INTERNATIONAL JOURNAL OF ONCOLOGY 22: 253-267, 2003
253
Applications of positron-emitting halogens
in PET oncology (Review)
MATTHIAS GLASER, SAJINDER K. LUTHRA and FRANK BRADY
Imaging Research Solutions Ltd., Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
Received August 2, 2002; Accepted September 26, 2002
Abstract. The positron-emitting radiohalogens 18F, 75Br, 76Br,
and 124I are reviewed regarding their relevance for positron
emission tomography (PET) in oncology. Relevant production
routes of these cyclotron-generated isotopes are given, followed
by publications that deal with applications of these radiohalogens. This article tries to cover the whole literature for
the non-conventional isotopes 75Br, 76Br, and 124I. From the
literature on 18F, only articles since 2000 are considered. Here,
the emphasis is also given to alternative biomarkers beyond
[18]2-fluoro-2-deoxyglucose ([18F]FDG).
Contents
1.
2.
3.
4.
5.
6.
Introduction
Fluorine-18
Bromine-75
Bromine-76
Iodine-124
Conclusions
1. Introduction
PET in oncology. Positron emission tomography (PET) is
a modern and powerful technology to study non-invasively
biological processes at the molecular level (1,2). This
highly sophisticated imaging method relies on coincidence
registration of annihilation photons having a characteristic
energy of 511 keV. Advantages of PET over single photon
emission tomography (SPECT) are the high sensitivity and
spatial resolution, and ability to give quantitative answers. PET
can thus be used to study pharmacokinetics and mechanism
of action of drugs.
_________________________________________
Correspondence to: Dr Matthias Glaser, Imaging Research
Solutions Ltd., Hammersmith Hospital, Du Cane Road, London
W12 0NN, UK
E-mail: [email protected]
Key words: positron, halogens, positron emission tomography
Besides many other applications, radiolabelled PET
tracers can also be used to investigate lesions such as
carcinomas. Here, PET is employed for diagnosis and staging
of diseases as well as judging the efficacy of anti-cancer
drugs (3). Generally, the result will reflect changes in
biochemistry rather than morphology. Thus, PET has always to
be considered being complimentary to ‘conventional’ means
of imaging such as computed tomography (CT) or magnetic
resonance imaging (MRI).
There is a wide range of positron-emitting halogens
available - with fluorine-18 as the most prominent among
them. The aim of this article is to review the use of those
radiohalogens in respect to PET oncology. There are already
several excellent reviews available that cover fluorine-18
applications in oncology (4-7). Thus, only the literature from
2000 to 2002 will be considered here.
In recent years a number of alternative PET halogens with
relevance to oncology have also emerged. These radionuclides
may not be as ideal as fluorine-18 in terms of radiophysical
properties but owing to the prolonged half-life they can be
shipped with less time constraints to nuclear medicine
departments away from cyclotrons. This fact is also underlined
by the new trend towards dual-head SPECT/PET cameras
(8). Accordingly, the use of those alternative radiohalogens
implies also different approaches of radiochemistry.
Positron-emitting halogens. A comprehensive list of medically
relevant non-conventional positron emitters has been reviewed
by Pagani et al (8). Here, we will focus on the positron-emitting
halogens 18F, 75Br, 76Br, and 124I which have been reported to
be useful for applications in oncology. Table I compares some
selected physical properties of these radioisotopes.
Generally, the decay of 75Br, 76Br, and 124I results in
positrons of higher energy compared with 18F. This means a
loss in spatial resolution since the positrons take a longer
distance in tissue until annihilation. These alternative radiohalogens also emit Á-rays of high energy resulting from electron
capture (75Br, 76Br, 124I) and internal transitions (124I). 75Br has
a half-life of the similar order of magnitude as 18F. However, it
produces the long-lived daughter nuclide 75Se (t1/2 = 120 days).
The latter isotopes have a relatively long half-life which is an
advantage for the radiosyntheses and the investigation of
long-term biological processes. Although the disintegration
of 76Br and 124I results in the stable isotopes 76Se and 124Te,
respectively, the increased effective dose might become a
limiting factor in clinical trials.
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GLASER et al: POSITRON-EMITTING RADIOHALOGENS IN PET ONCOLOGY
Table I. Some decay properties of the halogens reviewed in
this article (data from ref. 8).
–––––––––––––––––––––––––––––––––––––––––––––––––
Radiot1/2
Ratio Eß+max
Á energy
Effective
nuclide
of ß+ (MeV) per decay dose constant
(%)
(MeV) (µSv/MBq-h)
–––––––––––––––––––––––––––––––––––––––––––––––––
18F
110 min 97
0.635
5.37
75Br
97 min
71
1.74
0.473
7.85
76Br
16.2 h
54 3.98, 3.44 2.226
12.5
124I
4.15 days 23 2.13, 1.53, 0.852
4.91
0.808
–––––––––––––––––––––––––––––––––––––––––––––––––
Table II. Production routes for 18F (data from ref. 9).
–––––––––––––––––––––––––––––––––––––––––––––––––
Nuclear reaction
Energy range Theoretical thick target
(MeV)
yield (MBq/µAh)
–––––––––––––––––––––––––––––––––––––––––––––––––
20Ne(d,·)18F
14➝0
1110
18O(p,n)18F
16➝3
2960
16O(3He,p)18F
41➝14
481
–––––––––––––––––––––––––––––––––––––––––––––––––
2. Fluorine-18
Production of fluorine-18. Fluorine-18 can be produced using
three different nuclear reactions, shown in Table II. However, in
practice only the 20Ne(d,·) and 18O(p,n) processes are relevant.
Because of its high target yield the 18O(p,n) route has become
the favoured reaction, but the 20Ne(d,·) reaction is still used
in some PET centres (9). No-carrier-added (n.c.a.) [18F]fluoride
is obtained from proton irradiation of 18O-enriched water.
This is now the most effective method of generating n.c.a.
[18F]fluoride (9). The latter can probably also seen as the most
common starting material for 18F-labelled radiopharmaceuticals.
