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Chapter 08: Fluorine-18 Radiochemistry 289
Chapter 9
Labeling
withGallium-68
Benjamin P. Burke and Stephen J. Archibald
Positron Emission Tomography Research Centre, Department of
Biomedical Sciences, Faculty of Health Sciences, University of
Hull, Hull, HU6 7RX, UK
9.1 INTRODUCTION
Gallium-68 has seen the largest growth in nuclear medicine usage of any isotope over the
past 10 years. This is due to a combination of factors: the rise of PET/CT, the availability
of the isotope (driven by the
peptidic targeted agents, facile labeling processes, and the recognition of the potential
in the theranostics market. Obtaining accurate
scan numbers is challenging, but based on generator sales, it can be estimated that over
200 000 scans are carried out annually worldwide (using the conservative gure of 100
scans per generator sold). Licensed
statin receptors (SSTRs) are now considered the clinical standard for imaging neuroendocrine tumors (NETs), and the prostate-specic membrane antigen (PSMA) ligands in
development may shortly follow suit for prostate tumors. The likely future success of
68
Ga is built on the theranostic combination with
transition into routine clinical practice over the coming years. The Society for Nuclear
Medicine and Molecular Imaging (SNMMI) annual meeting has selected images with
gallium-68 radiotracers as the “Image of the Year” for four out of the ve years from 2015
to 2019, giving an accurate indication of the impact and level of interest in this isotope.
The short half-life (t
positron emission (88%) of
energy is higher (max 1.9 MeV, mean 0.89 MeV) than for uorine-18 (max 0.63 MeV, mean
0.25 MeV), the dierence in image quality is marginal when using modern clinical PET
68
Ge/68Ga generator), the development of clinically desirable
68
Ga positron emission tomography (PET)
68
Ga-radiopharmaceuticals for targeting the somato-
177
Lu, with more agents expected to
=68 minutes) and high percentage of radioactive decay by
1/2
68
Ga are well suited to PET imaging, and whilst the positron
Handbook of Radiopharmaceuticals: Methodology and Applications, Second Edition.
Edited by Michael R. Kilbourn and Peter J.H. Scott.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
scanners[1–3]. The long-lived parent isotope, 68Ge (t
=271 days), is generally produced
1/2
on an accelerator with a natural gallium or gallium-containing target, prior to separation
and incorporation onto a stationary phase for production of the
The use of
68
Ge/68Ga generators (which can produce radioisotope for up to 12 months)
68
Ge/68Ga generator.
allows for worldwide distribution and widespread use without the need for a cyclotron.
When compared with routine clinically used cyclotron produced isotopes (
use of a
68
Ga generator oers some advantages. PET centers that do not have a cyclotron
11C/18
F), the
and rely on delivery of uorine-18 tracers can introduce gallium-68 tracer production
by a relatively simple modication of an existing technetium radiopharmacy suite[4]. If
required to meet capacity demands, larger amounts of gallium-68 can be produced in a
standard biomedical cyclotron using a solid target. Recently, production methods have
been extended to solution targets, to allow cyclotron production of the isotope at sites
that are not equipped to handle solid targetry. Overall, there are a number of models for
the production of gallium-68 radiopharmaceuticals, adding to its potential utility.
The rst major successes in this eld were the
signicantly increased diagnostic capability compared to the established
68
Ga-octreotide derivatives, which oer
111
In derivatives
used in clinical single-photon emission computed tomography (SPECT) imaging. This
stimulated an increase in research activity due to the general applicability of peptide conjugates to many biological targets and diseases. Coupling this with the development of
protocols improving the chemistry for radiolabeling to simplify tracer synthesis further
adds to the future potential in this area. Cheaper and simpler protocols to access the
tracers will drive down the at-patient costs and increase widespread availability, ensuring
a bright future for gallium-68 PET imaging.
