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sometimes carried out two to three hours before the rst production elution to increase
the reactivity of the subsequently eluted
68
Ga and increase molar activity of the product.
Pre-purication of the 68Ga eluate before radiosynthesis reduces volume, removes metal
ion impurities, removes
cause a problem in radiolabeling). However,
ators with marketing authorization are low enough for direct administration; synthesis
units and kits have been developed to cope with the volume; and pre-purication is not
required for the routine radiosynthesis of somatostatin and PSMA targeted imaging
agents with adequate diagnostic performance (vide infra).
This leaves a question open regarding the future role of generator eluate processing.
There are potential situations where pre-purication becomes more important, or even
essential, for radiosynthesis:
• Removal of metal ions: lowering of acid concentration and/or volume is required to
produce a tracer with clinically useful diagnostic potential. Purication of generator
eluate increases the reactivity of
amount of precursor required for quantitative radiolabeling[16, 18]. Not carrying
out pre-purication therefore limits the maximum molar activity of the produced
tracers and restricts applications to those with high tissue receptor density[27,
99–102]. As recently discussed by Blower etal., molar activities of
pharmaceuticals can be 50-fold higher than
addressed as a potential limitation to the expanding tracer portfolio and applicability to a wide range of clinical situations.
• Reproducibility and robustness. Radiolabeling using pre-purication (and using syn-
thesis units) oers consistency, which is practically impossible without including
this step. There is variability between generators in terms of acid concentration
of eluate,
68
is also variability with the same generator over its lifetime (up to 12 months) and/
or the amount of time that has passed since the previous elution. Pre-purication
can take
68
tently. Manufacturers of kit radiopharmaceuticals also have the challenge of developing kits that are compatible with the full range of clinically used generators (or
cyclotron produced isotope), with variable volumes, acid concentrations, and contaminants. As options continue to diversify, there will be little point in developing
a kit system that only works in an idealized situation or for a single generator.
• Combining eluates from multiple generators. Using pre-purication allows for mul-
tiple generators to feed a single production (by reducing volume and issues with
contaminants). This is a situation that is becoming more important in routine
clinical production as an increase in demand has resulted in the need to have multiple generators in use.
68
Ge contamination, and decreases acid concentration (which can
68
Ge breakthrough levels of current gener-
68
Ga with a chelator or bioconjugate, lowering the
111
In-based radio-
68
Ga derivatives[28]. This needs to be
Ge breakthrough levels, volume, and metal ion contamination. There
Ga of variable quality and ensure that it is in a form that behaves consis-
Chapter 9: Labeling withGallium-68 305
9.5.2 Synthesis Units vs. Kits
(a) (b) (c)
(d) (e) (f)
As 68Ga-radiopharmaceuticals have become more popular, there have been signicant
changes in how they are produced clinically, moving on from manual radiosynthesis to exible and programmable synthesis units for developmental and early clinical trials work[88].
As the synthesis of an increased range of standard radiopharmaceuticals was established
for widespread use, there was a move to dedicated, user-friendly, cGMP- compliant syn-
thesis units with single-use disposable cassettes for specic tracers. [1,103]. A range of
synthesis units are now marketed with disposable cassettes for individual tracers designed
68
for
Ga (including those produced by iPHASE, ITM, Elysia-Raytest, Eckert and Ziegler,
Scintomics, and Trasis), with varying features and exibility (see Figure9.3). More recently,
there has been signicant investment in the development of kit-based
ceuticals in an attempt to emulate the simplicity and widespread success of
agents, including examples that have received marketing authorization[78, 104–106].
The choice between using a synthesis unit, kits, or a combination of both depends
on the specic goals of each center and the balance of routine clinical production vs.
research. Overall, kits and synthesis units each have individual advantages and disadvan-
tages, which are summarized in Table9.2.
Production of kit-based
authorization is by far the easiest route to access these radiotracers. A traditional radiopharmacy can be retrotted to produce
Figure 9.3
Common disposable cassette–
based synthesis
units used for
68
Ga
radiolabeling. (a)
Multisyn (iPHASE);
Source: iPHASE
Technologies. (b)
iQS-Theranostics
(ITM); Source:
ITM Medical Isotopes GmbH (c)
GRP2 (Scintomics);
Source: Scintomics
(d) Modular-Lab
eazy (Eckert &
Ziegler); Source:
Eckert & Ziegler
(e) Gaia (ElysiaRaytest); Source:
Elysia-Raytest (f)
EASY ONE (Trasis).