Carrier-added (c.a.) [18F]fluorine is produced by deuteron
irradiation of neon containing 0.1% [19F]fluorine in nickel target
chambers. Here, 18F can be trapped as 18F-19F gas or adsorbed
at the nickel wall. Alternative routes to c.a. [18F]fluorine are
proton irradiation of 18O-enriched oxygen, or proton irradiation
of 18O-enriched water followed by chemical conversion into
[18F]CH3F and electrical discharge in the presence of a trace
of cold fluorine gas.
The targetry and target chemistry of fluorine-18 has been
comprehensively reviewed in a monography by Stöcklin and
Pike (9).
Applications of fluorine-18 labelled radiopharmaceuticals
in oncology. [18F]FDG. The success of PET as a diagnostic
tool in nuclear medicine is mainly due to the use of [18]2fluoro-2-deoxyglucose ([18F]FDG) - not only in oncology, but
also in cardiology and neurology (17). [18F]FDG has become
a valuable diagnostic tool with numerous applications: Fig. 1
Figure 1. Numbers of annual publications on [18F]FDG from 1979 to 2001
(data retrieved by SciFinder).
illustrates the popularity of [18F]FDG as a substantial increase
in the number of publications on the subject. The term ‘PET
oncology’ is usually seen as a synonym of the application of
[18F]FDG for imaging with positron emission tomography in
oncology.
[18F]FDG as a glucose analogue is effectively retained
in vivo after conversion into [ 18F]FDG-6-phosphate by
hexokinase. The following metabolism is fairly slow, allowing
reasonable interpretations of PET images within the first half
hour after injection, but becomes more complex later on (10).
Since [18F]FDG accumulates in most malignant tumours,
the PET method can be used to localise them. The enhanced
tumour uptake can also be used to stage and detect residual
and recurrent cancer during a therapy.
Here, it is not the intended to cover the whole recent
literature on [18F]FDG in oncology. The European Organization
for Research and Treatment of Cancer (EORTC) published a
review paper on the use of [18F]FDG for measuring clinical
and subclinical tumour response with PET (11). The authors
conclude, that [18F]FDG in oncology has still some limitations
regarding its prognostic value. Further reviews on [18F]FDGPET in anti-cancer therapy have appeared (3,7,12-15). Lists
of types of tumours that have been diagnosed by [18F]FDGPET can be found in refs. 6 and 11. The method has also been
comprehensively reviewed for more than 20 tumours in terms
of sensitivity, specifity and percent in management change
by Gambhir et al (151).
The chemistry of [18F]FDG and other radiohalogenated
carbohydrates has been summarised in a paper by Adam
(16).
Alternative 18F markers for various oncological applications
are summarised in papers by Brady et al (4) and Varagnolo
et al (5). The following chapters compile new developments
since then.
[18F]FLT. 3'-deoxy-3-[18F]fluorothymidine ([18F]FLT, Fig. 2)
is a thymidine analogue. After the incorporation of FLT into the
DNA, the lack of the 3'-hydroxy group causes the termination
of the DNA polymerization. It appears that [18F]FLT may be
associated with proliferation and has the potential to become
a clinically useful radiopharmaceutical (17,169).
The radiochemistry and biology of [ 18F]FLT has been
recently summarised by Mier et al (18). Previously, [18F]FLT
INTERNATIONAL JOURNAL OF ONCOLOGY 22: 253-267, 2003
255
Figure 2. Preparation of [18F]FLT (20).
could be obtained in only moderate radiochemical yields
(19). Martin et al have now introduced a new precursor with
improved deprotection chemistry (Fig. 2) (20). The authors
tested six combinations of N-/O-protecting and leaving groups.
The best labelling was obtained with the N-Boc/O-4,4'-dimethoxytrityl protected nosyl precursor (r.c.y. 19.8%). The
novel method avoids the use of ceric ammonium nitrate for
N-benzyl deprotection (21) which was not compatible with
automation.
More recently, the dephosphorylation reaction of [18F]
FLT was studied in cell culture (168). This phenomenon led
to reduced uptake of the tracer, but seemed to play a less
important role in human PET studies.
Barthel et al reported the modulation of [18F]FLT uptake
in RIF-1 tumour bearing mice by 5-fluorouracil (5-FU) (170).
This intriguing finding opens up the prospect of monitoring
anti-cancer therapy by PET.
[18F]FCH. A known limitation of the [18F]FDG method is
its inability to detect very small tumours, brain tumours, and
to differentiate between malignant lesions and chronic
inflammation (22). [ 18F]fluoromethylcholine ([ 18F]FCH)
(Fig. 3) seems to mimic the in vivo behaviour of the established
11C-labelled choline as investigated by De Grado et al (23-25).
[18F]FCH can be prepared with 20-40% radiochemical yield
(24). There have been some promising PET studies with
[18F]FCH on patients with prostate and brain cancer, and
brain tumour. The tracer is rapidly cleared, but the kidneys
were found to be critical organs in terms of radiation dose
(23,25).
Use of fluorine-18 in gene therapy. Herpes simplex virus
type 1 kinase (HSV1-tk) as a reporter gene for monitoring
gene transfection remains in the focus of PET oncology.
Thymidine is incorporated into viral DNA, a process catalysed
by thymidine kinase (TK). Hence, expression of TK can
be detected and measured non-invasively by radiolabelled
thymidine analogues, a very specific means to detect a
successful gene transfection. A review article on imgaging
reporter gene expression by means of PET has been written
by Gambhir et al (26).
Hospers et al studied the accumulation of 9-[(3-[ 18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG)
(Fig. 3) in C6tk rat glioma cells and in nude rats carrying
both a C6 and C6tk tumour (27). The uptake in cell culture
was 35±5 times higher than in control tumours cells. The
Figure 3. Structures of 18F-radiopharmaceuticals.
investigators found a rapid in vivo clearance of the tracer and
a 15±5-fold higher accumulation in the transfected lesion 2 h
post injection.
