264
Current Radiopharmaceuticals, 2012, 5, 264-270
Radioarsenic from a Portable 72Se/72As Generator: A Current Perspective
B. Ballard, F.M. Nortier, E.R. Birnbaum, K.D. John, D.R. Phillips† and M.E. Fassbender*
Chemistry Division, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos NM 87545, USA
†
Present Address: U.S. Department of Energy, Office of Nuclear Physics, 100 Independence Avenue, Washington, DC
20585, USA
Abstract: Positron emission tomography (PET) of slower biological processes calls for the use of longer lived positron
emitting radioisotopes. Beyond radionuclide production considerations, practicality and rapidity of subsequent labeling
chemistry further limits the selection of radioisotopes with potentially favorable nuclear properties. One additional limitation is the availability of PET radiotracers at the point-of-care with appropriate on-site production methodologies or robust
radionuclide generator systems. The positron emitter 72As (half-life 26 h) is generated via decay of 72Se (half-life 8.5 d);
this pair comprises and excellent generator system for clinical availability of a longer lived PET isotope. Many 72Se/As
generator systems have been introduced utilizing the rich interplay of Se(IV)/Se(VI) and As(III) /As(V) chemical behavior. This paper describes available generator concepts, and briefly outlines some current arsenic labeling methodologies
for the introduction of radioarsenic into biomolecules.
Keywords: Arsenic-72, radionuclide generator, accelerator isotope production, radioarsenic labeling.
INTRODUCTION
Demand for Longer-lived Positron Emitters
Positron Emission Tomography (PET) provides a noninvasive means to quantitatively image biological processes
in vivo [1]. The commonly used PET isotopes 11C ( t = 20
min), 13N ( t = 10 min), 15O ( t = 2 min) and 18F ( t = 110
min) have short half-lives [2], and thus are not often suitable
for imaging of slower biological processes such as immunological responses in conjunction with labeled antibodies.
For this reason, there is a growing interest in longer-lived
positron emitters which would more adequately match the
biological half-life associated with the targeting vectors [3].
Fortunately, a number of longer-lived radioisotopes are
known with sufficiently high positron branching ratios suitable for PET imaging. Several recent reviews highlight the
advantages of longer-lived PET isotopes and the versatility
of their use in immunological imaging techniques [4-7]. A
comparison of the nuclear properties of several long lived
PET isotopes is given in Table 1 [2, 8].
Compared to the low-Z isotopes used in current PET procedures, many longer-lived positron emitters are associated
with high + endpoint energies, giving rise to reduced spatial
resolution in the PET image. They also tend to emit additional -rays, causing an increase in image noise [9]. The use
of proper correction factors, however, can mediate these undesired side effects [6].
properties. This allows sufficient time for parent nuclide
production and recovery, generator manufacturing, and the
shipment of the generator units to the point of care, supplying a continual source of the daughter nuclide for use in a
nuclear medicine clinic [10]. The advantages of such generator systems are well known. They provide a cost effective
alternative to on-site production and processing of radionuclides for nuclear medicine applications [11]. Generators
also supply radionuclides of high specific activity owing to
the inherent parent/daughter chemical separation mechanism
by repeated elutions [12].
Production of 72As for use in Nuclear Medicine
Arsenic has several isotopes which are appropriate for
PET imaging, namely 70As (t = 52.5 min, 100% +), 71As
(t = 64 h, 30% +), 72As (t = 26 h, 85% +) and 74As (t =
17.77 d, 29% +) [2]. Among the positron-emitting isotopes
of arsenic, 72As is of particular interest for PET. The physical
decay characteristics of this nuclide combined with the
unique chemistry of arsenic make it a very attractive building block for the synthesis of a variety of PET radiopharmaceuticals. The longest-lived radioarsenic isotope 73As (t1/2 =
80.3 d) has been considered for toxicological studies [13-15].
Both 73As and 74As production and recovery have been subject to research at Los Alamos for some time [16, 17].
Radionuclides produced in generators separate the imaging study from the usual necessity of an on-site cyclotron.
