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y
Eluate
IN
Glass Column
Parent Radionuclide
absorbed on
Solid Support
Daughter
Radionuclide
OUT
Internal Lead
Shielding
Generator Bod
Outer Casing
To achieve the true simultaneous production of two different radionuclides
from a single beamline, several investigators developed tandem systems using
inline combinations of gas and water targets. The concept is actually simple:
position a second target at the back of the first, separated by a suitable thin
foil, but design it such that the incident particle energies on each target are
appropriate for the cross-sections of the two desired radionuclides. Two different
tandem targets were designed to take advantage of the availability of higher-
energy protons from 30 to 50 MeV cyclotrons. Placement of an oxygen gas target
in front and a [
of oxygen-15 (
16
O]water target in the back allowed for simultaneous formation
16
O(p,pn)15O) and nitrogen-13 (16O(p,α)13N), with the front gas target
used to attenuate the bean energy to match the lower-energy cross-section for
nitrogen-13 production in the rear target[58]. Alternatively, a tandem water
target design placing a [
16
O]water target in front and a second small-volume
water target in back allowed simultaneous production of oxygen-15 in front, and
13
either
material)[59]. Finally, a dual
N or 18F in the rear target (depending on using 16O- or 18O-water target
11
C and 18F target was reported using a nitrogen gas
target in front that was “thin” to the particle beam, allowing protons of sufficient
energy to pass through a rear foil assembly and into a typical small-volume
18
[
O]water target placed at the rear[60].
Figure 3.3 Sche-
matic diagram of
the design concept
used for
68
Ga generators.
82
Rb and
3.2.6 Rubidium-82 andGallium-68
Two isotopes routinely used in human PET studies, 82Rb and 68Ga, have been available
from generator systems that utilize parent isotopes with suciently long half-lives (
Chapter 3: Production of Short Half-Life PET Radionuclides 55
68
Ge
T
=275 days; and 82Sr T
1/2
=25.55 days) that such generators can be shipped to remote
1/2
sites of use. The conceptual design of such generators is quite simple (Figure3.3), with
the long-lived parent radionuclide absorbed on a solid phase that is carefully selected
to allow rapid elution of the daughter radionuclide in a solution useful either directly
as a radiopharmaceutical (as for
82
Rb) or as a synthetic precursor (as for 68Ga), without a
signicant breakthrough of the parent radionuclide into the eluate.
More recently, targetry needed for the production of
68
Ga directly using small medical
cyclotrons has been introduced into the nuclear medicine community and oers an
additional option for use of that PET radionuclide.
3.2.7 Rubidium-82
Rubidium-82 is a very short half-life nuclide available from a 82Sr/82Rb parent/daughter
radionuclide generator[9]: the parent
molybdenum target[61]. The strontium-82 is loaded onto a tin oxide column and the
rubidium-82 selectively eluted using a 0.9% NaCl solution; the eluate is used immediately
for PET imaging studies. The generators can be eluted every 10 minutes, making them
particularly useful for repeated studies of cardiac blood ow. Quality control eorts for
the eluted radioactivity center on determining the extent of the breakthrough of
The generators have a limited useful lifetime of approximately four to eight weeks before
replacement is necessary to continue clinical studies.
The short half-life requires that the generator be located in close proximity to the
PET scanner, but the parent
82
Sr nuclide has a suciently long half-life of 25.5 days to
allow shipment to facilities that may not have local cyclotron access. Studies with
have been done for decades, with the radiopharmaceutical gaining US Food and Drug
Administration (FDA) approval in 1989, and it is used in many institutions around the
world[62]. Rubidium generators (e.g. Ruby Fill and Cardiogen-82) are commercially
available.
82
Sr is produced by proton irradiation of a
82
Sr.
