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Abstract
Radioarsenic labelled radiopharmaceuticals could be a valuable asset to Positron Emission Tomography (PET). In
particular, the long half-lives of 72As (T1/2 ¼ 26 h) and 74As (T1/2 ¼ 17.8 d) allow to investigate slow physiological or
metabolical processes, like the enrichment and distribution of antibodies in tumor tissue. This work describes the direct
production of no-carrier-added (nca) arsenic isotopes *As, with * ¼ 71, 72, 73, 74 or 77, the reaction to [*As]AsI3 and
its radiochemical separation from the irradiated solid germanium oxide via polystyrene-based solid-phase extraction.
The germanium oxide target, irradiated at a cyclotron or a nuclear reactor, is dissolved in concentrated HF and Ge is
separated almost quantitatively (99.97%) as [GeF6]2. [*As]AsI3 is formed by addition of potassium iodide. The
radiochemical separation yield for arsenic is 490%. [*As]AsI3 is a versatile radioarsenic labelling synthon.
r 2005 Published by Elsevier Ltd.
Keywords: As-71; As-72; As-73; As-74; As-77; Radiochemical separation; Solid-phase extraction
Table 1
Decay data of the most relevant arsenic isotopes (National Nuclear Data Center, 2004)
71 72 73 74 76 77
Property As As As As As As
reactor irradiated germanium or germanium oxide following the reaction 70Ge(a,2n)72Se - 72As (Al-
targets have been described in the past (Basile et al., Kourashi and Boswell, 1978; Jennewein et al., 2004a,
1984; Byrne, 1984; Mausner et al., 2004; Ward et al., b, 2005; Phillips, 1994; Phillips et al., 1991, 1992; Rösch
1970). In addition, strategies towards a versatile radio- et al., 2002; Rösch and Knapp, 2003), it can be produced
arsenic labelling chemistry were developed to generate directly in high yields, e.g. via the 72Ge(p,n)72As reaction
arsenic isotopes in chemical forms suitable for future using small-sized cyclotrons (Basile et al., 1984).
73
application in labelling chemistry, radiopharmacy and, As has a half-life of 80.3 d and decays exclusively via
ultimately, for molecular imaging using Positron Emis- electron capture, emitting only a g-ray of 53.4 keV.
sion Tomography (PET). Recent advances in using 74As Because of the long half-life, it is mainly applied as a
labelled antibodies directed against the apoptotic tracer for environmental sciences. It is currently
marker phophatidylserine (PS) in a Dunning R2337 produced via the Ge(p,xn)73As reaction with subsequent
AT1 prostate cancer model (Jennewein et al., 2004a, b) distillation and purification on a cation exchange
clearly demonstrate the potential of these radioarsenic column (Mausner et al., 2004).
74
isotopes. This strengthens the motivation to develop As is also a positron emitter, but has a much longer
adequate and reliable radiochemical separations. half-life (T1/2 ¼ 17.8 d) than 72As. It thus represents one
The decay properties of radioactive arsenic isotopes of the longest-living positron emitters with sufficient
are summarized in Table 1. bþ branching. It has a positron emission rate of 29%
71
As has a half-life of 65 h. It decays by 70% through with a low positron energy of E bþ mean ¼ 440 keV and an
electron capture and has a positron emission rate of electron emission rate of 34.2% and E b mean ¼ 137 keV.
30% with E bþ mean ¼ 350 keV. It can be produced by the The low positron energy provides a high local re-
70
Ge(d,n)71As reaction (Beard, 1960) and by Ge(p,x- solution, comparable to that of 18F, when measured
n)71As processes (Basile et al., 1984). via PET, as shown in Fig. 1. Here the spatial re-
72
As is a positron emitting arsenic isotope, with solution in dependency of positron energy was mea-
properties suitable for application in 72As-labelled PET- sured at the Small Animal PET of the University
radiopharmaceuticals. It has a positron emission rate of of Texas Southwestern Medical Center at Dallas for
88% with E bþ mean ¼ 1:17 MeV. Although the positron point sources (+ ¼ 1 mm) of 72As, 74As, 124I, 18F and
22
emission is accompanied by the emission of photons of Na.