The most desirable generators use a long-lived parent
nuclide that continually produces, by its radioactive decay,
a radioactive daughter nuclide with desirable imaging
Arsenic-72’s relatively high + abundance and hours-long
half-life allows for imaging of slower biological processes,
although the reported tissue range would limit the spatial
resolution achieved without correction factors being applied.
Combined with proper development of imaging protocols,
72
As is a highly promising candidate for imaging with PET
[8, 18-20].
*Address correspondence to this author at the Chemistry Division, Los
Alamos National Laboratory, P.O. Box 1663, Los Alamos NM 87545, USA;
Tel: 505-606-1801; Fax: 505-665-7306; E-mail: [email protected]
Arsenic-72 can be produced directly at a medium-energy
cyclotron utilizing a production energy window of
10-50 MeV. Direct production of this isotope has been investigated using charged particle irradiation of germanium tar-
1874-47/12 $58.00+.00
© 2012 Bentham Science Publishers
Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
Radioarsenic from a Portable 72Se/72As Generator
265
Table 1. Table of Nuclear Properties for Selected Long Lived Positron Emitters. The Reported -Intensities were Limited to the
Three Most Abundant Lines of Greater Than 1% Abundance [10,12]
Half-life
(h)
Radionuclide
18
F
1.83
Daughter
(half-life)
18
O (stable)
+ in MeV
(+ yield)
Tissue Mean Range
(mm)
0.63 (97%)
-energy in
keV(I %)
Generator Parent
(half-life)
0.69
--
Direct Production
Direct Production
Direct Production
Te (stable)
2.14 (24%)
3.25
602 (63%)
723 (10%)
1691 (11%)
76
Se (stable)
3.98 (56%)
5.07
559 (74%)
657 (16%)
1854 (15%)
25.9
72
Ge (stable)
3.32 (88%)
5.01
834 (81%)
630 (8%)
Se
(8.4 d)
86
Y
14.7
86
3.15 (34%)
2.46
628 (33%)
1153 (31%)
1076 (83%)
Direct Production
89
Zr
78.4
89
Y (stable)
0.90 (23%)
1.18
909 (99%)
Direct Production
44
Sc
3.9
Ca (stable)
1.47 (94%)
1.45
1157 (100%)
44
Ti
(60 yrs)
124
I
100.2
124
76
Br
16.0
72
As
Sr (stable)
44
72
Table 2. Direct Production Yields for 72As from Proton Irradiated natGe. Reported Radiochemical Impurities are Given as a Percentage of 72As Activity Produced [21,22]
Reaction
Energy Range
(MeV)
Yield (at EOB)
(mCi/μAh)
Impurity (%)
71
As
73
As
74
As
nat
Ge (p,xn) As [21]
18 8
2.5
8.6
1.8
6.3
nat
Ge (p,xn) 72As [21]
50 8
10.8
23
1.8
3.2
72
nat
GeO2 ( He,x) As [22]
37 18
0.21
27
NR
12
nat
GeO2 ( 4He,x) 72As [22]
40 10
0.14
37
NR
3
3
72
NR: values not reported by the authors
get material via several reactions: natGe(p,xn)72As, natGeO2
(3He,x)72As, and natGeO2 (4He,x)72As. Viable options for direct production of 72As are summarized in Table 2 [21, 22].
Arsenic-72 can also be produced indirectly, i.e. as a
daughter radionuclide of the longer-lived 72Se (t1/2 = 8.5 d). A
72
Se/72As generator for in-house use at a clinical imaging
center or regional radiopharmacy would provide the 72As
radiopharmaceuticals with high specific activity. A generator
would reach 70% of the maximum activity within 48 hours,
and full activity in 89 hours. An illustration of the 72As activity in growth for a 72Se/72As generator system is given in
Fig. (1).
Various methods for the production of 72Se have been described in the literature; deuteron- and proton-induced reactions on arsenic, as well as 3He and 4He induced reactions on
germanium have been investigated [23-26]. Alternatively,
72
Se can be obtained via proton induced reactions on bromine in the form of bromide salts [27, 28]. Table 3 illustrates
several routes of production of 72Se by bombardment of target material with charged particles.
