucose Analogs
Studies in which 18F-FDG has been used as a label for
other, more complex, compounds, such as peptides, which
cannot be directly labeled with 18F because of the stringent
conditions required for radiofluorination (high temperature,
strongly alkaline conditions) are of particular interest.
18F-FDG is incorporated into peptide molecules using vari-
ous approaches, such as formation of oxime bridges. The ba-
sic reaction scheme is shown in Fig. 3. This approach is
based on the fact that a dynamic equilibrium between the cy-
clic and linear forms of 18F-FDG develops at increased tem-
18F-FDG and Other Labeled Glucose Derivative 215
HO
HO
HO OH
O
O
O
O
2
N
NNNH2
CO
CO
CO
99mTc
Fig. 6. Glucose complex based on 99mTc-labeled tricarbonyl with
functionalization at the C2 atom.
peratures. The linear form contains a carbonyl group at car-
bon 1, which also forms a bond with the aminooxy functional
group of the peptide.
This approach was used successfully in the synthesis of
labeled derivatives of so-called RGD peptide, 18F-FDG-
RGD-R (R = arginine residue, G = glycine, D = aspartic
acid) and its cyclic trimer form 18F-FDG-cyclo(RGDDYK)
(Y = tyrosine residue, K = lysine) [78]. Labeled derivatives
of RGD peptide specifically bind avb3integrin, a receptor
expressed as a result of accelerated angiogenesis in different
types of solid tumors. Assessment of the density of avb3
integrin by PET using the appropriate RPP allow evaluation
of the efficacy of antiangiogenic preparations widely used in
recent times for the treatment of malignant tumors.
Another example of the use of 18FäFDG as a radioactive
synthone is the recently proposed synthesis of a folic acid de-
rivative for imaging of folate receptors (FR) by PET. Impair-
ments to the regulation of these receptors typically occurs in
various types of cancer (the FR-aisoform) and activated
macrophages (the FR-bisoform).The synthesis scheme
based on the so-called click chemistry scheme is shown in
Fig. 4. The first stage in the synthesis is preparation of
2-deoxy-2-[18F]fluoroglucopyranosyl azide ([18F]1), which
reacts with functionalized folic acid molecules (alkyne folate
2) in the presence of Cu(OAc)2(10 ml, 0.1 M) and sodium
ascorbate (50°C, 15 min) [79].
There is great interest in studies developing antitumor
RPP based on 18F-FDG. For this purpose, 18F-FDG is bound
with chemotherapeutic agents, particularly chlorambucil.
Nineteen new derivatives of chlorambucil with 18F-FDG
were synthesized [80]; binding of the agent occurred via the
carbon-1 atom of the glucose molecule. In vitro studies
showed that the cytotoxicity of the resulting compounds was
greater than that of unbound chlorambucil [80]. In vivo stud-
ies were performed using selected agents which inhibited
B16F0 and CT-26 cell proliferation at the micromolar level
in vitro. Both agents demonstrated antitumor activity in in
vivo experiments on mice with transplanted tumors [81].
Thus, the potential of using 18F-FDG as the basis for synthe-
sizing new selective RPP for antitumor therapy has been
demonstrated.
Labeled Glucose Derivatives Based on Generator PET
Radionuclides
As already noted, PET investigations with 18F-FDG has a
number of limitations associated particularly with the need to
use a cyclotron and costly equipment for automated synthe-
sis, which makes each clinical dose of RPP expensive. An al-
ternative is provided by use of generator radionuclides to
prepare RPP; the nuclide with the greatest potential is gal-
lium-68, whose nuclear physics properties are less optimal
than those of fluorine-18, but the fact that it can be prepared
from commercially available 68Ge/68Ga generators in medi-
cal institutions confers enormous advantages [82, 83]. The
halflife of the mother radionuclide germanium-68 is 288
days, such that the generator has a quite long service life.