74
834 keV (79.5%), 630 keV (7.9%), 1461 keV (1.1%) and As was one of the first isotopes used in the very
others (o 0.5%), the long physical half-life of 26 hours preliminary stages of PET in the 1950s and 1960s (Sweet
may render 72As a PET radionuclide of choice for the and Brownell, 1955; Leicester and Vanderfield, 1966;
quantitative imaging of biochemical and physiological Mealey, 1963; Wilcke, 1965a, b; Wilcke and Brock,
processes with longer biological half-lives, e.g. immu- 1965) called positrocephalography at that time. Due to
noimaging and receptor mapping. In these cases, the its long half-life, it is more appropriate for animal use
half-life of 72As is commensurate with the radiophar- than human use, but could also provide a useful tool for
macological requirements resulting from the relatively the study of long-lasting metabolic processes, like
slow localization kinetics of the labelled species. These antibody-antigen interactions or, in general, long term
virtues are comparable to those of 124I (T1/2 ¼ 4.18 d), pharmacokinetics of developmental drugs. 74As can be
but note that this radioisotope has a bþ -branching of produced best by the 74Ge(p,n)74As or 73Ge(d,n)74As
only 22%. In addition to production from a generator reaction at a small-sized cyclotron. Excitation functions
ARTICLE IN PRESS
M. Jennewein et al. / Applied Radiation and Isotopes 63 (2005) 343–351 345
Concentrated hydrofluoric acid (48%) and potassium volatilization. The use of metallic germanium was also
iodide were purchased from Aldrich. BOND ELUT evaluated, but GeO2 is preferable, since the macroscopic
ENV solid phase extraction cartridges with a sorbent Ge is already in the oxidation state +IV. However, to
mass of 50 mg and a volume of 1 ml were purchased date isotopically enriched germanium is only available
from Varian. as metal. If metallic germanium is used as target
material, small amounts of HNO3 must be added to
3.3. Radiochemical separation the HF solution to oxidise Ge(0) to Ge(IV) and thus to
dissolve the target. Heating of the target accelerates the
Irradiated germanium oxide targets were dissolved in dissolution process significantly, but leads also to a loss
5 ml conc. HF at room temperature for 1 h. Subse- of arsenic activity, due to the formation of *AsH3 as
quently, potassium iodide was added and stirred for described above. *AsH3 formation and volatilization
10 min. The amount of KI was varied between 0.1 and was not observed at room temperature. However, the
10 mg/ml HF. The mixture was transferred to an ENV- oxidizing conditions after addition of HNO3 in the
solid phase extraction cartridge. The cartridge-holder target solution lead to the formation of free iodine when
and fittings to standard size syringes were made in the adding potassium iodide in an exothermic reaction. The
machine-shop of the Institute of Nuclear Chemistry, procedures described in this article therefore are not
University of Mainz. The ENV cartridge was precondi- applicable to metallic germanium targets. If isotopically
tioned with 5 ml of MeOH, 5 ml H2O and 5 ml conc. HF enriched target material is used, an oxidation prior to
containing potassium (1 mg/ml). The nca [*As]AsI3 was irradiation is crucial.
fixed to the solid phase, while the macroscopic [GeF6]2 Following both p- and n-irradiation of 100 mg
nat
was eluted quantitatively with the mobile phase. After GeO2 targets, the optimum dissolution was achieved
the fixation of [*As]AsI3, excess HF was removed with a at room temperature after 20 min.
nitrogen-flow over the cartridge for 5 min. The elution of A comparison of g-spectroscopically measured As
[*As]AsI3 was performed with 500–1000 ml of various contents of the target solution before and after the solid-
organic solvents (toluene, chloroform, dichloromethane, phase extraction gives separation yields 490% for *As,
hexane, cyclohexane and ethanol). If the subsequent independent of the produced arsenic isotope. The
labeling chemistry requires anhydrous solvent condi- amount of Ge separated from the cartridge is 499.97%.
tions, a CaCl2 drying cartridge could be used.
4.2. Formation and fixation of [*As]AsI3
3.4. Determination of radionuclidic purity and
radiochemical separation yields Macroscopic AsI3 is dark orange, the melting point is
140.4 1C and the boiling point 371 1C (Smith, 1973). Its
The radionuclidic purity and radiochemical separa- solubility in polar solvents is limited and therefore it is
tion yields were determined using g-ray spectroscopy. slightly soluble in water, but well soluble in organic
Aliquots of the dissolved target were measured and solvents, like CS2, benzene, toluene, xylene and chloro-
quantitatively compared with the g-ray spectra of the form (Zingaro, 1994). The formation of macroscopic
solid phase extraction cartridges, eluates and waste- AsI3 under these conditions was observed when adding
solutions. The g-ray spectroscopy was performed using equimolar amounts of KI and macroscopic As2O3 to
an Ortec HPGe detector system, and the GammaVision conc. HF. The dark orange AsI3 precipitated immedi-
5.0 software by Ortec was used for peak area analysis. ately and quantitatively. AsF3 can also be formed in
conc. HF from As2O3, but not without the addition of
concentrated H2SO4 (Shriver et al., 1997).