Another study directly compared the potential of both
[18F]FHPG and the thymidine analogue 1-(2-fluoro-2-deoxyß-D-arabinofuranosyl)-5-[ 124I]iodouracil ([ 124I]FIAU, see
section: [124]IUdR) for transgene expression (122). However,
the results from testing several cell lines suggest [124I]FIAU
as the superior PET probe. This was also established by PET
scans of BALB/c mice bearing HSV-tk transfected fibrosarcomas (122).
Alauddin et al used 9-(4-[18F]fluoro-3-hydroxymethylbutyl)
guanine ([18F]FHBG) (Fig. 3) to image HSV-tk expression of
transducted human colon cancer cells (HT29) in vitro and nude
mice (28). The increase in uptake of [18F]FHBG compared to
non-transduced tumours was 71-fold and 13-fold respectively
after 5 h. PET scans from cynomolgus monkeys to study the
biodistribution indicated low accumulation of [18F]fluoride
in bone and a low level of recirculating labelled metabolites.
The authors conclude that [ 18F]FHBG will be useful for
HSV-tk based gene therapy of cancer in humans (28). So far,
investigations by Yaghoubi et al confirm this tracer to be safe
with excellent pharmacokinetic properties (162).
Furthermore, [18F]FHBG has been employed in several
animal studies using MicroPET (152-155,164), and also in
combination with optical imaging of D-luciferin as reporter
probe (165). Preliminary communications report the improved
synthesis (156) and automation of the [18F]FHBG preparation
256
GLASER et al: POSITRON-EMITTING RADIOHALOGENS IN PET ONCOLOGY
(157,158). The [ 18F]FHBG PET reporter probe was also
compared with the HSV-tk substrate FIAU (see section:
[124]IUdR) (159-161,163).
Iyer et al prepared 8-[18F]fluoropenciclovir ([18F]FPCV,
Fig. 3) and compared this new PET reporter probe with 8[18F]fluoroganciclovir ([18F]FGCV, Fig. 3) (164). [18F]FPCV
was able to detect lower levels of HSV1-sr39tk expression
in vivo (180).
A recent study on cell culture experiments suggests 2'deoxy-2'-fluoro-5-[18F]fluoro-1-ß-D-arabinofuranosyluracil
([18F]FFAU) as an alternative tracer for [18F]FHBG (166).
Another approach in imaging gene expression by PET
reporter probes utilizes the dopamine-D2 receptor (D2R). Here,
3-(2'-[18F]fluoroethyl)spiperone ([18F]FESP, Fig. 3) can be used
to visualize D2 receptor expression (152-154,164). [18F]FESP
and [18F]FHBG were applied together in an interesting novel
tetracyline inducible system to simultaneously introduce
D2R and HSV1-sr39tk genes, respectively (152). Liang et al
succeeded in generating a D2R mutant that lacks physiological
function (i.e., modulation of cAMP levels following ligand
binding), which is highly desirable for [18F]FESP (153). Also,
a bi-cistronic reporter gene HSV1-tk/D2R has been studied
with [18F]FPCV and [18F]FESP by Yu et al (179).
Nimmagadda et al measured biodistribution and DNA
uptake of 1-(2-deoxy-2-[18F]fluoro-1-ß-D-arabinofuranosyl)-3bromouracil ([18F]FBAU, see section: Various new bromine-76
labelled biomarkers) in normal dogs (171). It was found to
be resistant to metabolism and incorporated into DNA.
Further work is needed to assess the properties relative to
other thymidine and uridine analogue PET tracers.
Alauddin et al reported on the synthesis of 2'-deoxy-2'[18F]fluoro-5-methyl-1-ß-D-arabinofuranosyluracil ([18F]FMAU), which can be seen as a structural isomer of [18F]FLT
(172). A study on five patients revealed tumour visualization
in brain and thorax (173). Again, further investigations have to
be carried out in order to compare the potential of [18F]FMAU
in oncology with other tracers such as [18F]FDG and [18FLT].
Use of fluorine-18 in angiogenesis approach. Angiogenesis
is the process of the new formation of blood vessels starting
from an existing vasculature. This subject has attracted much
attention in cancer research. Tumour blood vessels are
genetically stable and are therefore a key area for therapy
development. The clinical issues and implications of tumour
angiogenesis pathways for nuclear medicine imaging have been
reviewed recently by van de Wiele et al (29). The authors state
that anti-angiogenesis is in particular useful for spontaneous,
small and slow-growing tumours.
A number of anti-angiogenesis studies are focused at
integrins. Haubner et al used 4-nitrophenyl 2-[18F]fluoropropionate to prepare the radiolabelled RGD peptide cyclo[-Arg-Gly-Asp-D-Phe-Lys(sugar amino acid)-] ([18F]GalactoRGD) which is known to bind on the ·vß3 integrin receptor
(30-32). A melanoma-bearing mouse was investigated by PET
and showed a high tumour/blood ratio of 27.5 after 120 min
post injection. This suggests that [18F]Galacto-RGD might
potentially be a promising PET tracer for imaging angiogenesis.
As a further angiogenesis marker, squalamine, a natural
aminosterol from tissues of dogfish sharks, has been radio-
Figure 4. Preparation of 2-L-[18F]fluorotyrosine (36).
fluorinated with 1-[18F]fluroro-3-tosylpropane (33). The biological evaluation of this tracer is still in progress.
Fluorine-18 labelled amino acids. It is assumed that the
increased metabolism of tumours also involves a faster protein
synthesis. Thus, in the search for tumour specific tracers as
better alternatives to [18F]FDG there has been much effort in
evaluating radiolabelled amino acids. Fluorine-18 is seen as a
better radioisotope compared to carbon-11, because the longer
half-life matches the protein metabolism more appropriately.
A review by Laverman et al gives a summary on 18 Ffluorinated amino acids as relevant for oncology (34).
More recently, Vasdev et al reported improvement of the
radiosynthesis of 3-L-[18F]fluorotyrosine and 3-L-[18F]fluoro·-methyltyrosine (35) (Fig. 3). The use of trifluoroacetic acid or
anhydrous hydrogen fluoride during the electrophilic labelling
with [18F]F2 gave rise to radiochemical yields up to 30%.