68Ga is used mainly for the synthesis of labeled octreotide
derivatives – potential agents for the diagnosis of neuroendo-
crine tumors with increased expression of somatostatin re-
ceptors, for visualization of prostate tumors, etc. Alternatives
to 18F-FDG include an agent synthesized on the basis of
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,
i.e., 68Ga-labeled glucosamine (68Ga-DOTA-DG) [84],
whose structure is shown in Fig. 5.
In comparison with the synthesis of 18F-FDG, the proce-
dure for introducing metals into various molecules is simple
and usually includes a step consisting of conjugation of 68Ga
and substrate with highly efficient labeling (85%) and
radiochemical purity of greater than 98%. In vitro investiga-
tions showed that 68Ga-DOTA-DG uptake into A430 epithe-
lial carcinoma cells after 60 min of incubation was 15.7%,
which was virtually the same as the uptake of 18F-FDG into
these same cells (16.2%). In contrast to 18F-FDG, addition of
excess glucose did not block access of 68Ga-DOTA-DG to
tumor cells. Comparative pharmacokinetic studies of this
new radiotracer in mice with epithelial carcinoma revealed
contents of (2.38 ±0.30)%, (0.75 ±0.13)%, and
(0.39 ±0.04)% per g of tumor at 10, 30, and 60 min after i.v.
administration respectively. The blood concentration was
virtually no different from that for 18F-FDG, while
68Ga-DOTA-DG contents in other organs were lower than
those of 18F-FDG. As compared with 18F-FDG, the numerical
tumor/blood, tumor/liver, and tumor/kidney activity ratios
were lower than those for 68Ga-DOTA-DG. PET investiga-
tions using microPET (small animals PET) supported the
view that clear tumor visualization could be obtained with
68Ga-DOTA-DG [84], which points to potential for further
study of this new RPP.
Glucose Derivatives Labeled with g-Emitting
Radionuclides for Use in PS and SPECT
Among the g-emitting radionuclides, the generator nu-
clide technetium-99m (99mTc) is of great interest, as it has op-
timum nuclear physics properties: a halflife of 6.04 hand a
g emission energy of 0.140 MeV. Rhenium-188 (188 Re) sig-
nificant also a generator nuclide. Because of the simplicity of
its preparation and the similarity of its chemical properties
with those of technetium, interest in its use had increased sig-
nificantly in recent years. Its nuclear physics properties
(T1/2 = 16.9 h, Eb-= 0.728 MeV (25%) and 0.716 MeV
(79%)) allows the required therapeutic dose to be created in
the tumor focus. 188Re also emits gphotons (Eg=
0.155 MeV), allowing the in vivo distribution of RPP to be
imaged [85].
As the glucose molecule contains only carbon and oxy-
gen atoms, it is quite difficult to form stable coordination
bonds with metal isotopes. Labeling therefore often uses glu-
cose derivatives with nitrogen or sulfur toms in their struc-
216 V. M. Petriev et al.
tures: 1-thio-D-glucose (1-TG), 5-thio-D-glucose (5-TG),
glucosamine, etc., as well as their salts and hydrates. In addi-
tion, radionuclides can bind with various ligands, which in
turn bind glucose or its derivatives.
The efficiency of labeling 1-TG with 99mTc is, according
to various authors, more than 96 – 99% [86 – 88]. The stabil-
ity of 99mTc-1-TG was greater at pH <7.0. The level of up-
take of compound into tumors depended on the ligand con-
centration: the highest level of 99mTc-1-TG uptake into tumor
cells was seen at the lowest ligand concentration (0.5 mg/ml
of 1-TG) [87]. Significant quantities of 99mTc-1-TG were
taken up by melanoma cells in vitro and in vivo [80].
The authors of [88] prepared 99mTc-1-TG and
99mTc-5-TG and tested their pharmacokinetic properties in
rabbits with transplanted VX-02 tumor cells. The activity
concentration in tumors after i.v. administration of
99mTc-1-TG was 4 – 6 times greater than in normal organs
and tissues, while the 99mTc-5-TG content was 2 – 3 times
higher. These studies showed that tumors could be imaged
using a gcamera [88].