82
Rb
3.2.8 Gallium-68
Using gallium-68 for medical imaging was rst described in the 1960s[63], but it had a
small clinical footprint for much of the following four decades. Gallium-68 is an attractive
alternative to uorine-18 due to its availability from a generator system, thus supporting
PET imaging capabilities at imaging facilities without a cyclotron. Additional attributes of
68
Ga make it a desirable PET trace. It is a positron-emitting (89% β+) radionuclide with a
relatively short half-life (T
68Ga3+
The
Lewis acid with an anity for binding ligands containing oxygen and nitrogen donors:
it is therefore suitable for conjugation not only to both large biomolecular vectors
using bifunctional chelators, but also to small molecules with rapid pharmacokinetic
proles such as peptides and peptidomimetics[64, 65]. This synthetic diversity,
together with the availability of
56 Handbook of Radiopharmaceuticals
cation is small with an ionic radius of 0.62 Å, and it behaves as a relatively hard
=67.71 minutes), which decays to the stable isotope zinc-68.
1/2
68
Ga from both generator systems and directly from
cyclotrons, has resulted in the rapid growth in interest in the development of gallium-68
radiopharmaceuticals[66, 67].
3.3 68Ge/68Ga GENERATORS
The most common source of 68Ga for radiopharmaceutical syntheses has been the
68
Ge/68Ga parent/daughter radionuclide generator. The parent isotope 68Ge (half-life of
270.95 days) is produced by proton irradiation of natural gallium (
68
Ge spontaneously decays to 68Ga via an electron capture reaction. The rst 68Ge/68Ga
generator was described in 1960 as a “Positron Cow,” where
68
Ge via liquid-liquid extraction[69]. Such systems using liquid-liquid extractions[69, 70]
have disadvantages for designing a generator for routine clinical use, prompting the
development of generators employing solid-phase ion-exchange systems. Building on the
concept by researchers who had developed ion-exchange chromatographic columns for
99
the
be loaded with
Though [
99m
Mo/
Tc generator[71], Greene and Tucker developed an alumina column that could
68
Ge; elution with an EDTA solution directly yielded [68Ga]Ga-EDTA[72].
68
Ga]Ga-EDTA proved a successful and clinically used radiopharmaceutical,
the generator was limited as it exclusively produced that single chemical species, and
methods to free the
68
Ga from the thermodynamically stable EDTA complex were dicult
and low-yielding[63]. More successful, and still used today, are ionic
utilizing inorganic matrices containing TiO
68
Ge and allow 68Ga desorptions upon elution with dilute hydrochloric acid solutions. Such
, SnO2, ZrO2, or CeO2, which selectively adsorb
2
solid-phase generators have a shelf life of 6–12 months and provide the [
is useful for subsequent radiopharmaceutical syntheses. The eluted
for levels of breakthrough of
68
Ge[73–75], dened as either the activity of 68Ge relative
to that of the generator column or, alternatively, the percentage of
68
eluted
Ga. Provided the eluted 68Ga radioactivity meets established breakthrough
limits, it can then be used for radiopharmaceutical syntheses.
The generator system is simple in design with a small footprint, consisting of a selfshielded body containing a chromatographic column to which the parent is embedded,
and an inlet and outlet for the solvent system that will selectively elute the daughter
from the column (Figure3.3). As of 2019, there were multiple commercially available
68
Ge/68Ga generators, with two of them–alliPharm, Eckert-Ziegler GmbH (Germany);
and Galli Ad, IRE ELiT (Belgium)–having marketing authorization in Europe and the
USA. Those two generators, along with generators from iThemba Labs (South Africa),
itG (Isotope Technologies Garching, Germany), and Obninsk (Russia), all utilize dilute
hydrochloric acid instead of an EDTA solution for elution, yielding cationic
making them appropriate for subsequent
Ad, and Obninsk generators employ a TiO
is SnO
based, and the itG generator utilizes a unique organic matrix of dodecyl gallate
2
68
Ga labeling chemistry. The GalliPharm, Galli
column system, whereas the iThemba system
2
attached to high-performance liquid chromatography (HPLC)-grade silica gel[73, 76, 77].
The use of the non-metallic solid phase by the itG generator allows for elution of
at lower HCl concentrations (0.05 M HCl), with lower retention of metal ions (Zn, Fe, Ti)
69
Ga(p,2n)68Ge)[68], and
68
Ga was separated from
68
Ge/68Ga generators
68
Ga]GaCl3 that
68
Ga must be tested
68
Ge relative to the
68
GaCl3 and
68
Ga
Chapter 3: Production of Short Half-Life PET Radionuclides 57
by the matrix leading to less contamination of the 68Ga eluate. All of the available ionic
generators produce
routinely used for
Despite
68
Ge/68Ga generators having played a major role in the development of
and access to
supply has been inconsistent and has not kept pace with the clinical demand for
68
Ga with low and acceptable 68Ge breakthrough, and all have been
68
Ga-radiopharmaceutical production for human PET imaging studies.