Hess et al prepared a new O-Boc protected trimethylstannyl
precursor for the electrophilic labelling of 2-L-[18F]fluorotyrosine. The tracer was obtained with 42.7±1.6% radiochemical yield in a two-step synthesis (n=6) (36) as shown in
Fig. 4.
In order to achieve metabolically stable tracers, several
non-natural radiolabelled amino acids have been prepared.
These compounds should act as pure markers for the transport of amino acids. Martarello et al have synthesised syn- and
anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic
acids (syn-/anti-[18F]FMACBC, Fig. 3) (37). In an animal
model, rats were implanted intracranially with 9L glioscarcoma
cells. After injection of syn- or anti-[ 18F]FMACBC high
tumour/normal brain uptake ratios have been observed (syn[18F]FMACBC: 7.5/1, 5/1 and anti-[18F]FMACBC: 7.5, 9/1
after 5 and 120 min, respectively). 2-Amino-3-[18F]fluoro-2methylpropanoic acid ([18F]FAMP, Fig. 3) and 3-[18F]fluoro2-methyl-2-(methylamino)propanoic acid ([18F]N-MeFAMP,
Fig. 3) were investigated by the same group using identical
methods (38). It was found, that the tumour accumulation
was even higher with tumour vs normal brain ratios of 36/1 for
[18F]FAMP, and 104/1 for [18F]N-MeFAMP after 60 min post
injection. There is also a short communication on uptake
profiles and transport mechanism of these two groups of amino
acid radiotracers (167). Thus, the non-natural 18F-fluorinated
amino acids should become an intriguing field for PET
oncology.
Fluorine-18 labelled peptides. Fluorine-18 labelled peptides are
another interesting field of PET oncology research. Sutcliffe-
INTERNATIONAL JOURNAL OF ONCOLOGY 22: 253-267, 2003
Goulden et al used p-[18F]fluorobenzoic acid as prosthetic
group to label RGD peptides (39). The radiosynthesis of
p-[18F]fluorobenzoic acid was carried out with 80-90% decay
corrected radiochemical yield using an FDG synthesizer. The
following incubation with immobilized peptide took only
2 min and gave the labelled peptides in yields >90% and high
purity. Unfortunately, the peptides were broken down within
5 min in vivo.
Bergmann et al radiofluorinated analogues of the
neuropeptide neurotensin as complementary PET tracer to the
somatostatin receptor (40). The researchers used the acylation
method via p-[ 18 F]fluorobenzoate on doubly stabilised
neurotensin derivatives. Although the tracer retained
receptor affinity and plasma stability up to 8 min, the tumour
uptake in nude mice bearing HT-29 tumours was not
sufficient for PET imaging.
N-succinimidyl p-[18F]fluorobenzoate (p-[18F]SFB, Fig. 3)
is often used as mild labelling reagent for peptides. In a preliminary communication Zijlstra et al describe the automated
synthesis of p-[18F]SFB for labelling annexin-V as potential
probe for imaging apoptosis (9th Workshop on Targetry and
Target Chemistry, Turku, Finland, F1.08, 2002).
Various new fluorine-18 labelled biomarkers. O6-alkylguanineDNA alkyltransferase (AGT) is known as a DNA repair
protein. The level of AGT is an important factor for the
resistance of tumour cells against alkylating chemotherapeutic
drugs. Vaidyanathan et al have synthesised the radiolabelled
guanine derivative 6-(4-[18F]fluoro-benzyloxy)-9H-purin-2ylamine ([18F]FBG, Fig. 3) for mapping AGT levels (41).
An evaluation in cell culture showed an IC50 value of 50 nM
on AGT expressing CHO cells. Schirrmacher et al labelled
the 9-position in 6-benzyloxyguanine to obtain 6-benzyloxy9-(2-[ 18F]fluoroethyl)-9H-purin-2-ylamine (Fig. 3) (42).
Unfortunately, the tracer revealed only poor binding
characteristics in vitro as well as in nude mice expressing
O6-methylguanine-DNA-methyltransferase.
As for multidrug resistance research concerns, there has
been a preliminary communication on the synthesis of
[18F]fluoropaclitaxel. This tracer might be useful for measuring
the efficacy of paclitaxel for individual patients and to study
potential P-glycoprotein modulators to improve paclitaxel
therapy (43). The biological evaluation of [18F]fluoropaclitaxel
is still in progress.
Kim et al suggested a new approach for PET oncology
in chosing the peroxisome proliferator-activated receptor Á
(PPARÁ) as target for tracer devlopment (44). This receptor was
found in many in vitro and in vivo tumour models. Two highaffinity thiazolidine compounds have been radiofluorinated.
Unfortunately, no selective tumour uptake or retention could
be observed in mice bearing human xenografts of breast
cancer.
Bonasera et al published a number of 18F-labelled 4(anilino) quinazolines for potential mapping of the epidermal
growth factor receptor tyrosine kinase (EGFr-tk) (45). However, despite good data from cell culture, kinetic factors and
a rapid blood clearance prevented useful PET imaging in
tumour-bearing mice. The 18F-chemistry of labelled steroid
molecules for imaging breast tumours has been reviewed in
an article by Katzenellenbogen (46). There are many synthetic
257
Table III. Production routes for 75Br (data from ref. 9).
–––––––––––––––––––––––––––––––––––––––––––––––––
Nuclear reaction
Energy range Theoretical thick target
(MeV)
yield (MBq/µAh)
–––––––––––––––––––––––––––––––––––––––––––––––––
76Se(p,2n)75Br
30➝22
3700
75As(3He,3n)75Br
36➝25
277
76Se(d,3n)75Br
35➝29
3034
75As(·,4n)75Br
65➝54
277
–––––––––––––––––––––––––––––––––––––––––––––––––
methods available. However, it is still difficult to prepare
ligands with high specific radioactivity from compounds that
have electron-rich rings and are not accessible to nucleophilic
aromatic substitution reactions.
3. Bromine-75
Production of bromine-75. The production methods of 75Br
have been comprehensively reviewed in the past (9,47-52).