An assessment of the different production pathways must
consider the production yield, the ease of the required separation chemistry, and the radiochemical purity of the 72Se
product. Production yields for 72Se from targets of elemental
or inorganic compounds of As, Ge, and Br are listed in Table
3. The highest production yield for 72Se is obtained via several proton induced reaction channels from RbBr salt targets,
although this production approach creates additional challenges in subsequent separations due to the complexity of the
product mixture in dissolved solutions. Irradiation of As targets with medium energy protons provides the next highest
yields for 72Se. In this approach, the subsequent processing
of multi-gram production targets leads to concerns with the
eventual waste disposal pathways.
The alkaline bromides balance a relatively inexpensive
and biologically benign proton beam target material with
sufficiently high yields for the production of 72Se. Alkaline
bromides also have high solubility in water, allowing for a
smooth dissolution of the target material following the irradiation without the introduction of toxic solvents. Moreover,
alkaline bromides have high molten salt thermal conductivity, which is important for target robustness during irradiation. Sodium bromide possesses the highest conductivity
in the series at 0.31 Wcm-1K-1, versus (0.22, 0.17, 0.14)
Wcm-1K-1 for KBr, RbBr, CsBr, respectively [29]. Overall,
the preference for a bromide salt target is based upon three
considerations: low cost, low alkaline metal activation in the
proton beam and a reasonably high thermal conductivity.
266 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
Ballard et al.
Fig. (1). Re-extraction of 72Se generated 72As from the liquid-liquid generator system described in this work.
Table 3. Possible Routes for the Production of 72Se. Targtes Consist of Elemental Metallic Germanium or Arsenic; Others are
Inorganic Compounds such as Cu3Ge and KBr
Reaction
Energy Range
Yield(mCi/μAh)
72
(MeV)
75
As (p,4n) [17]
75
As (d,5n) [17]
nat
3
Ge ( He, xn) [20]
70
3
Ge ( He, xn) [20]
nat
£
4
Cu3 Ge ( He,xn) [18]
70
4
§
Cu3 Ge ( He,xn) [18]
nat
K Br (p,x) [21]
nat
K Br (p,x) [21]
nat
Rb Br (p,x) [22]
¥
72
72
Generator systems based on Se/ As have been discussed previously in the literature, using both Se carrier and
no-carrier-added designs. Al-Kouraishi et al. introduced a
72
Se/72As generator based on cation exchange [25]. In this
method, the 72Se produced by alpha irradiation of an enriched 70Ge target was precipitated via the addition of stable
selenous acid followed by reduction using sulfur dioxide
solution. The precipitated selenium was then centrifuged and
washed prior to suspension in deionized water. The suspen-
Se
0.21
57
0.03
56 26
0.15
32
0.08
36 (incident)
0.08
NR
NR
36 (incident)
0.22
NR
NR
28 10
0.0005
0.09
0.0004
28 10
0.002
0.4
0.0003
100 69
0.10
7.18
0.12
62 42
0.05
2.36
0.03
£: Germanium enriched to a 96.4% Ge content. NR: values not reported by the authors. §: The enrichment in
70
Ge(0.48%). ¥: Values measured as yields from a spallation target irradiated at the LAMPF facility.
Se/As Generator Systems Described in the Literature
75
Se
45 24
800 incident
70
73
Se
3.03
70
Ge was
70
30.3
70
3.03
70
Ge(96.75%), Ge(1.12%), Ge(0.29%),
70
Ge(1.36),
sion was loaded onto a cation exchange column and held for
90 hours for the in-growth of the 72As daughter. The column
was warmed to 60 °C by a water jacket, and deionized water
was used to elute 60% of the newly generated 72As from the
column. Another generator system developed within the Los
Alamos Isotope Program utilized added Se carrier and subsequent precipitation to achieve Se/As separation upon 72As
daughter in-growth [19, 30]. Briefly described, selenium was
precipitated as Se(0) by hydrazine and collected by vacuum
filtration. The selenium was redissolved by addition of 3%
(by volume) H2O2 in 6M HCl, which oxidizes the selenium
Radioarsenic from a Portable 72Se/72As Generator
to Se(IV), and the 72As was allowed to grow into equilibrium
with the 72Se parent. After sufficient time, separation of ingrown 72As was achieved by a repetitive hydrazine precipitation and subsequent filtration. This process requires the addition of stable selenium in the form of selenous acid, giving a
final selenium concentration of 6 x 10-4 M. This technology
has been patented in the US as well as in Europe [31]. A
recent study by Chajduk et al. established a method to separate Se/As based on sorption of aromatic orthodiamines onto
polystyrene column materials. Radioactive tracer experiments were caried out utilizing 75Se and 76As produced from
neutron irradiation of natural Se and As materials. In these
studies, Se(IV)/As(III) distiribution coefficients (Kd) were
measured where 75Se and 76As served as surrogates for 72Se
and 72As. The resultant Kd showed the ability to quantitatively sorb 75Se while recovering >95% of the loaded 76As
activities [32].