68
Ga-based radiopharmaceuticals, the commercial 68Ge/68Ga generator
68
Ga.
Additionally, there remain technical challenges associated with generators[78]. The low
quantities that can be eluted from available generators (approximately 1.85–3.7 GBq,
50–100 mCi) limit the numbers of patient studies that can be scheduled in a single day
(often only two to four possible). The
68
Ga elution quantities decline steadily with use
and time, making consistent patient scheduling dicult. Finally, as elution quantities
68
of
Ga decrease, the percentages of the breakthrough radionuclide 68Ge increase,
eventually exceeding allowable limits and requiring the use of a new, fresh generator.
3.3.1 Cyclotron Production of 68Ga
To meet the growing demand for gallium-68 labeled radiopharmaceuticals, the direct
production of
nuclear medicine community, including publication of a technical document from the
IAEA[79], publication in late 2018 of a European Pharmacopeia monograph for the direct
accelerator-based production of [
the equipment and processes involved[81, 82].
Of several possible nuclear reactions, the formation of
68
of
Zn (68Zn(p,n)68Ga) is the mostly widely utilized method on a cyclotron. Targetry
options include both solid and liquid targets. The proton irradiation of highly enriched
68
Zn produces 68Ga, but also small amounts of the longer-lived isotopes 66Ga and 67Ga;
the isotopic contamination is attributed to the trace amounts of
in the isotopically enriched
68
Zn. More signicant is the production of the isotopic contaminant 67Ga that occurs with
the use of proton energies above 12.2 MeV, due to the competing
reaction. For that reason, incident proton energies are often degraded appropriately to
produce
production of sucient yields for clinical applications. Regardless, if opting for liquid or
solid target approaches to the direct production of
68
the
Ga from the irradiated 68Zn is required.
68
Ga using a cyclotron has garnered much interest by the international
68
Ga]GaCl3[80], and the development and patenting of
68
Ga by proton irradiation
66
Zn and 67Zn present
68
Zn, as commonly the available targets are not 100% pure
68
Z(p,2n)67Ga nuclear
68
Ga of high radionuclidic purity while utilizing enough current to support the
68
Ga, an ecient means for purifying
3.3.2 Solid Target Production of 68Ga
Four types of targets are used for solid target production of 68Ga: foils, pressed, fused,
and electroplated[79]. The
of highly enriched foils has been limited. A pressed target is a metal disk with a central
cavity into which a hydraulically pressed
is produced by melting zinc pellets into a recess on an aluminum disk[84]. The most
58 Handbook of Radiopharmaceuticals
68
Zn foils are purchased commercially, but the availability
68
Zn pellet is positioned[83], and a fused target
widely reported solid targets for 68Ga production have, however, been the electroplated
targets, using
backing[85–88]. Such targets are capable of yielding curie amounts of
68
Zn electrodeposited onto a copper, nickel, platinum, or silver support
68
Ga suitable
for radiopharmaceutical syntheses. The general production process for preparation,
irradiation, and processing of such targets involves multiple steps: formation of the solid
electroplated target, transfer of the target to the target holder, irradiation, transfer of
the target to a hot cell, and dissolution of the target to provide impure
solution. This is then followed by chemical separation and purication of the desired
from the target
68
Zn (discussed in a later section). The recovery of the target 68Zn metal
68
Ga in an acidic
68
Ga
and nally reformation of the solid target is feasible but may not be practical on a routine
basis. Of the multiple steps in the process, the one resulting in the most signicant
exposure to the personnel involved is the step of chemical separation and purication
68
of the
Ga. The solid target has to be retrieved and moved to a hot cell after irradiation
for processing: if accomplished by manual retrieval of the target, a very high personal
radiation dose burden arises from the radioactive eld of the target itself in addition to
any surrounding metal contaminates and/or cyclotron components that were activated
in the irradiation process. For that reason, high-yielding routine production of
68
Ga
from solid targets necessitates an automated target transfer system and optimally an
automated system rather than manual operations for the subsequent processing steps.