Table III gives a selection of pathways that have been explored.
The most suitable routes appear to be the 75As(3He,3n)75Br and
the 76Se(p,2n)75Br processes with a preference of the former
reaction (9). The target material consists normally of alloys
such as [75As]Cu3As, [76Se]Ag2Se, or [76Se]Cu2Se. The 75Bractivity is extracted from the solid target by dry distillation
(see section: Production of iodine-124).
Applications of bromine-75 labelled radiopharmaceuticals
in oncology. The introduction of bromine into biologically
active molecules for PET offers two advantages over other
halogenation reactions. First, bromine chemistry is easier to
handle than fluorine chemistry and secondly, compared with
iodination, the bromine radiotracers are expected to be much
more stable in vivo due to the higher binding energy of
bromine-carbon.
Bromine-75 has been used for recoil labelling, but the more
common method is direct electrophilic substitution including
enzymatic protocols (51,53). There are not many examples for
the use of 75Br in tracers with relevance for PET oncology so
far. This might be due to the cyclotron production requiring a
relatively high beam energy which is available only in a few
centres. Furthermore, there are difficulties in the targetry and
target chemistry of the radioisotope. Whereas the short halflife of 75Br is clearly favourable for applications in nuclear
medicine, the biological effect of the long-lived daughter
isotope 75Se (t1/2 = 120 days, EÁ = 864 keV) has not been fully
investigated yet.
Kloster et al synthesised L-3-[ 75Br]bromo- · -methyltyrosine ([75Br]BMT) as a potential pancreas imaging probe
(54). No-carrier-added [75Br]BMT was obtained with 85%
radiochemical yield. PET scans from mice revealed a rapid
pancreas uptake, which was 9.7±1.4-fold higher than the liver
uptake.
Terpstra et al mentioned in an abstract the labelling of
estrogens to measure the density of estrogen receptors in breast
cancer (55) - however without biological evaluation.
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GLASER et al: POSITRON-EMITTING RADIOHALOGENS IN PET ONCOLOGY
Table IV. Production routes for 76Br (data from ref. 9).
–––––––––––––––––––––––––––––––––––––––––––––––––
Nuclear reaction
Energy range Theoretical thick target
(MeV)
yield (MBq/µAh)
–––––––––––––––––––––––––––––––––––––––––––––––––
75As(3He,2n)76Br
18➝10
11
76Se(p,n)76Br
16➝10
296
77Se(p,2n)76Br
25➝16
259
–––––––––––––––––––––––––––––––––––––––––––––––––
Figure 5. Structures of 76Br-radiopharmaceuticals.
4. Bromine-76
Production of bromine-76. Table IV gives a short summary
of the production methods for 76Br. The preferred method
for the generation of 76Br by a low-energy cyclotron is the
76Se(p,n)76Br reaction with a practial yield of 70 MBq/µAh
(56). However, the enriched target material [76Se]Cu2Se is
relatively expensive. The 76Br activity is normally recovered by
dry distillation (see section: Production of iodine-124). Some
other articles deal with the targetry and target chemistry of
76Br (9,47,50,52,57). Maziere and Loc'h published a review
on aspects of production and radiochemistry of 76Br and other
radiobromine isotopes (58).
Applications of bromine-76 labelled radiopharmaceuticals in
oncology. [76Br]BrdU. The thymidine analogue 5-[76Br]bromo2'-deoxyuridine ([76Br]BrdU, Fig. 5) was prepared from a
5-trimethylstannyl precursor for the first time by Koziorowski
and Weinreich (59). Bergström et al investigated the biodistibution of this proliferation tracer in Sprague-Dawley rats
and pigs (60). The rats showed high tracer uptake in all organs,
that was not related to DNA incorporation. In the pigs the
highest incorporation was found in the red bone marrow
with 70-80% DNA incorporation. However, the correction
for [76Br]bromide was a problem for the PET analysis. A
subsequent study from the same group aimed at solving the
issue of high background by the use of diuretics in rats - with
partial success (61).
Figure 6. Preparation of [76Br]FBAU.
Table V. Summary of studies on antibodies labelled with 76Br.
–––––––––––––––––––––––––––––––––––––––––––––––––
Refs.
Antibody
Target
Type of
IRa
study
(%)
–––––––––––––––––––––––––––––––––––––––––––––––––
A33 (IgG1)
Colonic
In vitro
75
(64)
cancer cells
3S193
Anti-Ley,b
In vitro
c
38S1
Anti-CEA
In vitro
d
38S1 (IgG1κ) Anti-CEA
Rats
80±2
(65)
A33
SW1222 cells
In vitro
?
(66)
38S1
Anti-CEA
In vitro
76±2
(67,68)
–––––––––––––––––––––––––––––––––––––––––––––––––
a Immunoreactivity; b Anti-blood group Lewis y ; c Anti-carcinoembryonic antigen; dAccumulation index = 2.9±0.8% (i.e., tissue
weighted maximum tumour uptake).
[76Br]BFU. The next step by Lu et al was the development of
5-[76Br]bromo-2'-fluoro-2'-deoxyuridine ([76Br]BFU, Fig. 5)
(62). Here, in rats the highest radioactivity uptake was
observed in spleen and small intestine with about 90% DNA
incorporation. More than 95% of urine activity was found to
be unchanged [76Br]BFU. This result was also supported by a
second study that used 2-[14C]thymidine for comparison (63).
However, a forced diuresis by cimetidine was required here
too.
with 125I-radioiodine from the corresponding
body.
Antibodies labelled with 76Br. Bromine-76 has been used to
label proteins such as antibodies by direct methods (64-66)
and by N-succinimidyl 4-[76Br]bromobenzoate (p-[76Br]SBB,
Fig. 5) (66-68). Table V shows a summary of these studies.