Source: Trasis.
68
Ga-radiopharmaceuticals that have received marketing
68
Ga-radiopharma-
99m
Tc imaging
68
Ga products. The quality-control requirements
306 Handbook of Radiopharmaceuticals
Kits Synthesis units
C18
Order of addition is variable
Advantages Disadvantages Advantages Disadvantages
• Simple
• Less risk of contamina-
tion
• Cheaper infrastructure
• User dependent
• Lower QC burden
a
• Radiopharmacy compat-
• Low flexibility
Radiation protection issues
• Running costs
a
• Limited molar
activity
• No pre-purication
• Robust Flexi-
bility
• Pre-purica-
tion possible
• Larger footprint
Initial cost
• Longer time taken
• Higher QC burden
ible
• Lower failure rate
a
Based on current kits with marketing authorization vs. unlicensed synthesis unit produced products.
for these products are also relatively simple and quick, with no major additional infrastructure required. This route, however, is very limiting and relies on future products
all being kit-produced and gaining marketing approval before being introduced. The
current products with marketing authorization are heated and two-step (addition of
buer to reaction vial); see Figure9.4. There is signicant interest in the development of
single-vial room-temperature kit products, given their simplicity (vide infra). Production
of unlicensed products (either kits moving toward authorization or products made on a
synthesis unit) increases the quality-control requirements, both pre- and post-release. A
center could transition from producing approved kit-based products to supporting the
Table 9.2
ary of the
m
advantages and
disadvantages of
kit and synthesis
unit-based produc-
68
tion of
a
pharmaceuticals.
Ga-radio-
Sum-
Synthesis Unit
room temperature
Notes
Inclusion is situation dependent
Kit
two-step
Kit
single-vial
cartridge
Elution QC
ElutionBuffer Kit vial
Elution
Pre-
purification
Reaction
vial
Kit vial
Heating
Heating Cooling
Sterile
Filtration
QC
QC
Chapter 9: Labeling withGallium-68 307
Figure 9.4 Steps
for the produc-
68
tion of
Ga-radio-
pharmaceuticals
(synthesis unit
and kits).
development of unlicensed kits by ensuring that they have the required quality control
(a) (b)
(QC) equipment and adequate stang levels to support this.
If there is a need to produce either rst-in-human tracers or agents that have not
yet been produced in kit form to support phase II/III clinical studies, the use of a syn-
thesis unit is essential. Using a disposable cassette–based synthesis unit to produce
68
Ga-radiopharmaceuticals oers the best compromise between cGMP compliance and
exibility in the production of current and future tracers. In broad terms,
68
Ga synthesis
procedures between dierent tracers are very similar, with only a limited number of variables to change: ligand amount, buer type/amount, optional pre-purication, reaction
temperature/time, and optional post-synthesis purication (see Figure9.4). Hence, minor
modication of automated step parameters is relatively simple, and facile modication of
cassettes produced for other established tracers can be exploited. Using this approach, it
is relatively easy to take a synthesis unit that is producing one tracer and modify it to pro-
duce a novel tracer for a rst-in-human study, whilst remaining cGMP compliant.
One of the potential weaknesses of kit radiosynthesis compared to the use of synthesis units is the manual involvement of a human operator during synthesis: this has
the potential to cause inconsistencies between users and can lead to radiation protection concerns for personnel in high-volume centers. Radiation protection may be a key
consideration for routine
68
Ga-radiopharmaceutical production going forward and may
have a signicant inuence on decisions for production methodologies selected. Facilities often underestimate the signicance of high-energy positrons from
on previous experiences with
99m
Tc or 18F). For example, a 37 mCi (1 GBq) source of 68Ga
68
Ga (based
unshielded at 30 cm in a glass with 2 mm thickness (for example, in a kit) has a dose rate of
50 m Sv h
−1
–nearly 30-fold higher than 18F and 250-fold higher than
99m
Tc.