Foils, pressed, and electroplated targets have the additional option of being able to
undergo
occurs by heating the irradiated zinc and etching the
68
Ga extraction by thermal diusion rather than target dissolution[89, 90]. This
68
Ga activity o of the zinc surface
with a dilute acid. The isolation yields for the process are high (approximately 60–70%)
and have a short processing time (under 10 minutes). If desired, zinc foils can be reused
without going through the target reformation process, although the
68
Ga yields will
decrease with continual use. The reported example[89] of gallium extraction by thermal
diusion was primarily performed manually in a model system by measuring
66
Ga and 68Ga
(produced from irradiated natural zinc) to minimize the eective dose to the radiochemist
and projected possible yields scaled to the abundance of the starting zinc isotopes. While
the proof-of-concept studies are encouraging, an automated approach to performing the
thermal diusion separation would be necessary for a commercial setting.
If multi-curie yields of
68
Ga are required, solid target production is needed[87, 91]: a
solid target will always have a higher concentration of zinc and thus a larger cross-section
for the nuclear reaction when compared to a liquid target. These higher production
yields are, however, associated with the limitation that appropriate infrastructure will
be needed for solid target production, handling, and processing. This is a high capital
investment that may not be available for a developing site or a viable modication option
for established cyclotron facilities.
3.3.3 Liquid Target Production of 68Ga
Liquid targets, in which an aqueous solution of the enriched target material (usually [68Zn]
Zn(NO
) is irradiated with low-energy protons, oer increased simplicity as they present
3)2
Chapter 3: Production of Short Half-Life PET Radionuclides 59
a similar workow to the production of [18F]uoride ion and are instantly compatible with
laboratory setups in existing PET centers. When compared to the cyclotron production
of the other short-lived PET radionuclides (
15
O, 13N, 11C, 18F), the targetry development
is actually quite recent, but the targets are very similar to those utilized for uorine-18
production and share many of the operating considerations and problems.
3.3.4 General Considerations for Liquid Targets for 68Ga
Production
The design and operation of aqueous targets for radionuclide production, including 68Ga,
share many of the challenges met with small-volume (approximately 2 ml) water targets
for uorine-18 production[92]. Surfaces in contact with the aqueous target volume (target
body, innermost foil) are typically made of inert metals (e.g. niobium or titanium), with
additional foils (e.g. aluminum or Havar backing foils) chosen to maintain good stability
in the face of increased intra-target pressures resulting from proton-induced radiolysis
of the water media: the combined foil system should be designed to keep the incident
proton energy below the 12.2 MeV threshold to avoid
pressurized with inert gas, which aids in maintaining the target solution within the beam
strike region. Whereas with uorine-18 production, the composition of valves and tubing
is carefully selected to minimize dilution of the molar radioactivity with uorine-19, for the
68
Ga targets the tubing and valves associated with target loading and unloading must be
chosen to be inert to the acidic solutions utilized, and all target materials and chemicals
utilized carefully chosen to minimize contamination by metal ions.
The proton irradiation of aqueous solutions, as for
radionuclide contaminants that must be appropriately accounted for and removed in the
subsequent steps of processing. At the end-of-bombardment (EOB), a large portion of the
radioactivity delivered to a hot cell consists of gaseous
reaction. Small amounts of
16
[
O]water contains trace amounts of [18O]water), and volatile 11C species are generated
from the nitrate anion through the
18
F are also produced via the 18O(p,n) 18F reaction (typically,
14
N(p,α)11C reaction. While these co-contaminants will
not interfere with subsequent metal-coordinating
produced on the cyclotron needs to be delivered to a hot cell with appropriate ventilation
to accommodate signicant amounts of radioactive gas. Finally, as with any irradiation
of an aqueous solution in a metal target, there is the possibility of contamination of
the desired radionuclide (in this case,
68
Ga) with trace amounts of other radioactive and
nonradioactive metallic species arising from the target body or the foil material[93, 94].