Lövqvist et al used nude rats bearing human colon carcinoma
xenografts for testing a directly labelled anti-carcinoembryonic
antigen antibody (38S1) (65). The catabolism resulted in free
radiobromine that revealed a lower excretion rate as compared
Various new bromine-76 labelled biomarkers. Kao et al
prepared the thymidine analogue 1-(2-fluoro-2-deoxy-ß-Darabino furanosyl)-5-[76Br]bromouracil ([76Br]FBAU) using a
two-step reaction (Fig. 6) (69). Incubation of [76Br]FBAU with
hepatocytes suggested the compound was stable for up to 4 h.
Yngve et al synthesized N-succinimidyl 5-[76Br]bromo-3pyridinecarboxylate ([76Br]SBPC) and [76Br]p-SBB to label
the somatostatin binding peptide octreotide (70). The reagent
–––––––––––––––––––––––––––––––––––––––––––––––––
125
I-38S1 anti-
INTERNATIONAL JOURNAL OF ONCOLOGY 22: 253-267, 2003
259
Table VI. Production routes for 124I.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Reaction
Energy
Target
Yield
Impurities at EOB
Refs.
(MeV)
enrichment (%)
(MBq/µAh)
(%)
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
121Sb(·,n)
125I, 126I
20
57
0.37-0.74
(71)
124
15➝8
15
16➝6
91.7
95
96.7
18.9
20.4±2.2
23.7a
126
36.8➝33.6
98.7
66.6a
125
21➝15
20.1➝10.5
98.3
93
81a
43.3
Te(d,2n)
Te(p,3n)
Te(p,2n)
125
I, 126I, 131I (0.8)
125I (0.5)
?
?
123
I (7.4), 125I (0.9)
123I (8), 125I (5)
(92)
(90)
(93)
(94)
(89)
(95)
124
123I (41)
13➝9
99.51
20a
(91)
12
96.2
3.4
?
(74)
15.1
>99
4.4
?
(96)
14.5
?
9.3
?
(88)
125
123
12.5
99.3
5.4
I (0.05), I (11)
(97)
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Te(p,n)
aTheoretical
value.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
methyl 4-[76Br]bromobenzimidate did not couple with octreotide. The [76Br]SBPC labelled octreotide showed better binding
in meningioma tissue compared with the conjugate obtained
with [76Br]p-SBB.
Sosabowski et al used [76Br]p-SBB in a preliminary study
to label doxorubicin and daunorubicin as potential PET marker
for multidrug resistance (143). The tracers were tested on rat
fibrosarcoma cells but no data was given.
5. Iodine-124
Production of iodine-124. A summary of the production
methods for 124I including isolated yields is given in Table VI.
The very first attempts to produce 124I by a cyclotron used
natural antimony as target material for · particles (71,72).
However, the achievable target yields were rather poor. The
antimony route was re-investigated recently (73). Better results
have been obtained later with proton and deuteron irradiation
of targets made of isotopically enriched tellurium. Early radiochemists used demanding wet chemistry methods to extract
124I from antimony targets. Wet chemistry was also employed
to extract the radioiodine from 124Te target material after a
(d,2n) reaction. This area was pioneered by Lambrecht and
co-workers (74-78).
The more convenient technique of dry distillation was
introduced by van den Bosch et al (79). The method has seen
many attempts for improvement and refinement since then
(80-87; Qaim SM, et al, 9th Workshop on Targetry and Target
Chemistry, Turku, Finland, C06, 2002; Comor JJ, et al, 9th
Workshop on Targetry and Target Chemistry, Turku, Finland,
C03, 2002). After irradiation of isotopically enriched [124I]-
tellurium dioxide, the target is inserted into a quartz apparatus
and heated up to the melting point of TeO2 (730˚C) while a
stream of gas transfers the volatile radioactivity into a trap.
This trap consists normally of a capillary or vial containing
alkaline trapping solution. The transport gas can be oxygen
(82), air (80), or helium (reported for distillation of 75Br) (48).
There is some controversy as to what kind of gaseous species
of radioiodine are beeing formed during the distillation process
(i.e., iodine oxide or radical) (57,80). The solid target can be
re-used many times because the loss of target material is
usually very low (~0.1%). In the long-term, this compensates
the initial high costs of enriched tellurium.
Further, [124Te]tellurium diselenide has been used as target
material (57,88). Also, lower melting 124Te-metal (m.p. 450˚C)
was used in a novel setup to collect 124I ‘on-line’ as it is being
produced by a vertical beam-line (Runz A, et al, 9th Workshop
on Targetry and Target Chemistry, Turku, Finland, C08, 2002).
The 126 Te(p,3n) 124 I process requires relatively high
beam energy and has not yet been scrutinised in terms of
contamination with long-lived 125I (t1/2 = 60 days) which is not
favourable for medical applications. The 125Te(p,2n)124I reaction
leads to very high yields of 124I, but produces also considerable
amounts of 125I (89). The 125I impurity is also significant in the
124Te(d,2n)124I process (90). It arises here from the 124Te(d,n)125I
reaction, which cannot be suppressed. The 124Te(p,n) 124I
reaction gives the best radionuclidic purity of 124I but has a
lower thick target yield (81,91). Here the extent of 125I byproduct only depends on the level of enrichment of 124Te
material. The 123Te(d,n) 124I reaction was investigated by
Scholten et al but was found to be not useful in terms of
reasonable target yield of 124I and impurity level of 123I (98).
260
GLASER et al: POSITRON-EMITTING RADIOHALOGENS IN PET ONCOLOGY
Applications of iodine-124 labelled radiopharmaceuticals in
oncology. General. When iodine-124 became available to
clinical medicine from dedicated cyclotrons 40 years ago, it
was perceived as alternative therapeutic radionuclide to reactor
produced iodine-131. It was also recognized, that the highenergy positrons from incorporated 124I should have a similar
effect in tissue as ß- particles from 131I. In vivo experiments
showed a more uniform radiation dose of 124I compared to 131I.
With 124I, the accuracy of the measurements could be improved
by coincidence detection (71).
However, the rather demanding nature of early radiochemistry, the complex decay scheme, the low abundance of
positrons, and an unfavourable dosimetry (99), can all be
seen as impediments to the widespread use of 124I.
In 1996 Pentlow et al published a study on tumour-like
phantom sources of 124I using several PET scanners (100).