Recently, there has been some interest in automating kit radiosynthesis: for example,
using the KitLab (Eckert and Ziegler, Germany) or MorGaNA (Tema Sinergie, Italy); see
Figure9.5. Such systems can integrate generator elution and be used to carry out kit
radiosynthesis without manual manipulation; whilst both systems have their individual
limitations, they may be appealing for high-throughput services. This blurring of the lines
between kit radiosynthesis and automated synthesis units may lead to systems that allow
Figure 9.5
Integrated synthesis units. (a)
KitLab (Eckert &
Ziegler); Source:
Eckert & Ziegler (b)
MorGaNA (Tema
Sinergie). Source:
Tema Sinergie
Handbook of Radiopharmaceuticals
for the re-inclusion of simple, disposable, pre-purication cartridges (if the quality of
the clinical data can be improved by doing so). Alternatively, developers of a future
68
Ga-
radiopharmaceutical may choose to market the product as a bespoke, integrated, simple
automated kit/synthesis unit, which could include a pre-purication step and even quality
control, giving hospitals a complete package for individual radiotracer production and
analysis[16, 107–109].
The development of 68Ga-radiopharmaceuticals is arguably the fastest-moving area in
nuclear medicine, emerging from research studies 10 years ago to become the gold standard for some clinical situations. A detailed review of how
have been developed and their use in clinical practice (both current and potential future
opportunities) is beyond the scope of this chapter. Herein, an overview of the key clinical
68
Ga-radiopharmaceuticals and their principal applications is given, followed by details of
their respective radiosyntheses.
The recent increasing interest in
emitter
177
Lu (t
=6.7 days) for radioligand therapy (R LT ); which requires a targeting
1/2
68
Ga is inextricably linked to the use of the beta
peptide that is coupled to a radioisotope emitting beta or alpha radiation that binds to
specic receptors expressed on the surface of tumor cells. Matched-pair theranostics (in
68
which
dosimetry, and treatment monitoring, and
signicant clinical interest in the past few years.
central to the majority of
Ga PET is used for localization, characterization, staging, target identication,
177
Lu RLT is used for therapy) have prompted
68
Ga/
68
Ga-radiopharmaceuticals under development. The market
interest in this area was demonstrated recently by Novartis’ acquisition in 2018 of both
Advanced Accelerator Applications (AAA) for $3.9 billion (SomaKit TOC, NETSPOT, LUTATHERA) and Endocyte for $2.1 billion ([
177
Lu]LuPSMA-617).
68
Ga-radiopharmaceuticals
177
Lu theranostic combinations are
9.6.1 Somatostatin Receptor (SSTRs) Targeting
Well-dierentiated NETs often overexpress SSTRs on their cell surface[110, 111]. Targeting SSTRs for imaging has a long history, with
examples of receptor-targeted peptide molecular imaging[112]. Octreoscan ([
D-Phe1-octreotide, Curium Pharma) has been used clinically since the mid-1990s and was
the rst registered and commercially available radiometal-based peptide for imaging[1].
Imaging SSTRs can be used for disease staging and to inuence treatment decisions,
especially in selecting patients for SSTR peptide therapy[113, 114], or more recently
for RLT. In 2001, [
68
Ga]Ga-DOTA-TOC was shown to have superior diagnostic capability
compared to Octreoscan[49]; this led to a surge of research, which has resulted in the
transition from
111
In SPECT to 68Ga PET as the gold standard for imaging of NETs. This is
111
In-SPECT SSTR imaging one of the rst
111
In]-DTPA-
Chapter 9: Labeling withGallium-68 309
largely because of increased sensitivity, improved target-to-background contrast, and
H2N
H2N
H2N
O
DOTA-TOC DOTA-TAT EDOTA-NOC
lower radiation dose[115, 116]. In addition, practical considerations also favor
111
with
In SPECT often requiring two scans on dierent days. Other peptides with slight
68
Ga PET,
modications to the peptide sequence have subsequently been developed, notably
DOTA-TATE and DOTA-NOC (see Figure9.6)[117–119]. Peptide sequence modication
causes a slight variation in the anities for the various receptor subtypes; all three bind
to SSTR2, whereas [
68
[
Ga]Ga-DOTA-TOC also binds SSTR5 (with a lower anity than [68Ga]Ga-DOTA-NOC),
whereas [
68
Ga]Ga-DOTA-TATE has a higher selectivity for SSTR2[110, 120]. However, in
68
Ga]Ga-DOTA-NOC also has a good anity for SSTR3 and SSTR5; and
practice, there is limited clinical evidence of dierences in their diagnostic capability as
SSTR2 expression is generally the most abundant on NETs relative to the other SSTRs.
