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expensive, and the beam current tolerated is limited due to the poor thermal conductivity of the calcium oxide or carbonate material. Purication of scandium radioisotopes
is dependent on the target material used for production. Calcium metal targets rapidly
dissolve in water, whereas the carbonate form will dissolve in a weak acid. Following
this, the scandium radioisotopes can be separated from the target material using ion-
exchange chromatography and/or extraction techniques[23–28]. Titanium targets are
more dicult to dissolve and typically require the use of strong acid such as sulfuric
(H
) under reux conditions and/or the use of hydrouoric acid (HF). Following target
2SO4
dissolution, the scandium radioisotopes are typically puried using ion-exchange chromatography [68]. For enriched titanium and calcium targets, recycling of the target material
may be required.
The production of alpha emitters can be achieved via high-energy proton routes or irradiation of targets with alpha beams. Both of these nuclear reaction routes have limited
availability due to infrastructure requirements.
Several high-energy facilities have focused on the development of charged-particle
reaction routes for the production of
in limited quantities from generators produced with legacy nuclear material[29].
can be used as a therapeutic radionuclide directly or can be used for the formation of a
225
213
Ac/
Bi generator where the daughter nuclide (
radionuclide[30, 31]. The production of
high-energy protons has the potential to lead to wide-scale applications with this
therapeutic radionuclide[32–34]. One drawback to this production method is the coproduction of
227
Ac (t
=21.8 years), a long-lived contaminant that limits the usable time
1/2
window or expiry of the produced
ever, recent publications have reported the development of ion-exchange methods
leading to high recovery yields and purity[35, 36]. Other groups have explored the feasi-
bility of the production of
225
Ac via the
of working with a long-lived radioactive target material (
a dicult production path.
The short-lived
149
Tb is unique in that it decays by both alpha emission and positron
decays. While promising for applications involving both diagnosis and therapy, production
has thus far been limited to a single site via spallation reactions on tantalum targets[12].
The radiohalogen alpha emitter
ation of naturally monoisotopic bismuth targets via the
Careful monitoring of the alpha beam energy is necessary to avoid the
reaction as the decay of
While the short half-life of
210
At leads to the long-lived alpha emitter
211
At prevents widespread distribution, a network of regional
sites could enable multiple clinical trials with this isotope. Purication of the radionuclide
can be accomplished via dry distillation or wet chemistry techniques[39, 40].
225
Ac (t
=10 days), which is currently available
1/2
213
Bi) can be used as the therapeutic
225
Ac via irradiation of thorium targets with
225
Ac. The purication chemistry is challenging; how-
226
Rn(p,2n) reaction[37]. However, the challenges
226
Rn, t
=1600 years) make this
1/2
211
At (t
=7.2 hours) can be produced via alpha irradi-
1/2
209
Bi(α,2n)
211
At reaction[38, 39].
209
Bi(α,3n)
210
Po (t
=138 days).
1/2
210
225
Ac
At
Chapter 5: Production ofTherapeutic Radionuclides 95
Recently, interest has increased in the use of Auger electron emitters for targeted
therapy. The short tissue range of Auger electrons limits their use to the development
of therapeutics that can be transported into or are in close proximity to the cell nucleus.
However, advances in the production of Auger electron-emitting radiometals and radio-
halogens are enabling progress in the eld.
While the radionuclide
tions via planer or single photon emission computer tomography (SPECT), its utility as
a therapeutic radionuclide has also been reported[41, 42]. Limouris etal. showed the
therapeutic eect of Auger electrons of
targeting liver neuroendocrine carcinoma metastases[43]. Moreover, the production
methods for this radionuclide via proton irradiation of enriched
established and used for commercial production.
Cobalt-58m (t
=9.1 hours) production has been studied by several groups as an Auger
1/2
electron-emitting radionuclide and as a potential therapeutic analog to the positronemitting isotope
enriched
58
55
Fe or deuteron irradiation of 57Fe[44, 45]. After irradiation, the iron target is
dissolved in acid, and the radiocobalt can be puried via ion-exchange techniques.
The radiolanthanide
electron-emitting radionuclide with therapeutic applications. This radionuclide can be
produced via the proton or deuteron irradiation of holmium targets or indirectly via
the higher-energy reaction routes:
166
Er(p,2n)
165
Tm → EC/β+ →
the target material is dissolved and separated using anion exchange. In the case of the
higher-energy reaction, a two-step process is necessary to achieve a high-specic-activity
product. In this scenario, the
allowed to decay, and then the
The production of several other radiometals is ongoing at several sites. For example,
the Auger electron emitter
natural barium targets[50]. Additionally,
a therapeutic pair with the imaging isotope
nuclides can be produced via proton irradiation of electroplated enriched tin isotopes:
119
Sn for
119g
Sb, and
mony, the irradiated target is dissolved in acid, and the radionuclides are puried using a
weak anion exchange resin[51, 52]. In the case of the enriched tin targets, the enriched
material is recycled.