Good results were obtained after i.v. administration of
99mTc-5-TG to mice with MC26 intestinal carcinoma [89].
Tumor tissue concentrations were (1.6 ±0.3)% and
(1.2 ±0.3)%, while the tumor/muscle ratio was 2.7:1 and 4:1
at 1 and 3 h respectively. Elimination of 99mTc-5-TG was via
the kidneys. In addition, uniform uptake of 99mTc-5-TG into
tumors was seen, i.e., the agent had affinity for tumor infarct
and necrosis zones [89].
Studies reported in [90] showed that 99mTc-1-TG and
99mTc-5-TG uptake into colorectal carcinoma and pulmonary
adenocarcinoma tumor cells in vitro was lower than that of
18FäFDG. 99mTc-1-TG and 99mTc-5-TG accumulated predom-
inantly in cell membranes [90].
Studies reported in [91] included the synthesis and evalu-
ation of the biodistribution of agents based on ethylenedi-
cysteine-glucosamine labeled with 99mTc and 68Ga
(99mTc-EC-GA and 68Ga-EC-GA) in vivo. Studies of
pharmacokinetic properties were performed in mice with
transplanted mesothelioma. 99mTc-EC-GA contents in tumor
tissue were (0.47 ±0.06)%/g, (0.12 ±0.01)%/g, and
(0.08 ±0.00)%/g at 30 min, 2 h, and 4 h respectively after
i.v. administration. Levels of 68Ga-EC-GA uptake into tu-
mors were (0.70 ±0.06)%/g, (0.72 ±0.06)%/g, and
(0.92 ±0.08)%/g at 15, 30, and 60 min respectively. Tumors
could be imaged by scintigraphy using 99mTc-EC-GA and
PET with 68Ga-EC-GA [91].
Comparative studies of the pharmacokinetic properties
of 99mTc-EC-GA and 18F-FDG were performed on mice [92].
The animals received i.m. A549 lung cancer cells. Uptake of
activity into tumors after i.v. administration of agent was
(0.79 ±0.16)%/g, (0.42 ±0.12)%/g, and (0.41 ±0.16)%/g at
30 min, 2 h, and 4 h respectively. 18F-FDG contents in tumor
tissue were higher: (2.23 ±0.15)%/g, (1.70 ±0.17)%/g, and
(1.61 ±0.18)%/g at 30 min, 2 h, and 4 h respectively. The
greatest 99mTc-EC-GA contents were seen in the liver
(5.81%/g), kidneys (5.69%/g) and spleen (4.21%/g) at the
2-h time point. Scintigraphic images of tumors were obtained
1, 30, and 120 min after administration of agent, the smallest
imaged tumor size being 3 mm [92].
Another study also yielded scintigraphic images of tu-
mors with 99mTc-EC-GA [93] and the potential for using this
agent for assessing treatment efficacy was demonstrated.
Dosimetric studies of 99mTc-EC-GA were performed in
the clinical management of seven patients with non small
cell lung cancer [94]. The greatest dose absorption occurred
in the urinary bladder (0.0247 mGy/MBq). High absorbed
doses were also seen in the kidneys (0.0123 mGy/MBq) and
lungs (0.0056 mGy/MBq). The effective equivalent dose was
0.0059 mSv/MBq, which was five times lower than that fol-
lowing administration of 18F-FDG. Agent was eliminated
from the blood: the blood 99mTc-EC-GA concentration 1 h af-
ter injection was 0.005% of the activity given. None of the
patients experienced any serious side effects. Uptake of
agent into tumors was 3 – 4 times higher than that in sur-
rounding healthy tissues. Images of primary tumors in the
lungs were obtained by single-photon emission computed to-
mography (SPECT) [94]. In addition, studies reported in [94]
showed that the presence of several hydroxyl groups made
the study compound hydrophilic, which promoted faster
elimination via the kidneys. The hydrophilicity of the agent
limited its passive diffusion across cell membranes, with the
result that the uptake of 99mTc-EC-GA into the brain de-
creased. Thus, 99mTc-EC-GAis a potential RPP for tumor di-
agnosis.