Individual anity and specicity data for these and other SSTR-targeting radiopharmaceuticals have been summarized by Pauwels etal.[121].
In practice, all three tracers (TOC/TATE/NOC) are used routinely, and selection
is more often governed by other factors, including local marketing authorization,
commercial availability, tradition, individual clinician preference, and RLT considerations. This is borne out by the fact that in 2016, the Food and Drug Administration
(FDA) approved NETSPOT ([
approved SomaKit TOC ([
68
Ga]Ga-DOTA-TATE) and the European Commission
68
Ga]Ga-DOTA-TOC); both were commercialized by AAA
(Saint-Genis-Pouilly, France), with the European market favoring the more established
imaging product, whereas the US market approved the product with the same peptide
as the subsequently approved [
177
([
Lu]Lu-DOTA-TATE) received European approval in 2017 and FDA approval in 2018
177
Lu]Lu-DOTA-TATE therapy[122–124]. LUTATHERA
after the NETTER-1 trial demonstrated a signicant eect, with progression-free
survival at 65.2% at 20 months, compared to 10.8% for patients treated with high-dose
peptide (see Figure9.7)[125, 126].
O
NH
O
N
H
NH
O
OH
O
N
H
HN
OH
HN
O
HN
H
OH
N
OH
O
S
S
O
O
N
H
N
HO
N
O
HO
O
N
OH
N
O
O
NH
O
N
H
NH
O
OH
O
N
H
HN
OH
HN
O
HN
H
OH
N
OH
O
O
S
S
O
O
N
H
N
HO
N
O
HO
O
N
OH
N
O
O
N
H
NH
O
N
H
NH
O
HN
O
Figure 9.6 Chemical structures of common SSTR targeting ligands with structural differences
highlighted.
310 Handbook of Radiopharmaceuticals
O
OH
HN
O
HN
H
OH
N
OH
O
S
S
O
O
N
H
HO
N
N
N
OH
N
HO
O
(a) Progression-free Survival
100
90
80
70
60
50
40
(% of patients)
30
20
Progression-free Survival
10
No. at Risk
177
Lu-DOTATATE
group
Control group
0
510152025
0
Months since Randomization
116977659422819123 20
11380472817104 3100
177
Lu-DOTATATE
P<0.001
Control
(b) Overall Survival (Interim Analysis)
100
90
80
70
60
50
40
(% of patients)
30
Overall Survival
20
10
30
No. at Risk
177
Lu-DOTATATE
group
Control group
0
510152025
0
Months since Randomization
116108 96 79 64 47 31 21 830
113103 83 64 41 32 17 5100
177
Lu-DOTATATE
P = 0.004
Control
30
Figure 9.7 Interim analysis of NETTER-1 trial. (a) Kaplan–Meier analysis of progression-free survival. Source:
Strosberg, J., El-Haddad, G., Wolin, E. et al. [125]. © 2017 Massachusetts Medical Society. (b) Overall survival.
Source: Strosberg, J., El-Haddad, G., Wolin, E. et al. [125]. © 2017 Massachusetts Medical Society.
[68Ga]Ga-DOTA-TOC and [68Ga]Ga-DOTA-TATE were commonly produced on synthesis
units for a number of years and had become established tracers. Focus then switched to
making production easier by moving away from synthesis units with the development
of kit-based products–resulting in SomaKit TOC and NETSPOT reaching the market.
Production in kit form allows for more widespread use, even in centers that had no
experience of producing PET radiopharmaceuticals, as they could access the generator-
produced isotope. Both products use DOTA as the chelator and therefore require heating
(7 minutes at 95 °C) to quantitatively radiolabel at a peptide amount (40 μg) that is accept-
able for administration.