Several Auger electron-emitting radiohalogens have also been studied as potential
therapeutics. In contrast to radioactive metals, the radiohalogens may aord dierent
strategies for incorporation into target molecules used in radiotherapy. For example, the
long-lived iodine radionuclide
radionuclide[53].
111
In (t
=2.80 days) is typically used for imaging applica-
1/2
111
In-octreotide in a small patient trial (n=13)
111
Cd targets are well
Co[44]. Cobalt-58m can be readily produced via proton irradiation of
165
Er (t
=10.36 hours) has also been suggested as an Auger
1/2
117
Sn for
nat
Er(p,xn)
165
Er[46–49]. For the lower-energy holmium reaction routes,
165
Tm is rst separated from the Er target material and
165
Er is puried from the
135
La (t
=19.5 hours) can be produced via irradiation of
1/2
117
Sb. For production of both radiolanthanum and radioanti-
125
I (t
=59.4 days) has been investigated as a therapeutic
1/2
165
Tm (t
=1.25 days) → EC/β+ →
1/2
165
Tm[49].
119g
Sb (t
=38.2 hours) has been suggested as
1/2
117
Sb[51, 52]. Both of these antimony radio-
165
Er or
96 Handbook of Radiopharmaceuticals
Production of the Auger electron-emitting radiohalogens 77Br (t
Converter
Bremsstrahlung
get
80m
and
Br (t
=4.42 hours) via proton or deuteron irradiation of isotopically enriched
1/2
=2.38 days)
1/2
selenium targets has been investigated by several groups. These radionuclides can be
used as therapeutic pairs with their diagnostic counterparts,
76
Br (t
=16.2 hours), respectively. As elemental selenium has poor thermal and chemical
1/2
properties for a target material, refractory compounds of selenium such as Cu
75
Br (t
=97 minutes) and
1/2
Se or NiSe
2
typically are used[54]. Isolation of the produced radiobromine is typically achieved via
dry distillation techniques or thermal diusion; however, wet chemistry methods have
also been reported[54–56]. The production of
77
Br and
80m
Br via the irradiation of krypton
gas targets has also been explored[57]. While the yield of the krypton reactions is lower
than that obtained by selenium irradiation, this route oers the potential advantages of
decreased radionuclidic impurities and simple separation chemistry.
RADIONUCLIDES USING
Photonuclear reactions occur via the absorption of photons by atomic nuclei followed by
the ejection of protons (γ,p), neutrons (γ,n), or heavy particles (γ,x) and can be used to pro-
duce neutron-rich beta emitters, proton-rich positron emitters, and alpha emitters. His-
torically, photonuclear reactions have not been used to produce signicant quantities of
therapeutic radionuclides due to the low ux densities (γ s
limiting the yield of produced radioactivities. However, research in this area is increasing
due to developments in accelerator technology leading to a new generation of eLINACs
capable of electron beam currents up to or exceeding 100 mA. Two methods, bremsstrahlung radiation and Compton backscattering, can be used to obtain photons with energy
sucient to induce these reactions.
Bremsstrahlung radiation is generated by the deceleration of high-energy electrons
produced by an eLINAC in the electric eld of nuclei contained in a converter material, as
shown in Figure5.1.
−1
) attainable at γ ray sources,
Radiation
eLINAC
e− beam
γ
48
Ta r
Ti(γ,p)47Sc
Figure 5.1 An example of a photonuclear reaction to produce 47Sc. An electron
beam and converter are needed to generate a bremsstrahlung photon beam, which
can then be used to induce a photonuclear reaction.
Chapter 5: Production ofTherapeutic Radionuclides 97
The kinetic energies lost by the decelerating electrons are emitted as photons with
a continuous spectrum of energies. Importantly, the use of dense, high Z material (e.g.
tungsten or tantalum) as a converter increases the energy loss of the accelerated electrons, shifting the peak photon intensity to higher energies. Alternatively, the direct
collision of laser beams with high-energy (>100 MeV) electrons can result in Compton
backscattered (CBS) photons with a well-dened energy range[58].
The most recent generation of eLINACs can produce bremsstrahlung or CBS pho-
tons with ux densities up to 10
in magnitude to thermal neutron ux densities (10
14
–1015 γ s−1. At a ux density of this magnitude, similar
13
–1016 n cm−2s−1), therapeutic radio-
nuclides could be produced in high specic activity and supplied via dierent photo-
nuclear reactions. Early studies of photonuclear production have focused on modeling
the yield and specic activity of radionuclides that are inaccessible or can only be produced in limited quantities with nuclear reactors or charged-particle accelerators[58].