Several no-carrier added concepts have also been proposed in the literature, largely based on proton irradiation of
arsenic target material. Jennewein et al. developed a nocarrier-added AsCl3 distillation-type generator [33]. In this
work, 72Se was produced by 3He irradiation of a natural germanium target material. The germanium was distilled off as
the volatile GeCl4 species for recycling, while the selenium
was retained in the concentrated HCl solution used to dissolve the target. In-grown 72As was removed as the volatile
AsCl3 by distillation at 105 ˚C for 10 minutes in a gaseous
HCl stream, and collected on a charcoal filter to give a radiochemical yield of greater than 99%. Jennewein et al. also
reported a working system which used a solid phase support
to extract generated 72As from elemental 72Se(0) sorbed on a
polystyrene solid support [26]. In this process, irradiated
germanium target materials were dissolved in an HF/HNO3
mixture and the Se reduced to Se(0) by the addition of hydrazine or SO2. The solution was then passed through a Varian ENV (500μL bed volume) solid phase extraction cartridge to adsorb the selenium to the solid support while the
germanium was eluted with the mobile phase. The ingrown
72
As was eluted with 2 mL of HFconc with a 50% yield and <
0.1% breakthrough of 72Se parent. After elution, the 72As was
converted to 72AsI3 by the addition of KI, with reaction
yields of >95%. This technology has been patented in
Europe [34].
A New Chelation-based
rator
72
Se/72As Radionuclide Gene-
In a recent publication [29], we successfully introduced a
Se/72As generator principle based on chelation/ liquidliquid extraction. Proton irradiations of NaBr targets were
carried out at the LANL Isotope Production Facility (IPF).
Direct water dissolution of the NaBr target matrix recovered
>99% of the produced 72Se. Bromide was quantitatively removed by oxidation to elemental bromine followed by distillation. The oxidation was performed by slowly adding HCl
followed by addition of a 30% H2O2 giving a mole ratio of
2:1 Cl-/Br- and 1:1 H2O2/Br- in the solution after addition.
Chemical processing of the target matrix in the presence of
excess HCl, which quantitatively reduced any Se(VI), ensured that all Se in solution was converted to Se(IV) [35].
Following the distillation of bromine, the residual activity
72
Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
267
was dissolved in 0.1M HCl in preparation for separation of
selenium isotopes from the target matrix.
Solvent extraction experiments previously illustrated that
the hydrated diethyldithiocarbamate ligand in a hydrochloric
acid matrix selectively extracts selenium into the organic
phase [29]. Selenium recovery from the target matrix in an
initial bulk extraction was 94±2 %, as measured in the organic phase subsequent to extraction, while 95±2 % of the
directly (i.e., via nuclear reaction with protons) formed radioarsenic (as evident by the presence of 74As) remained in
the aqueous phase.
A liquid-liquid extraction prototype system was used to
establish proof-of-principle for a chelation-based 72Se/72As
radionuclide generator system. The organic phase containing
the selenium was repeatedly extracted to demonstrate a simple generator system. The 72Se containing generator phase
was repeatedly allowed to accumulate 72As daughter activity,
and the decay product 72As was periodically re-extracted into
aqueous phases to determine parent “break-through” and
daughter extraction yield. The selenium “break-through”
amounted to 0.9±0.1 % with respect to the selenium activity
load at the beginning of each extraction; 76 ± 1 % of the
decay generated 72As activity was repeatedly “milked’ every
48 hours from the generator for a period of 8 days. The
aqueous re-extraction of 72As and selenium are illustrated in
Fig. (2).