There are two options used for 68Ga production: by decay of 68Ge (t
erator, or from
focus on the development of easy-to-use cGMP
majority of clinical
68
duced
Ga is a more recent development, driven by increasing demand for the isotope
placing a strain on generator production capacity and the limit on the total amount of
68
Ga produced from each generator (some high-demand sites now have racks of genera-
tors in use at any one time).
The simplest way to produce
not require a change in infrastructure and is compatible with most cyclotron sites[5–8].
An amount of
in around an hour (bombardment and separation). Standard synthesis units can be used
for both processing of the feed from the cyclotron and synthesis of the radiotracer. There
is potential corrosion from the use of concentrated acid, and care needs to be taken
because the hot cell environment can contain radioactive gaseous waste, as
pounds are a byproduct.
292 Handbook of Radiopharmaceuticals
68
Zn using a cyclotron. Over the past 20 years, there has been signicant
68
Ga imaging uses isotope produced by this method. Cyclotron-pro-
68
Ga equivalent to the yield from one or two generators can be produced
=271 days) in a gen-
1/2
68
Ge/68Ga generators (vide infra); the
68
Ga on a cyclotron is by using a liquid target, as this does
13
N com-
68
Ga can also be produced on a cyclotron using a solid target [9–11], with up to a
10-fold increase in the amount of
68
Ga produced in comparison with a generator. Irra-
diation times and separation chemistry are similar to using a liquid target, but with the
increased practical complexities of handling the solid target. However, if a high-demand
center is equipped to handle these challenges, the reward in terms of cost per dose will
make this method viable. As with any cyclotron production, especially with metals, production of unwanted radiometal byproducts must be considered; with
of the main contaminants,
of enriched
68
Zn target material[5, 9]. In addition, there are complexity considerations
66
Ga and 67Ga, is inversely proportional to the isotopic purity
68
Ga, the amount
related to post-production isotope purication, which are not present with generator-
produced
68
Ga.
68
Ge/68Ga generators provide isotope without the need for a cyclotron and can be
incorporated into existing radiopharmacies with only minor facility modication. All
modern generators can provide ionic
year. Whilst there may be some specic centers in which cyclotron-produced
68
Ga in hydrochloric acid every few hours for up to a
68
Ga oers
the best solution for routine clinical imaging (dependent on facility capability and clinical
demand), the majority of centers will likely continue to use generator-produced isotope
in the short term.
For radiolabeling, the characteristics of an ideal
68
Ga generator are:
• Low elution volume (high activity per volume)
• Low [H]
+
concentration (compatibility with direct kit synthesis or pre-purication)
• Low level of germanium-68 breakthrough
• Consistency of elution characteristics over the generator lifetime
• Low amount of metal ion contamination
• High isotope yield
• Simplicity of use
• Compatibility with licensed radiopharmaceuticals
Currently, ve main
Table9.1). The most widely used generator–GalliaPharm, produced by Eckert &
Ziegler (EZAG)–received marketing authorization in 2014. This was followed by the
Galli Ad–produced by IRE ELiT–which received marketing authorization in 2018. The
maximum generator size available is currently 50 mCi (1.85 GBq), although larger genera-
tors are currently in development. The level of breakthrough of
major limiting factors in gaining marketing authorization, so generators using TiO
columns are the only ones currently licensed. Ideally,
with the capability to use the generator eluate directly (for the lifetime of the gener-
ator) with a single-vial lyophilized kit to rapidly produce a radiotracer with high molar
activity (i.e. both pre-purication and radiosynthesis using a synthesis module would
become obsolete). To achieve this, the generator used must elute
weak acid solution to be easily buered; this eluate must maintain acceptable amounts
68
Ge/68Ga generator products are being used globally (see
68
Ge has been one of the
68
Ga will ultimately emulate
68
Ga in a low volume of
-based
2
99m
Tc,
Chapter 9: Labeling withGallium-68 293
294 Handbook of Radiopharmaceuticals