Another glucose derivative suitable for making RPP is
diethylenetriaminopentaacetic acid-deoxyglucose (DTPA-
DG). 99mTc-labeled DTPA-DG was prepared at high radio-
chemical purity (98.6%) [95]. I.v. administration of
0.037 – 0.111 MBq of 99mTc-DTPA-DG to rats with trans-
planted MCF-7 tumors was followed by significant levels of
activity in tumor tissue: (5.12 ±1.43)%/g (10 min),
(3.10 ±0.87)%/g (1 h), (2.10 ±0.02)%/g (2 h),
(1.59 ±0.04)%/g (4 h), and (1.69 ±0.03)%/g (8 h), which
were greater than with 18F-FDG [95]. The level of the agent
in muscle tissue with induced inflammation was no greater
than (0.81 ±0.03)%/g [96]. A high concentration of agent
was seen in the kidneys, at up to (28.86 ±8.88)%/g, and the
liver, at up to (5.20 ±0.93)%/g. Significant activity levels
were not seen in the other internal organs or tissues. The tu-
mor/brain and tumor/muscle activity ratios for 99mTc-
DTPA-DG were higher than those for 18F-FDG. At 4 h after
administration, these values were (19.88 ±3.45) and
(4.30 ±0.89) for 99mTc-DTPA-DG and (0.65 ±0.09) and
(0.36 ±0.06) for 18FäFDG [95].
A number of studies have demonstrated tumor imaging
after i.v. administration of 99mTc-DTPA-DG using a gcamera
[95 – 97]. Tumors were best detected 2 h after administration
of 99mTc-DTPA-DG [96].
The properties of 188Re-DTPA-DG are in many respects
similar to those of 99mTc-DTPA-DG. DTPA-DG was labeled
18F-FDG and Other Labeled Glucose Derivative 217
with 188Re in the presence of tin ions and sodium gluconate
at pH 7 with an incubation time of 3 h at a temperature of
37°C. The radiochemical purity of the resulting agent was
95.0% [98, 99]. 188Re-DTPA-DG was shown to have a sig-
nificant antiapoptotic effect against MCF-7 breast cancer and
A549 lung carcinoma cells in vitro, which may indicate that
it is an effective RPP for intratumor radiotherapy [100].
Pharmacokinetic studies in mice with transplanted tumors
showed that a significant proportion of the agent was taken
up by tumor tissue. At 3, 12, and 24 h, uptake levels were
(1.98 ±0.29)%/g, (2.89 ±0.43)%/g, and 0.42 ±0.06)%/g re-
spectively [98]. After i.v. administration, the ratio of activity
in tumor tissue to normal tissue was 5.9 and 7.8 at 12 and
24 h respectively [99]. A significant quantity of agent accu-
mulated in the kidneys and gallbladder. Excretion of agent
was mainly by the kidneys [99, 100]. An entirely minor level
of activity was noted in the thyroid, lungs, intestine, muscle,
and bone tissue. Slowing of tumor growth was seen after ad-
ministration of this agent [98, 99]. Thus, tumor volume 21
days after injection of 188Re-DTPA-DG was (823.6 ±50.58)
mm3, compared with (1162.7 ±73.08) mm3in the control
group (p< 0.01) [99].
99mTc-Nitrido-deoxyglucose dithiocarbamate (99mTc-N-
DG-DTC) and 99mTc-oxo-deoxyglucose dithiocarbamate
(99mTc-O-DG-DTC) were proposed as RPP for tumor diag-
nosis [101, 102]. The radiochemical purity of 99mTc-N-
DG-DTC after preparation was 90% and remained at this
level for 6 h [101]. Studies of the pharmacokinetics of this
substance in mice with S180 tumors showed that a signifi-
cant quantity was taken up by tumor tissue. The tumor/blood
and tumor/muscle ratios increased over time and reached
maximal values of 2.32 and 1.68 respectively at 4 h after ad-
ministration [101].