A previous study demonstrated that As(III) is much more
strongly coordinated by dithiocarbamates than As(V) [36].
Thus, As(V) is expected to have a substantially lower organic/aqueous distribution coefficient than the trivalent
form. Generator yield will consequently depend strongly on
the As(V)/As(III) ratio. Any arsenic-72 remaining in the
organic layer will likely occur in the trivalent state. The utility of alternate dithiocarbamate ligand systems as selective
chelators for separation of selenium from arsenic is currently
being investigated. A complete flow scheme from production
to distribution of the chelation-based generator system is
illustrated in Fig. (3). A comprehensive comparison of the
72
Se/72As generator systems discussed is provided in Table 4.
Labeling Chemistry of Arsenic
The utility of any new radiopharmaceutical based on
analogous natural or synthetic biomolecules requires that
biological activity be retained following the addition of the
radioactive moiety. Incorporation of the radioactive label
often introduces significant structural perturbations which
often induce a change in the biological function of targeted
molecules such as peptides. However, incorporation to larger
biological targeting vectors such as monoclonal antibodies
do not cause this response. Arsenic has been incorporated
into biologically active compounds with minimal alteration
of the pharmacological response [37]. Similar synthetic
methods can be readily applied to different arsenic isotopes
to generate radiopharmaceuticals to be used as imaging as
well as therapy by introducing other arsenic radioisotopes,
namely the -emitters 76As (t = 26.4 h, 100% -) or 77As
(t = 38.8 h, 100% -). Both therapeutic isotopes can be produced with relatively high yields at nuclear reactors, while
the imaging isotopes are primarily produced via a cyclotron
[38].
268 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
Ballard et al.
Fig. (2). Re-extraction of 72Se generated 72As from the liquid-liquid generator system described in this work.
NaBr, 50g, p-irradiation
100 μA, 10 h
NaBr dissolution, water
oxidization:
H2O2, HCl
Br2 release
evap, reconst,
DDTC, pH 1.3
liquid-liquid extraction
ethyl acetate
22NaCl
waste
72
Se organic phase
evap, reconst
liquid-liquid re-extraction
H2O2, HCl, pH1
72
Se aqueous phase
generator loading
Fig. (3). Schematic flow chart for parent recovery and loading of a chelation based 72Se/72As generator system.
Radioarsenic from a Portable 72Se/72As Generator
Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
269
Table 4. Comparison of Some Published 72Se/72As Generator Systems. Some Studies did not Utilize the Actual 72Se/72As Pair, but were
Tested with Isotopic Surrogates Only
Method of Separation
Selenium Carrier Per
72
Se Generator
Se(IV) sorption
H2SeO3 (10mg)
Se(0) percip./filtration
Se(0) (5mg)
72
Se Loading Per Batch
(MBq)
72
As Elution
Yield (%)
72
Se Break-Through (%)
Ref.
NR
60
not detected
25
~30,000
> 95
< 0.1
30
no carrier added
75
76
NR
< 0.001 (as Se)
32
AsCl3 distillation
no carrier added
75
77
Se/ As surrogates
> 99
<1
33
Se(0) sorption
no carrier added
<5
30-60
0.1-1.5
26
liquid/liquid extraction
no carrier added
1100
76
<1
29
Se(IV) chelation/sorption
Se/ As surrogates
75
NR: values not reported by the authors
Simple organoarsenic precursors and subsequent labeling
with monodentate thiol-containing ligand systems have been
previously illustrated [39-41]. Recently, Jennewein et al.
successfully developed a method to label N-succimidyl Sacetylthiacetate(SATA) derivitized bavituximab with 74As.
The bavituximab-SATA-74As conjugate retained its immunoreactivity after complexation, as well as exhibiting
good in vitro stability in fetal bovine serum. During the subsequent biodistribution studies with Dunning prostate
R3327-AT1 tumor bearing rats, tumors were clearly visible
after 48 hours, exhibiting 8-fold higher uptake at 72 hours as
compared to the control antibody [37, 38].
Research Reactor (MURR). The research described in this
paper was funded by the United States Department of Energy, Office of Science via an award from The Isotope Development and Production for Research and Applications
subprogram in the Office of Nuclear Physics.