The authors concluded that quantitative imaging with 124I
can give results of almost the same quality as 18F. The loss in
spatial resolution was found to be similar as in images obtained
by conventional PET nuclides. A recent study by Herzog
et al came to the same conclusion with the statement that
quantitation of 124I imaging might be further improved by
developing of specific corrections (101). New prospects are
opening up with the introduction of 124I-PET-CT imaging
(102,150). Other applications of 124I are listed below.
[ 124 I]iodide. As mentioned earlier, 124 I can be used as
therapeutic radioisotope. In fact, the calculated effective dose
is in the same order of magnitude as 131I. For example, the
effective dose of 124I is 1.5 mSv/MBq and for 131I 2.4 mSv/
MBq - assuming a 35% thyroid uptake in both cases (103).
Possibly the first reported 124I scan was performed on a
rat thyroid (71). The first clinical case of thyroid carcinoma
treatment with 124I was published in 1960 (104). The rather
low amounts of 124I producible at that time were a limiting
factor. Lambrecht et al reported the first PET scan of thyroid
carcinoma (105). A combined dose of 124I and 131I has been
used to treat hyperthyroidism with accompanying PET (106).
Ott et al used 124I scans in Grave's disease before and after
thyroectomy (107).
The real virtue of [124I]iodide can probably be seen in the
use of its positron component to work out the functional
volume of thyroids. This information is needed as accurately
as possible in order to calculate the individual dosimetry of
patients undergoing 131I therapy for thyrotoxicosis (102,108111). The functioning volume of the thyroid of 22 patients
could be determined by 124I with an accuracy of ±4-14% (112).
Frey et al examined thyroids of 38 patients with 124I-PET. The
investigators observed considerable regional uptake differences
in multinodular goitres (181). Flower et al carried out a doseresponse study on 65 patients using 124I-PET scans in order
to calculate the 131I dose that would be needed to achieve
euthyroidism (113).
The benefits of [18F]FDG have been recently combined
with 124I for evaluation of glucose and iodide metabolism in
suspected recurrent thyroid carcinoma (174).
124
[ ]IUdR. The use of carbon-11 labelled thymidine as a marker
of tumour cell proliferation is limited by the short half-life
of 11C (t1/2 = 20 min) because it does not cover the time that
Figure 7. Structures of 124I-radiopharmaceuticals.
is needed for sufficient clearance of unbound tracer and
metabolites. Therefore, metabolite correction with complex
models needs to be carried out (114).
Consequently, the 124I analog of thymidine 5-[124I]iodo-2'deoxyuridine ([124I]IUdR, Fig. 7) has been synthesised by
Blasberg et al and used in a study of 20 patients with various
brain tumours including meningiomas and gliomas (115). The
investigators measured the incorporation clearance constant
(Ki), standard uptake value (SUV) and tumour/brain radioactivity concentration, that were all related to tumour type
and grade, tumour labelling index, and survival after the PET
scan. However, the rapid metabolic degradation of the tracer in
blood was seen as a disadvantage. The [124I]IUdR was prepared
by electrophilic iodination of 2'-deoxyuridine (UdR) (115-117), or
5-trimethylstannyl-2'-deoxyuridine (TMSUdR) (Koziorowski J,
et al, XIIth International Symposium on Radiopharmaceutical
Chemistry, Uppsala, Sweden, p. 128, 1997) using IodoGen.
[124I]FIAU. Following the death of a patient with liver-directed
adenovirus vector-mediated gene therapy, the Recombinant
DNA Advisory Committee of the NIH, USA, called for
improved assays to measure transgene expression (118). Here,
INTERNATIONAL JOURNAL OF ONCOLOGY 22: 253-267, 2003
261
Table VII. Summary of studies on antibodies labelled with 124I.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
% ID/gb
Refs.
Antibody
Target
Type of study
IRa (%)
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
3F8 (IgG3)
Neuroblastoma
1 patient (PET)
40
0.0045
(135)
rats
?
?
(136)
CE-25,
CE-4-8-13
CEA producing
colon carcinoma
Mice
80-90
15.4
(137)
Anti-CEA (minibody)
scFv-CH3
Colon carcinoma
(LS174T), rat glioma (C6)
Mice (PET)
96
6-14
(133)
MX35, MH99
(IgG1)
Ovarian cancer
(SK-OV-7*, SK-OV-3**)
Rat (PET)
61*
65**
1.56*
1.24**
(138)
HMFGI (IgG1)
Breast ductal carcinoma
9 patients (PET)
>80
0.002-0.0077
(139)
H 17E2 (anti-PLAP)
PLAPc
Mice
?
4.26
(127)
huA33
Colorectal cancer (SW1222)
Mice (PET)
78
50.0±7
(140)
ICR 12 (IgG2a)
Breast carcinomad
Mice (PET)
80-90
12.6
(141)
HuMV833 (IgG4κ)
VEGFe
3 patients (phase I)
?
?
(134,175)
VG76e (IgG1)
VEGF
Mice (PET)
34-45
5.9
(97,132)
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
aImmunoreactivity; bMaximum
product;
eVascular
tumour uptake; cHuman tumour, expressing placental alkaline phosphatase, PLAP; dc-erbB-2 proto-oncogene
endothelial growth factor.
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
the long half-life of 124I could be in particular helpful to
evaluate future approaches for gene therapy. 1-(2-fluoro-2deoxy-ß-D-arabinofuranosyl)-5-[124I]iodouracil ([124I]FIAU,
Fig. 7) used to image the HSV1-tk expresssion, can be seen
as a first example in this sense. Tjuvajev et al published a PET
study on rats bearing multiple tumours derived from W256
rat carcinoma and RG2 rat glioma cells (119). [124I]FIAU was
obtained by direct radioiodination of 2'-fluoro-1-ß-D-arabinofuranosyl-uracil using IodoGen. It was possible, not only to
localise the site of gene expression non-invasively, but also
to measure the level of HSV1-tk expression with [124I]FIAU.