99mTc-O-DG-DTC was prepared using a deoxyglucose
dithiocarbamate and 99mTc(V)-glucoheptonate ligand ex-
change reaction. The reaction was run in neutral medium at a
temperature of 100°C for 15 min [102]. The radiochemical
purity of 99mTc-O-DG-DTC was greater than 90%. Analysis
of the biodistribution of the agent in mice with S180 tumors
showed that the agent was taken up predominantly by tumor
tissue and remained in this tissue for prolonged periods of
time. Tumor 99mTc-O-DG-DTC contents were greater than
those of other 99mTc-labeled glucose derivatives. The tu-
mor/muscle ratio for the study agent was higher than that of
18FäFDG [102].
Glucose and its derivatives can also be labeled using the
carbonyl complex [99mTc/Re(CO)3(H2O)3]+[103 – 107]. The
three water molecules in this complex are labile, so they can
easily be substituted with mono-, bi-, and tridentate ligands.
This method yielded 99mTc-2-deoxy-D-glucose [105]. Phar-
macokinetic studies on mice with transplanted
C57BL/6 melanoma demonstrated increased uptake of la-
beled agent in tumor tissues, so these agents have potential
for the diagnosis of melanoma. Other studies showed that
complex glucose derivatives prepared by reaction with
[99mTc(CO)3(H2O)3]+using click chemistry methods (Fig. 6)
were characterized by significantly lower levels of uptake
into induced lung tumors in mice than 18F-FDG. The fact that
in contrast to 18F-FDG, these 99mTc/188Re derivatives do not
follow the main glucose transport pathway via Glut1 trans-
porter protein, is of fundamental importance.
Studies reported in [106] synthesized two agents labeled
with 99mTc: 99mTc-2-deoxy-2-amino(ethylcarbamate)glucose
(99mTc-EC-DG) and 99mTc-2-deoxy-2-amino-(1,2-dihydro-
xypropyl)glucose (99mTc-DHP-DG). Labeling was with
[99mTc(CO)3(H2O)3]+. The radiochemical purities of
99mTc-EC-DG and 99mTc-DHP-DG were 96% and 93% re-
spectively. The pharmacokinetics of these compounds were
studied in healthy mice. The greatest levels of uptake of
these agents were in the liver, intestine, and kidneys. The
99mTc-EC-DG content in the brain was 2.8 times lower than
that of 18FäFDG ((0.61 ±0.09)%/g vs. (1.7 ±0.2)%/g at
60 min). The 99mTc-DHP-DG content in the heart at 60 min
after administration was 1.9 times lower than that of
18FäFDG ((1.16 ±0.10)%/g vs. (2.2 ±0.05)%/g).
Scintigraphic images were 2 h after substance administra-
tion. The resulting compounds could be used to image the
brain and heart [106, 108].
99mTc-D-glucose-mercaptoacetyltriglycine was prepared
at high radiochemical yield [109]. Biological studies and
scintigraphic imaging of Ehrlich tumors in mice showed high
levels of substance uptake into tumor tissue and a high tu-
mor/muscle ratio [109].
Thus, analysis of published data provides evidence that
along with 18FäFDG, glucocorticoid derivatives labeled with
other radionuclides such as 99mTc can be useful for the diag-
nosis of tumor diseases using single-photon emission com-
puted tomography for the diagnosis not only of tumor
neoplasms, but also inflammatory processes and also for
evaluating the efficacy of chemotherapy. Deoxyglucose de-
rivatives accumulate to significant quantities in actively pro-
liferating cells, providing clear imaging of tumor or inflam-
matory tissue both by PET and using a gcamera.In vivo and
in vitro experiments have shown that the radiochemical pu-
rity and stability of labeled deoxyglucose derivatives are
quite high. Activity accumulation levels in tumor tissue are
several-fold higher than in healthy tissue. Some RPP based
on glucose labeled with 188Re are potential compounds for
intratumor radiotherapy.
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