The maximum theoretical molar activity of
(Table3.1), but to date, there has been minimal discussion of the molar activities achieved
68
from
Zn cyclotron targets: although it was reported the molar activity from cyclotron
production (368 GBq μmol
−1
) was signicantly higher than from a 68Ge/68Ga generator[87],
it was still a small percentage of the theoretical (102.3 TBq μmol
low eective specic activities are reported for nal
seems to be due to the excess chemical precursors used to eectively chelate the
67
Ga formation. Targets may be over-
68
Ga targets, produces several other
13
N produced by the 16O(p,α)13N
68
Ga reactions, the crude 68Ga solution
68
Ga is actually higher than for 18F and 11C
−1
). In general, rather
68
Ga-radiopharmaceuticals. This
68
Ga
60 Handbook of Radiopharmaceuticals
and the diculties encountered in trying to separate the chemical precursor from the
68
nal
Ga-chelated radiotracer. The result is that, at present, typical reported “eective”
molar activities (radioactivity per total mass of ligand, chelated plus unchelated)
obtained for nished human
25 –5 0 GBq nmo l
−1
[95, 96], although a higher value (1200 MBq nmol−1) was reported
68
Ga radiopharmaceuticals are often in the range of
for use in animal studies[97]. These values do not come close to those obtained with
18
F or 11C labeled radiotracers, which limits applications of such 68Ga-radiotracers to
receptor targets with high tissue concentrations. In the future, perhaps, preparation and
application of true high-molar-activity
68
Ga-radiotracers might be achieved.
3.3.5 Aqueous 68Ga Target Development
Initial work with liquid targets for the production of radiometals via irradiation of nitrate
salts was performed by Vogg etal. with the irradiation of Sr(NO
laid the groundwork for subsequent investigations of metallic radionuclide production
via cyclotron irradiation of salt solutions, and Jensen and Clark published the initial work
on cyclotron production of
aqueous solution of
68
1.7 M [
Zn]Zn(NO3)2 in 0.2 M nitric acid as a target solution[93], as compared to irradiation
68
Ga using proton irradiation of a liquid target containing an
68
ZnCl2[99]. A signicant improvement by Pandey etal. was to use
of chloride salts, which resulted in decreased rates of water radiolysis, decreased the
target pressure during irradiation and increased the Havar foil life, and reduced longlived radiometal contaminants. While that target system was useful for producing
and puried [
time-consuming
point for liquid target
68
Ga]GaCl3, the methods were plagued by low and inconsistent yields and a
68
Ga/[68Ga]GaCl3 separation/purication process. This was a great starting
68
Ga production, but the process needed to be optimized to provide
a high-yielding and reproducible method appropriate for routine clinical use.
Subsequent studies at the Mayo Clinic evaluated irradiations of varying [
(0.6–1.42 M) concentrations in nitric acid (0.8–1.2 N) for 60 minutes at 30–50 μ A[100].
The highest yields reported were an impressive 9.85 ± 2.09 Gbq (266 ± 57 mCi) (EOB,
decay corrected) using the target solution of 1.42 M [
irradiations for 60 minutes at 40 μA. The
purication and [
68
Ga]GaCl3 formation and was further used to synthesize [68Ga]Ga-PSMA-
68
Ga produced in this manner underwent
68
Zn]Zn(NO3)2 in 1.2 N HNO3, with
HBED under Current Good Manufacturing Practice (cGMP) compliance. This method
provided clinically useful cyclotron production of
68
Ga from a liquid target, with one
possible complication being the potential degradative eects of irradiation of targets
with high zinc and nitric acid concentrations.