CONFLICT OF INTEREST
Declared none.
REFERENCES
[1]
SUMMARY AND CONCLUSIONS
Arsenic-72 is of particular interest. It is a positron emitter
with a half-life of 26h, rendering itself conducive to the imaging of longer-term biological processes. Moreover, the
longer half-life allows for more elaborate chemical modification and labeling methodologies subsequent to 72As production and recovery. The isotope is a daughter of another radioisotope, 72Se, so that the system 72Se/72As is independent
of any accelerator facility in close proximity. Owing to favorable combination of half-life and particle emission energies, several neutron deficient radioisotopes of arsenic could
be used as PET imaging agents. The utility of these isotopes
is limited by three factors: (1) accelerator isotope production
capability, (2) efficiency of chemical product isotope recovery and (3) availability of end-user labeling techniques.
While recent progress is evident in all three areas, additional
studies will be required before the versatility of arsenic can
be exploited to the full potential. To bring any of these successfully to the clinic generator performance, portability,
ease of use, and biocompatibility need to be assessed. Furthermore, the presence of other selenium and arsenic isotopes would need to be evaluated.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
ACKNOWLEDGEMENTS
The authors would like to acknowledge the efforts of the
LANL Isotope Production Facility and Hot Cell Facility personnel for their support in conducting target irradiations,
target transportation, and for their general operational support. The authors would also like to acknowledge the contributions and helpful discussions provided by our collaborators at the University of Missouri and Missouri University
[12]
[13]
[14]
Nickles, R. J. The production of a broader palette for PET tracers.
J. Labelled Compd. Radiopharm., 2003, 46 (1), 1-27.
Firestone, R. B.; Chu, S. Y. F.; Baglin, C. M. Table of Isotopes, 8th
ed. update; Wiley & Sons: New York, 1999.
Pagani, M.; Stone-Elander, S.; Larsson, S. A. Alternative positron
emission tomography with non-conventional positron emitters: effects of their physical properties on image quality and potential
clinical applications. Eur. J. Nucl. Med., 1997, 24(10), 1301-1327.
Mushtaq, A. PET without cyclotron. Ann. Nucl. Med., 2009, 23(3),
321-323.
Zeglis, B. M.; Lewis, J. S. A practical guide to the construction of
radiometallated bioconjugates for positron emission tomography.
Dalton Trans., 2011, 40(23), 6168-6195.
Qaim, S. M. Development of novel positron emitters for medical
applications: nuclear and radiochemical aspects. Radiochim. Acta,
2011, 99(10), 611-625.
Rice, S. L.; Roney, C. A.; Daumar, P.; Lewis, J. S. The next generation of positron emission tomography radiopharmaceuticals in
oncology. Semin. Nucl. Med., 2011, 41(4), 265-282.
Nayak, T. K.; Brechbiel, M. W. Radioimmunoimaging with
Longer-Lived Positron-Emitting Radionuclides: Potentials and
Challenges. Bioconj. Chem., 2009, 20(5), 825-841.
Laforest, R.; Liu, X. Image quality with non-standard nuclides in
PET. Q. J. Nucl. Med. Mol. Imaging, 2008, 52(2), 151-158.
Lebowitz, E.; Richards, P. Radionuclide generator systems. Semin.
in Nucl. Med., 1974, 4(3), 257-268.
Phillips, D. R.; Peterson, E. J.; Taylor, W. A.; Jamriska, D. J.;
Hamilton, V. T.; Kitten, J. J.; Valdez, F. O.; Salazar, L. L.; Pitt, L.
R.; Heaton, R. C.; Kolsky, K. L.; Mausner, L. F. Production of
strontium-82 for the Cardiogen® PET generator: a project of the
Department of Energy Virtual Isotope Center. Radiochim Acta,
2000, 88(3-4), 149-153.
Knapp, F. F., Jr.; Mirzadeh, S. The continuing important role of
radionuclide generator systems for nuclear medicine. Eur. J. Nucl.
Med., 1994, 2(10), 1151-1165.
Zhao, F.-J.; Stroud, J. L.; Khan, M. A.; McGrath, S. P. Arsenic
translocation in rice investigated using radioactive 73As tracer.