To date, the photonuclear production of a limited number of therapeutic radionu-
clides has been experimentally investigated. Moreover, unlike the extensive nuclear
data available to inform therapeutic radionuclide production via neutron capture and
charged-particle reactions, cross-section data on photonuclear reactions is limited.
Therefore, the successful development of photonuclear production will require future
work to expand the existing nuclear data sets on these reactions. Early research on
four therapeutic radionuclides that could be produced by photonuclear reactions is
illustrated next.
The therapeutic radionuclide
charged particles and neutrons. Alternatively,
48
via the
Ti(γ,p)47Sc reaction and 48Ca(γ,n)47Ca → β− → 47Sc. Rotsch etal. investigated the
47
Sc (discussed earlier) has been produced using both
47
Sc can be produced directly or indirectly
direct route using natural titanium, a 35 or 40 MeV electron beam, and a tantalum or
tungsten converter. A typical four-hour irradiation yielded approximately 180 MBq.
Following chemical purication, >90% of the
suitable for direct radiolabeling[59]. The indirect route produces
which decays by emission of a 1.3 MeV γ ray and a beta particle to
be produced using either natural calcium or enriched
47
Sc was recovered with chemical purities
47
Ca (t
=4.54 days),
1/2
47
Sc. The 47Ca can
48
Ca, with the latter resulting in
a higher molar activity. Rane etal. investigated the indirect route using Monte Carlo
N-Particle eXtended (MCNPX) radiation transport code to predict the production
rate on an enriched
48
Ca target using bremsstrahlung photons generated by a 40 MeV
electron beam, 1 mA beam current, and tungsten converter. The predicted values were
than validated using a 39 MeV electron beam, 12.5 μA beam current, and tungsten
converter. Based on these parameters, an enriched target will result in tens of MBq/g of
47
Ca. Calcium-47 incorporated into a 47Ca/47Sc generator system, at equilibrium with its
radioactive daughter
radionuclide[60]. Further, with the long half-life of
47
Sc, would provide a similar amount of this promising therapeutic
47
Ca, this generator could be
distributed regionally. For both production routes, enriched targets should be used to
optimize yield, molar activities, and radionuclidic purity.
229
225
Ac (discussed earlier) can be obtained via the chemical
Th (t
=7932 years) sample undergoing decay to its
1/2
225
Ac
The therapeutic radionuclide
separation of a radioactive
98 Handbook of Radiopharmaceuticals
daughter (
229
erates approximately 37 GBq of
indirectly by the
duced by this route could be incorporated into a
Th →
225
226
Ra(γ,n)
225
Ra →
Ac). However, the current supply of
225
Ac per year. Alternatively,
225
Ra photonuclear reaction. Radium-225 (t
225
229
Th is limited and gen-
225
Ac can be produced
225
Ra/
Ac generator. The use of
=14.9 days) pro-
1/2
225
Ac
as a therapeutic radionuclide would require hundreds of MBqs and tens of GBqs for
clinical trials and commercial supply, respectively[61]. Melville and Allen investigated
the use of charged-particle and photonuclear reactions to produce
225
Ac. In this study,
an 18 MeV electron beam, 26 μ A beam current, and tungsten converter were used to
generate bremsstrahlung photons. The measured rate on a low-power medical eLINAC
was 14.2 kBq μA
−1 h−1
[61]. Further, this group showed that increasing the eLINAC power
and maximum electron beam energy to 40 MeV will double the number of photons, with
energy near the peak cross-section from 25% to 56%[61]. Thus, the extrapolated rate on
a high-power eLINAC with a 40 MeV electron beam, 1 mA beam current, and similar tungsten converter would be approximately 30 kBq μA
−1 h−1
. At this rate, a two-week irradiation
could produce up to 10 GBq; however, much work must be done in the future to realize
195m
225
Ac.
Pt (t
=4.02 days) and
1/2
117m
Sn (t
=13.8 days) decay by emission
1/2
this method of production for
The nuclear isomers
of an imageable 99 and 159 keV γ ray, respectively, and low-energy conversion and Auger
electrons. Both isomers have been suggested as potential therapeutic radionuclides.