4. Results and discussion The amount of KI necessary for quantitative forma-
tion of nca [*As]AsI3 was evaluated (cf. Fig. 2). After the
4.1. Target dissolution addition of 2 mg KI per ml HFconc. (12 mmol/ml), the
yield was 9575% and did not change with the increase
For optimum target dissolution, it is important to use in the KI concentration.
precipitated germanium oxide and not burned germa- Bond Elut ENV, a high-purity styrene divinyl benzene
nium oxide as target material, as the latter is not soluble (SDVB) polymer has been optimized for the extraction
at room temperature. Higher temperatures should be of polar organic residues, such as herbicide metabolites
avoided, since an increased temperature leads to the and explosives from large volume water samples.
formation of arsine (AsH3) and thus to significant Although primarily developed for environmental appli-
volatilization of activity (460%, Tb(AsH3) ¼ 62.5 1C cations, it can also be used for clinical purposes such as
(Smith, 1973)). Low temperatures, fast target dissolution the extraction of metabolites from human fluids. Bond
and the quantitative formation of nca [*As]AsI3 mini- Elut ENV features a 125 mm highly cross-linked
mize the formation of arsine and loss of activity due to spherical polymer with a surface area of 500 m2/g and
ARTICLE IN PRESS
M. Jennewein et al. / Applied Radiation and Isotopes 63 (2005) 343–351 347
120 30
100 25
80
60
15
40
10
20
0 5
0
0 2 4 6 8 10 12
0 200 400 600 800 1000 1200 1400 1600 1800
KI [mg/ml HF] Eluted volume [µl]
Fig. 2. Yield of nca [*As]AsI3 versus the potassium iodide Fig. 3. Typical elution profile of a nca 77AsI3 loaded
content in conc. HF. Nca [*As]AsI3 was eluted with chloroform polystyrene ENV cartridge (eluted with ethanol, percentage of
after fixation on an ENV solid phase extraction cartridge. eluted activity based on the activity-balance of all the fractions,
total elution volume 1.8 ml).
32768
9
8192 10
2048
7+8
512
counts
11
128
32768 9
32 78
8192
counts
2
3
8 2048
262144
65536 10
16384
4096
1024
counts
256
1-5
64
2
262144 3
16 1
counts
65536
5
16384
9 4
4 4096
Fig. 4. Radiochemical purity of the separated nca 77AsI3 in ethanol: (a) g-ray spectrum of the target after dissolution in conc. HF;
measurement time ¼ 1 h; (b) g-ray spectrum of 77As; measurement time ¼ 10 h.
solutions necessary and the apparatus can be flushed separation of 72As. In previous works of our group, the
with nitrogen. This system is well suited for future radionuclide generator system 72Se/72As was described
automation. (Jennewein et al., 2004a, b, 2005). The idea of a
The separation method introduced here was exempli- generator seems to be very appealing in a clinical
fied by 77As and 74As, but the main impact may lie in the environment without a cyclotron. However, the produc-
ARTICLE IN PRESS
M. Jennewein et al. / Applied Radiation and Isotopes 63 (2005) 343–351 349
7
1 Product
2 SPE
5 6
3 4 Waste
8
Fig. 5. Scheme of the described extraction system for the separation of nca radioactive arsenic isotopes from reactor or cyclotron
irradiated germanium oxide targets: 1. Nitrogen; 2. HF with KI; 3. Organic solvent; 4. Reactor with target; 5. cartridge for separation
of [72As]AsI3; 6. Drying cartridge; 7. Product, nca [72As]AsI3; and 8. Waste.
tion yields of 72Se (Basile et al., 1984; Horiguchi et al., Boehringer Ingelheim Fonds for Basic Medicinal
1983; Dmitriev, 1986) are rather low from the viewpoint Research, represented by Dr. H. Fröhlich.
of preparing generators for a sufficient supply of 72As.
In contrast, the production yields in the direct produc-
tion of 72As via the 72Ge(p,n)72As reaction would be
relatively high. From the systematics, the maximum of References
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