Plant Soil, 2012, 350(1-2), 413-420.
Villa-Bellosta, R.; Sorribas, V. Arsenate transport by sodium/phosphate cotransporter type IIb. Toxicol Appl. Pharmacol.,
2010, 247(1), 36-40.
270 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
Ballard et al.
Turkall, R.; Skowronski, G.; Suh, D.; Abdel-Rahman, M. Effect of
a chemical mixture on dermal penetration of arsenic and nickel in
male pig in vitro. J. Toxicol. Environ. Health Part A, 2003, 66(7),
647-655.
Fassbender, M.; Taylor, W.; Vieira, D.; Nortier, M.; Bach, H.;
John, K. Proton beam simulation with MCNPX/CINDER'90: Germanium metal activation estimates below 30 MeV relevant to the
bulk production of arsenic radioisotopes. Appl. Radiat. Isot., 2012,
70(1), 72-75.
Brown, D.; Greene, J. 10th international symposium on the synthesis and applications of isotopes and isotopically labelled compounds-production of isotopes, Session 14, Thursday, June 18,
2009. J. Labelled Compd. Radiopharm., 2010, 53(5-6), 332-345.
Le Loirec, C.; Champion, C. Track structure simulation for positron emitters of physical interest. Part III: The case of the nonstandard radionuclides. Nucl Instr Meth Phys Res Sect A: Accelerators, Spectrometers, Detectors and Associated Equipment, 2007,
582(2), 665-672.
Phillips, D. R.; Hamilton, V. T.; Taylor, M. D.; Farnham, J. E.;
Emran, A. M.; Rowe, R. W.; Pattel, D. Generator-produced arsenic-72 in positron emission tomography. Radioact. Radiochem.,
1992, 3(4), 53-58.
Converse, A. K.; Nye, J. A.; Barnhart, T. E.; Dick, D. W.; AvilaRodriguez, M. A.; Sundaresan, R.; Dallas, C. B.; Nickles, R. J.; Kalin, N. H.; Roberts, A. D. MicroPET performance in the presence
of the third gamma. In: Nuclear Science Symposium Conference
Record, 2003 IEEE, Portland, Oregon, USA, October 19-25, 2003;
pp 1797-1799.
Spahn, I.; Steyn, G. F.; Nortier, F. M.; Coenen, H. H.; Qaim, S. M.
Excitation functions of natGe(p,xn)71,72,73,74As reactions up to 100
MeV with a focus on the production of 72As for medical and 73As
for environmental studies. Appl.Radiat. Isot., 2007, 65(9), 10571064.
Guillaume, M.; Lambrecht, R. M.; Wolf, A. P. Cyclotron isotopes
and radiopharmaceuticals—XXVII. 73 Se. Int. J. Appl. Radiat. Isot.,
1978, 29(7), 411-417.
Mushtaq, A.; Qaim, S. M.; Stöcklin, G. Production of 73Se via (p,
3n) and (d, 4n) reactions on arsenic. Int J Radiat Appl Instrum A:
Appl. Radiat. Isot., 1988, 39(10), 1085-1091.
Blessing, G.; Lavi, N.; Qaim, S. M. Production of 73Se via the
70
Ge([alpha], n)-process using high current target materials. Int J
Radiat Appl Instrum A: Appl. Radiat. Isot., 1992, 43(3), 455-461.
Al-Kouraishi, S. H.; Boswell, G. G. J. An isotope generator for
72
As. Int. J. Appl. Radiat. Isot., 1978, 29(11), 607-609.
Jennewein, M.; Qaim, S. M.; Kulkarni, P. V.; Mason, R. P.; Hermanne, A.; Roesch, F. A no-carrier-added 72Se/72As radionuclide
generator based on solid phase extraction. Radiochim Acta, 2005,
93(9-10), 579-583.
Faßbender, M.; de Villiers, D.; Nortier, M.; van der Walt, N. The
nat
Br(p,x)73,75Se nuclear processes: a convenient route for the production of radioselenium tracers relevant to amino acid labelling.
Appl. Radiat. Isot., 2001, 54(6), 905-913.