When using kit
68
Ga radiopharmaceuticals, practical aspects for interfacing with
the generator must be considered. For example, the radiolabeling of SomaKit TOC
68
([
Ga]Ga-DOTA-TOC) has been shown to be compatible with both the GalliaPharm (Eckert
& Ziegler Radiopharma GmbH) and Galli Ad (IRE ELiT) generators. However, the dierences in the generator elution mechanism mean a dierent setup is needed for radiolabeling. When using the Galli Ad generator, less buer is used (because of the lower
elution volume), water needs to be added (to keep the total reaction volume the same as
with the GalliaPharm), and the reaction vial needs to be linked (in serial) to a secondary
vacuum vial or pump (or transferred post-elution). In this case, use of the GalliaPharm
generator is more straightforward, adding only buer and eluting in to the reaction vial;
however, it should be noted that this is a result of the design of SomaKit TOC for use with
the GalliaPharm generator (before the Galli Ad received marketing authorization). Future
kits will need to be compatible with all approved generators, or minor product variations
marketed to map on to each generator.
Chapter 9: Labeling withGallium-68 311
68
Ga labeling of octreotide derivatives for PET imaging of SSTRs in NETs is the most
established area in clinical
68
Ga radiopharmaceuticals, but it is still a highly active area of
research[121]. There is signicant interest in developing modied peptides that have a
broader receptor anity prole, to both increase tumor uptake and expand the range
of tumors amenable to SSTR imaging. In addition, selective SSTR antagonists are being
developed that do not internalize after receptor binding, with the theory that they would
occupy more receptor sites than the agonists. This can result in higher overall tumor
uptake. Given the success of SomaKit TOC and NETSPOT, and the desire for agents to be
compatible with
177
Lu radiolabeling, any next-generation agents are likely to be DOTA-
based and developed for production with a heated kit.
Prostate cancer is one of the most common cancers in men worldwide, with a reported
1.3 million new cases and 300 000 deaths in 2018 alone[127, 128]. Staging of disease
has previously relied on morphologic visualization of tumor lesions using computed
tomography (CT), magnetic resonance imaging (MRI), or bone scintigraphy. [
2-uoro-D-glucose ([
derivatives ([
11
18
F]FDG) has low uptake in most prostate cancer tumors; and choline
C]choline, [18F]uoromethylcholine, and [18F]uoroethylcholine), although
widely used, have limited accuracy in initial staging. Specic tumor localization in early
biochemical recurrence is also very challenging using established methods[129, 130],
especially in patients with “low” prostate-specic antigen (PSA) levels[131]; and whilst
18
[
F]uciclovine (Axumin) has received approval, issues with specicity can result in false
disease upstaging[132–134].
PSMA is a type II integral membrane glycoprotein that is signicantly overexpressed
in the majority of prostate cancers but has low expression in both benign tumors and
non-target tissues, making it an ideal target for molecular imaging[128, 132]. PSMA-
targeted radiopharmaceuticals can be used for initial staging, can identify patients
for RLT, and give a more accurate indication of biochemical recurrence. Overall, this
approach is key to the future of patient management in prostate cancer. PSMA-tar-
geted radiopharmaceuticals are now preferred to [
18
F]uciclovine or choline deriva-
tives for imaging patients with biochemical recurrence by the European Association of
Urology[135].
A range of PSMA-targeted radiopharmaceuticals are being used in clinical practice
(see Figure9.8); and whilst at the time of writing, there are no PSMA-targeted radiopharmaceuticals with marketing authorization, the trial results published so far are exciting
high levels of interest. There is no stand-out leader from the various agents available
with regard to diagnostic and clinical utility, with the European Association of Nuclear
Medicine (EANM) and SNMMI treating the three most common
68
([
Ga]Ga-PSMA-11, [68Ga]Ga-PSMA-617, and [68Ga]Ga-PSMA-I&T) as interchangeable[136].
68
Ga-PSMA agents
Ultimately, the widespread use of one or more PSMA-targeted radiopharmaceuticals
18
F]2-Deoxy-
312 Handbook of Radiopharmaceuticals
Figure 9.8 Chemical structures of common PSMA derivatives used for 68Ga imaging.
or products is likely to be governed by factors other than diagnostic accuracy, including
regulatory status, availability, price, simplicity of production, how well established the
tracer is in clinical use, and availability of a therapeutic congener.