The animals were scanned up to 48 h after the injection of the
radiotracer. [124I]FIAU has also been used to detect differential
viral infectivity of three HSV variants (178) and for monitoring
the transcriptional activiation of p53-dependent genes by a
dual reporter gene (HSV1-tk/GFP) (177).
Jacobs et al used [ 124I]FIAU-PET imaging in a small
group of patients with recurrent glioblastoma (118,120)
within a phase I/II trial. The HSV1-tk expression was induced
by a cationic liposomal vector. There was accumulation
of [124I]FIAU at the site of gene transfection in one of five
patients. The PET image was co-registrated with MRI,
[11C]methionine, and [18F]FDG scans.
[124I]FIAU was used in vitro and in vivo to investigate the
expression of the fusion gene of E. coli cytosine deaminase
(CD) and HSV1-tk. This was seen as a tool to assess the
sensitivity of transfected cells towards 5-fluorocytosine (5-FC)
and ganciclovir (GCV) in on-going clinical trials (121).
Brust et al compared [18F]FHPG with [124I]FIAU both
cell culture models and in mice transfected with CMS-STK
tumour cells (122). They found a significantly higher uptake of
[124I]FIAU in all cases, suggesting that future clinical research
should be focussing on the uridine type of HSV1-tk substrate
rather than on the acylguanosine type.
A preliminary study on comparison of [124I]FIAU with
18
[ F]FHBG also reported a 15-fold higher accumulation of
[124I]FIAU in RG2-tk+ rat xenografts (159). Similarly, Min
et al showed a better uptake for [ 124I]FIAU in C6-stb-tk+
tumours of mice (161).
Recently, Ponomarev et al reported in a communication
on [ 124I]FIAU in a TKGFP-based cis-reporter system to
image p53 gene expression in tumours in vitro and in vivo
(176).
[124I]mIBG. The functional analog of norepinephrine known
as meta-iodobenzylguanidine (mIBG) labelled with radioiodines 123I and 131I is an established radiopharmaceutical for
imaging the adrenal. This can be explained by the central role
of the medullary gland regarding synthesis and storage of
catecholamines. Pheochromocytomas and neuroblastomas
262
GLASER et al: POSITRON-EMITTING RADIOHALOGENS IN PET ONCOLOGY
including sporadic and extra-adrenal lesions as well as
medullary hyperplasia have been diagnosed with this
compound (123,124).
Using the ammonium sulfate (125) or copper(II) nitrate
(76) assisted isotopic exchange reactions, the 124I analogue
of mIBG (Fig. 7) has been prepared. The radiochemical
yields were 89-98% and 70-90%, respectively. Ott et al used
[124I]mIBG in a clinical study to predict the corresponding 131I
radiation doses for the whole body, normal liver and neural
crest tumours (126). Uptake was found in various tumour sites
in lung, liver, and abdomen.
Antibodies labelled with 124I. The use of antibodies for tumour
diagnosis and therapy clearly benefits from the long half-life
of 124I. For instance, an IgG antibody has an effective biological
half-life of 48 h, which is well compatible with iodine-124's
t1/2 of 4.2 days (127). Again, the use of 124I labelled antibodies
might provide dosimetry information for radioimmunotherapy
(RIT) (128). The potential use of 124I labelled antibodies in
radiotherapy has also been claimed by a patent (129). The
majority of the labelling has been carried out by established
electrophilic substitution reactions on tyrosine side chains
(130). However, there are also reports describing the use
of lysine conjugation via the Bolton-Hunter reagent (97,
131,132).
An overview of several applications for 124I labelelled
antibodies in oncology is given in Table VII. Most of these
studies do report on studies using animal xenografts of
human tumours. The slow pharmacokinetics of antibodies
can be seen as a considerable disadvantage in RIT. However,
the renewed interest in the antibody approach arises from
the availability of genetically engineered ‘minibodies’ (133),
and endothelial targets that are exposed during angiogenesis
(97,132,134).
124
I and MDR. Iodine-124 could also be a useful radioisotope
to investigate the phenomenon of multidrug resistance (MDR)
that occurs during chemotherapy. In a preliminary report
Sosabowski et al prepared the N-p-[124I]iodobenzoyl derivatives
of doxorubicin and daunorubicin, respectively (Fig. 7). The
researchers tested the tracers on inherently resistant rat fibrosarcoma cells, that express both MDR proteins (P-gp and
MRP). The data showed that the new compounds are substrates
for MDR proteins and might be useful in further in vivo
applications on this subject. At present, the 99mTc tracer
Sestamibi is dominating this field (143). [124I]Iodocolchicine
(Fig. 7) is another promising candidate for probing MDR with
PET. However, there are no data available yet (142).
[ 124 I]annexin-V. During the complex phenomenon of
genetically programmed cell death, or apoptosis, cell
membranes are reverting before rupture, and are exposing
phosphatidylserine residues. The 36 kDa proteine annexin-V
binds with high affinity to these surfaces (K = 10-9 M). Thus,
this biomolecule has the potential to become a radiotracer in
PET diagnosis of apoptosis during oncolytic therapy (144,145).
Iodine-124 was the first PET nuclide to be used to synthesise
such a radiopharmaceutical as a marker for apoptosis (146).
The nuclide was conjugated indirectly by using the prosthetic
group N-succinimidyl m-[124I]iodobenzoate ([124I]m-SIB, Fig. 7)
(146-148) as well as directly by employing the IodoGen
method (149).
6. Conclusions
Positron-emitting radiohalogens are playing an increasingly
important role in PET oncology. The last two decades have
also seen considerable improvements in the generation of
useful PET radiohalogens by medical cyclotrons as well as in
the corresponding target chemistry.
Whereas the clinical potential of tracers containing the
non-conventional 76Br or 124I may be seen as rather low, these
probes are very useful in preclinical experiments such as in
those using small animal scanners (e.g. for testing new anticancer drugs). Studies for PET based imaging of biological
processes on a molecular level might also benefit from the
longer half-life of 76Br and 124I.
The labelling of peptides and proteins with positronemitting halogens still needs the development of techniques
of generic value.
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