The institutions in Europe and the United States that have pursued the optimization
of liquid targets for
68
Ga production have focused on using low nitric acid concentrations
in the target media. A collaborative eort between GE Healthcare and Mayo Clinic[91]
reported high yields of [
(EOB + 30 minutes) using a target of 1.0 M [
68
Ga]GaCl3 at 30 minutes past EOB of 2.5 ± 0.1 GBq (68 ± 4 mCi)
68
Zn]Zn(NO3)2 in 0.2 N HNO3 and irradiations
of 26 μA for 60 minutes. A high radionuclidic purity of >99.8% was obtained, which is
well above the >98% European Pharmacopoeia acceptance guideline. Investigators in
to produce 86Y[98]. This
3)2
68
Ga
68
Zn]Zn(NO3)2
Chapter 3: Production of Short Half-Life PET Radionuclides 61
Italy reported 68Ga yields of EOB of 4.3 ± 0.3 GBq (116 ± 8 mCi) (EOB) using 1.7 M [68Zn]
Zn(NO
in 0.2 N HNO3 and irradiations of 32 minutes at 46 μA, with a high radionuclidic
3)2
purity of >99.9% up to three hours EOB[101]. The University of Michigan utilized similar
irradiation and synthetic conditions (1.0 M [
68
Zn]Zn(NO3)2 in 0.2 N HNO3, 60 minutes,
30 μA) to produce 3.1 ± 0.4 GBq (112 ± 16 mCi) (EOB), which could be converted to
1.5 ± 0.2 GBq (54 ± 8 mCi) (EOB + 30 minutes) of [
(45 ± 6 mCi) of [
68
Ga]Ga-PSMA-11 at 40 minutes EOB, all with high radionuclidic purity
68
Ga]GaCl3 and then to 1.2 ± 0.2 GBq
of >99.8%.
At the end of 2019, there were commercially available liquid targets (IBA and GE
Healthcare) for cyclotron production of
functions to irradiate a [
68
Zn]Zn(NO3)2 solution in dilute nitric acid. As a representative
example, the design of the GE Healthcare
68
GE
Ga PETtrace Liquid Target is a small volume (including the target lines/dead volume,
68
Ga. For both systems, the targetry is similar and
68
Ga liquid target is shown in Figure3.4. The
the total target ll volume is approximately 2.2 ml) constructed of a niobium target body
and an entry foil pack consisting of an external 200 μm aluminum foil (for particle energy
degradation), an intermediate 25 μm Havar foil for support, and an internal 25 μm niobium
foil for chemical inertness with the target media. The thick aluminum foil serves as a
degrader and provides additional protection against target foil failures and the acidic
target solution being sucked into the cyclotron vacuum chamber.
3.3.6 Processing Cyclotron-Produced 68Ga for
Radiopharmaceutical Use
The process for 68Ga purication is similar whether the radionuclide is obtained from
solid or liquid targets and involves the steps needed to separate the desired
radionuclidic and chemical impurities and deliver a form (usually
68
GaCl3) useful for
radiopharmaceutical syntheses. A variety of solid phases have been utilized for
purication[79]: the two-column process[80, 91] used at the University of Michigan for
liquid target processing is representative of the methods employed by many institutions.
The irradiated target solution is transferred via lines from the cyclotron vault to a hot
68
Ga from
68
Ga
Figure 3.4 The
68
GE
Ga PETtrace
liquid target used
for cyclotron production of
68
Ga.
62 Handbook of Radiopharmaceuticals
cell and diluted with a volume of water to reduce the nitric acid concentration to <0.1 M,
and the
(0.1 N) nitric acid: this separates the
The column is then eluted with 1.5 N HCl, and the eluted
68
Ga is initially trapped on a hydroximate resin. The resin is washed with dilute
68
Ga from the 68Zn, which is not retained on the resin.
68
GaCl3 is trapped on a second
column containing a triphenylphosphine oxide (TOPO) based resin. That resin can be
washed with a NaCl/dilute HCl and nally eluted with water to provide a dilute acidic
solution of the desired
68
GaCl3. Although 68GaCl3 is not the nal radiopharmaceutical of
clinical value, quality control analyses are often performed on this intermediate to assure
it is appropriate for use in radiopharmaceutical preparations. The important measures
are radiochemical (percentage of
impurities;
Fe and Zn (<10 μg G Bq
68
Ge breakthrough for generator eluate), and concentrations of the metal ions
−1
for each).
68
Ga as 68GaCl3) and radionuclidic purities (66Ga and 67Ga
3.3.7 Future ofGallium-68
The University of Michigan and Mayo Clinic have performed full validation of their
cyclotron-produced [
studies with [
68
liquid targetry and/or automated chemical processing systems for the production of
68
Ga-radiopharmaceuticals will undoubtedly contribute to the continued development of
new radiopharmaceuticals for PET imaging applications.
68
Ga]GaCl3 and [68Ga]Ga-PSMA-11, and FDA-approved clinical
Ga]Ga-PSMA-11 began in early 2019. The commercial availability of
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64 Handbook of Radiopharmaceuticals