68
[
Ga]Ga-PSMA-HBED-CC ([68Ga]Ga-PSMA-11) is by far the most widely applied tracer
in clinical practice, especially in Europe, with over 90% of
68
Ga-PSMA clinical trials using
this tracer; it was rst developed in 2012 by the Heidelberg group and rapidly translated
to clinical studies[137, 138]. The peptide structure is also not covered by any patents,
reducing barriers to widespread use. [
68
Ga]Ga-PSMA-11 incorporates HBED as a chelator,
and most clinical studies are performed with tracer produced at elevated temperatures
using a synthesis module. However, buoyed by the success of SSTR-targeted kit prod-
ucts, there has been signicant interest in developing a PSMA kit. Advanced Nuclear
Chapter 9: Labeling withGallium-68 313
Medicine Ingredients (ANMI, now a Telix company) developed a kit for room tempera-
68
ture [
Ga]Ga-PSMA-11 production (Illumet in the USA), in which the peptide and buer
are stored individually and mixed before adding to the gallium-68 and incubating at
room temperature[139]. As mentioned previously,
68
[
Ga]Ga-PSMA-11) forms multiple species (stereoisomers), which may have dierent
68
Ga radiolabeling of HBED (as in
complex stability, receptor anity, and/or biodistribution[15, 140]. Radiolabeling at
room temperature results in a more complex situation with the formation of the most
thermodynamically stable isomer taking multiple hours or days[56]. Whilst this situation
is chemically inelegant, concerns about individual aspects (stability, anity, and/or bio-
distribution) can be rapidly alleviated if the diagnostic results are demonstrated to be
adequate, especially if they are comparable with the well-established [
68
Ga]Ga-PSMA-11
that is produced at elevated temperature. The presence of reversible stereoisomerisation is acknowledged in the draft European Monograph “Gallium (
tion.” Whilst a heated
68
Ga kit is practically much easier to use than a synthesis unit,
68
Ga) PSMA-11 Injec-
room temperature kits are even more straightforward, with a decrease in synthesis time
(especially for cooling) and elimination of additional practical cGMP considerations due
to heating.
From the perspective of simplicity, there are clear advantages to having a single-vial,
room temperature kit radiopharmaceutical. In addition to the reduction in production
time and complexity, there is a lower risk of contamination, and fewer consumable
items are required per production. Direct elution of licensed generators into a lyophilized reaction vial containing the required peptide, buers, and stabilizers followed by
rapid room temperature quantitative radiolabeling ready for administration is an opti-
mally simplistic procedure. Isotopia (Israel) is developing a room temperature single-
vial kit for [
68
Ga]Ga-PSMA-11 production (IsoPROtrace-11), which uses less peptide (10
vs. 40 μg) than Illumet, therefore increasing molar activity. Theragnostics (UK) is also
translating a room temperature single-vial kit (THP-PSMA) for
68
Ga PSMA imaging into
clinical use and announced a global commercial partnership with GE Healthcare in late
2019. In this case, THP is used as the chelator[141–144], circumventing the issue of the
formation of multiple species, and potentially avoiding the non-specic uptake seen
68
with [
Ga]Ga-PSMA-11[145, 146]. However, given the disparity in the volume of clinical
data compared to [
68
Ga]Ga-PSMA-11, more work is required to conrm comparable
diagnostic potential with similar exibility for routine clinical use and variation in
dose amounts.
DOTA-PSMA derivatives PSMA-617 and PSMA-I&T have also been developed for
radiolabeling with
68
using
Ga is routinely carried out using a synthesis unit; the inclusion of DOTA means any
68
Ga for imaging and
177
Lu for therapy[53, 147–151]. Radiosynthesis
transition to kit form will likely require heated kits, similar to the licensed SSTR-targeted
products. Both PSMA-617 and PSMA-I&T have shown signicant promise in clinical
therapeutic studies when radiolabeled with
ness of [
177
Lu]Lu-PSMA-617 therapy is being evaluated in the VISION Study: an 80-insti-
177
Lu (see Figure9.9)[153, 154]. The eective-
tution, 750-participant, global phase 3 clinical trial in men with progressive metastatic
castration-resistant prostate cancer.
314 Handbook of Radiopharmaceuticals