Phillips, D. R.; Moody, D. C.; Taylor, W. A.; Segura, N. J.; Pate,
B. D. Electrolytic separation of selenium isotopes from proton irra-
Received: February 10, 2012
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
diated RbBr targets. Int. J. Radiat. Appl. Instrum. A: Appl Radiat
Isot, 1987, 38(7), 521-525.
Ballard, B.; Wycoff, D.; Birnbaum, E. R.; John, K. D.; Lenz, J. W.;
Jurisson, S. S.; Cutler, C. S.; Nortier, F. M.; Taylor, W. A.; Fassbender, M. E. Selenium-72 Formation via natBr(p,x) Induced by 100
MeV Protons: Steps Towards a Novel 72Se/72As Generator System.
Appl Radiat Isot, 2012, 70(4), 595-601.
Phillips, D. R.; Hamilton, V. T.; Nix, D. A.; Taylor, W. A.; Jamriska, D. J.; Staroski, R. C.; Lopez, R. A.; Emran, A. M. In: Chemistry and concept for an automated selenium-72/arsenic-72 generator, New Trends in Radiopharmaceutical Synthesis, Quality Assurance and Regulatory Control, Emran, A. M., Ed.; Plenum Press,
1991; pp 173-182.
Phillips, D. R. Production of selenium-72 and arsenic-72.
WO9304768A1, 1993.
Chajduk, E.; Doner, K.; Polkowska-Motrenko, H.; Bilewicz, A.
Novel radiochemical separation of arsenic from selenium for
72
Se/72As generator. Appl. Radiat. Isot., 2012, 70(5), 819-822.
Jennewein, M.; Schmidt, A.; Novgorodov, A. F.; Qaim, S. M.;
Roesch, F. A no-carrier-added 72Se/72As radionuclide generator
based on distillation. Radiochim Acta, 2004, 92(4-6), 245-249.
Jennewein, M.; Roesch, F.; Brockmann, J. Production and purification of carrier-free 72As and carrier-free 72As(III)-halides.
DE10344101B3, 2004.
Saygi, K. O.; Melek, E.; Tuzen, M.; Soylak, M. Speciation of selenium(IV) and selenium(VI) in environmental samples by the combination of graphite furnace atomic absorption spectrometric determination and solid phase extraction on Diaion HP-2MG. Talanta, 2007, 71(3), 1375-1381.
Wenclawiak, B. W.; Uttich, S.; Deiseroth, H. J.; Schmitz, D. Studies on bulky residual group substituted arsenic(III) dithiocarbamate
structures. Inorg. Chim. Acta, 2003, 348, 1-7.
Jennewein, M.; Hermanne, A.; Mason, R. P.; Thorpe, P. E.; Rösch,
F. A new method for the labelling of proteins with radioactive arsenic isotopes. Nucl. Inst. Meth. Phys. Res. A, 2006, 569(2), 512517.
Jennewein, M.; Lewis, M. A.; Zhao, D.; Tsyganov, E.; Slavine, N.;
He, J.; Watkins, L.; Kodibagkar, V. D.; O'Kelly, S.; Kulkarni, P.;
Antich, P. P.; Hermanne, A.; Roesch, F.; Mason, R. P.; Thorpe, P.
E. Vascular Imaging of Solid Tumors in Rats with a Radioactive
Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine.
Clin. Cancer Res., 2008, 14(5), 1377-1385.
Goetz, L.; Norin, H. Synthesis of 73As-radiolabelled arsenobetaine
and arsenocholine for metabolic studies and their fate and distribution in laboratory animals. Int. J. Appl. Radiat. Isot., 1983, 34(11),
1509-1517.
Hosain, F.; Emran, A.; Spencer, R. P.; Clampitt, K. S. Synthesis of
radioarsenic labeled dimethylchloroarsine for derivation of a new
group of radiopharmaceuticals. Int. J. Appl. Radiat. Isot., 1982,
33(12), 1477-1478.
Emran, A.; Hosain, F.; Spencer, R. P.; Kolstad, K. S. Synthesis and
biodistribution of radioarsenic labeled dimethylarsinothiols: Derivatives of penicillamine and mercaptoethanol. Int. J. Nucl. Med.
Biol., 1984, 11(3–4), 259-261.
Revised: March 20, 2012
Accepted: April 23, 2012