Platinum-195m could allow combined chemo- and radiotherapy with cisplatin-based
drugs. Platinum-195m can be produced via the
reactor; however,
195m
Pt produced by this reaction is destroyed by the
194
Pt(n,γ)
195m
Pt reaction in a nuclear
195m
Pt(n,γ)
196
Pt
reaction, resulting in a low specic activity[58]. Platinum-195m can be produced by the
photonuclear reactions,
nat
platin,
PtCl2(NH3)2, with bremsstrahlung photons generated from a 26 and 34 MeV
195
Pt(γ,γ′)
195m
Pt and
197
Au(γ,np)
195m
Pt. Dykiy etal. irradiated cis-
electron beam; however, the recoil energies (several keV) associated with the many
191
193m
platinum radionuclides produced (
formation of (PtCl
)2− and (PtCl6)2−. In the same work, using a 34 MeV electron beam,
4
Pt,
Pt,
195m
Pt, and
was produced using gold NPs irradiated with bremsstrahlung photons. The
chemically separated and used to synthesize
195m
the
Pt-cisplatin was used in cell viability studies to show improved cell-killing ecacy
195m
PtCl2(NH3)2. Following radiosynthesis,
197
Pt) led to disassociation and
195m
Pt was
195m
relative to normal cisplatin compounds[62]. Tin-117m has been used in clinical studies
for palliative care in patients with bone metastases[63, 64]. Tin-117m can be produced
via the
117
Sn(n,nγ)
117m
Sn reaction; however, the thermal neutron cross-section is small,
resulting in a low molar activity[58]. Tin-117m can be produced by the photonuclear
reactions
117
cross-section of the
current, tantalum converter, and 98.5% enriched
Sn(γ,γ′)
117m
118
Sn and
Sn(γ,n)
118
117m
117m
Sn(γ,n)
Sn. Danagulyan etal. measured the cumulative
Sn reaction using a 40 MeV electron beam, 10 μA beam
118
Sn target. The measured cross-section
was 17.5 ± 1.7 mb. Although the magnitude of this cross-section is small, the advantage
of photonuclear production of
The only radiocontaminants are the short-lived
(t
=43.2 minutes)[65]. In both cases, the utility of these radionuclides have been shown;
1/2
117m
Sn is the absence of other coproduced radionuclides.
117m
In (t
=116.2 minutes) and
1/2
117g
In
however, the existing production methods using neutron capture results in low specic
Pt
Chapter 5: Production ofTherapeutic Radionuclides 99
activities. Photonuclear production of these promising nuclear isomers could result
in much higher specic activities. Compared to previous work using neutron capture
reactions, this could increase the specic activities by a factor of 1700 and 12, respectively[58].
Therapeutic radionuclides may also be produced by in-ight projectile fragmentation.
This technique uses the high-energy collision of heavy nuclei with a light target. The
heavy ion fragments into a number of product radionuclides that are used for down-
stream experiments. Typically, this method will generate many radionuclides but select
only one for study via an electromagnetic separation. The unwanted radionuclides are
diverted and stopped in a solid or liquid media, often referred to as a beam dump. Facil-
ities capable of producing the beams necessary to induce these reactions are exceedingly rare. Moreover, these facilities are often dedicated to studying questions in basic
nuclear science.
Recent studies have focused on developing new methods to characterize the contents
of these beam dumps and strategies to chemically extract a single target radionuclide
from a mixture of tens to hundreds of dierent radionuclides. Mastren etal. showed
67
that
Cu (also discussed earlier) coproduced in a large ensemble of radionuclides rang-
ing in atomic number from ~19 to 34 and captured in an aqueous beam dump could be
separated with high yield (74% ± 4%) and >99% radiochemical purity[66]. Abel etal. modeled the production rate of therapeutic radionuclides expected at the Facility for Rare
225
47
Ca
Ac for
Isotope Beams located at Michigan State University. In this work, it was shown that
47
for a
Ca/47Sc generator,
direct targeted alpha therapy or a
37 GBq d
−1
, 15.9 GBq d−1, and 1.7 GBq wk−1, respectively[67].
211
Rn (t
=14.6 hours) for a
1/2
225
Ac/
211
211
Rn/
At generator, and
213
Bi generator could have production rates up to
5.7 SUMMARY
A variety of nuclear reaction routes are available that lead to the high-yield production of therapeutic radionuclides that decay by alpha, beta, or Auger electron
emission. In several cases, there may be multiple routes leading to the radionuclide
of interest. Important considerations for the production of therapeutic radionu-
clides include target material chemistry and cost, specic activity requirements, and
infrastructure needs. Interestingly, as novel accelerators become more common or
accelerator technologies advance, rarely used routes like photonuclear reactions and
in-ight fragmentation may become feasible future means of producing and supplying
therapeutic radionuclides.
100 Handbook of Radiopharmaceuticals
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104 Handbook of Radiopharmaceuticals