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K41400
2
~
Natural abundance/%
60
m/z
Mg Zr MgCl
2
(11. 3)
Links between zirconium and the nuclear industry go deeper than just radionuclides. Zirconium has a very low absorption cross-section for thermal neutrons,
which in combination with the high hardness, high resistance to corrosion, and high
ductility, makes Zr a versatile metal. When zirconium is alloyed with other metals,
including tin, niobium, chromium, and nickel (amongst others), the so-called zircalloys (containing ~95% Zr by weight) are common materials used as cladding for
nuclear fuel rods.
Zirconium has three stable nuclides (Figure11.2; 90Zr [natural abundance (NA)=51.45%],
91
Zr [NA=11.22%], and 92Zr [NA=17.15%]) and two nuclides that are observationally stable (
[NA=2.80%]). Interestingly,
(ββ) decay yielding daughter nuclides
isotopic pattern is very useful in characterising zirconium ion coordination complexes by
high-resolution mass spectrometry[6].
In total, there are 34 known isotopes of zirconium with mass numbers ranging from 78
to 112. At least six additional metastable states have also been reported (all nuclear data
in this chapter are from the National Nuclear Decay Center [NNDC]; Brookhaven National
Laboratory, Upton, NY; www.nndc.bnl.gov, accessed 17 January 2019). A subsection of the
chart of nuclides showing some of the isotopes of zirconium encountered in the context
of radiochemistry and nuclear medicine research is presented in Figure11.3. In addition,
a list of zirconium nuclides and their respective radioactive properties (isotopic mass,
94
Zr, t
=5.2 × 1019 years [NA=17.38%]; and 96Zr, t
1/2
94
Zr and 96Zr have been predicted to undergo rare double-β
94
Mo and 96Mo, respectively[4, 5]. The distinctive
=2.35 × 1019 years
1/2
Figure 11.2 Natural
isotopic abundance
pattern of stable
zirconium isotopes
as observed by
mass spectrometry.
50
40
30
20
10
Zirconium
0
89
90 91 92 93 94
95
96 97
Chapter 11: The Radiochemistry ofZirconium 345
Atomic number (Z)
...
Neutron number
Figure 11.3
Portion of the chart
of nuclides showing
relevant isotopes
of zirconium and
their respective
decay modes.
...
16.5 h
86
Y
14.74 h
79.8 h106.6 d39
87 88 89
86
Zr
Zr Zr Zr
1.68 h 83.4 d 78.41 h
87 88 89
YY
(p,pn)
......
Y
IT β+ βββ–
(p,n)
(p,2n)
90
Zr
40
91
Zr
40
92
93
Zr
Zr
1.5×10
6
40
Metastable
nuclides
(O.S.) = Observationally
Stable
y
94
Zr
(O.S.)
89m
Y
15.6 s
95
Zr
64.0 d
89m
Zr
4.16 m
96
Zr
(O.S.)
97
Zr
16.7 h
stable
half-life, decay mode, and primary daughters) is given in Table11.1. In the broader context
of radiochemistry, naturally occurring isotopes of zirconium, in particular
90
Zr, are target
materials for cyclotron-induced (p,x)-type transmutation reactions to form various radionuclides of niobium. Of the radionuclides of element 41 that can be produced from solid
metal zirconium targets, niobium-90 (t
=14.60 hours, I(β+)=53%, E
1/2
(β+)=0.35 MeV)
mean
has been proposed as a potential alternative to copper-64 and zirconium-89 for immunoPET. However, the concomitant release of high-energy and high-intensity γ-rays at 2186 keV
(18.0%) and 2319 keV (82.0%) will likely prevent the clinical translation of
90
Nb compounds
based on dosimetry concerns. The use of zirconium as a target is not considered further;
but for more detailed information, the reader is referred to the publications by Rösch and
co-workers[7–9]. The remainder of this chapter explores the production, chemistry, and
radiochemistry of zirconium-89 for PET, but it is also worth mentioning that zirconium-97
(t
=16.75 hours, I(β−)=100%, E
1/2
(β−)=704 keV, E
mean
(β−)=1915.7 keV) is a potent β− emit-
max
ter. At present, the are no known sources of zirconium-97, but if access to this radionuclide could be established, it would represent an ideal scenario in which the radioisotopes
89
Zr/97Zr would form a matched pair for the synthesis of chemically identical diagnostic and
radiotherapeutic agents.
346 Handbook of Radiopharmaceuticals
Zirconium-89 (t
is the most important radionuclide of element 40 and has been utilised in an increasing
number of preclinical and clinical studies. The fact that zirconium-89 has been translated to human trials is testament to the sterling work performed over the last three
to four decades by research groups in Europe and the United States, and throughout
the world[10]. Many excellent review articles on zirconium-89 have appeared, but rapid
advances in the eld mean that the reader is urged to exercise caution when referring to
the various reported methods therein[11–20].
=78.41 hours, I (β+)=22.74%, E
1/2
(β+)=395.5 keV, E
mean
(β+)=2399 keV)
max
Table 11.1 List oftheobserved nuclides ofzirconium.
Isotopic mass
Nuclide
78
Zr 77.95523 >17 0 ns EC
79
Zr 78.94916 56 ms (β+, p) or β+
80
Zr 79.9404 4 .6 s β+
81
Zr 80.93721 5 . 5 s β+
82
Zr 81.93109 32 s β+
83
Zr 82.92865 41. 6 s β+
84
Zr 83.92325 25.9 min β+
85
Zr 84.92147 7.86 min β+
86
Zr 85.91647 16 . 5 h β+
87
Zr 86.914816 1. 68 h β+
88
Zr 87.910227 8 3. 4 d EC
89
Zr 88.908890 78. 41 h EC, β+
89m
Zr
(metastate)
90
Zr 89.9047044 Stable 51.45% abundance
91
Zr 90.9056458 Stable 11.22% abundance
92
Zr 91.9050408 Stable 17.15% abundance
93
Zr 92.9064760 1.61 × 1 06 yr β−
94
Zr 93.9063152 O.S. ββ predicted 17.38% abundance
95
Zr 94.9080426 6 4 . 0 d β−
96
Zr 95.9082734 O.S.
97
Zr 96.9109531 16 .75 h β−
98
Zr 97.912735 3 0 . 7 s β−
99
Zr 98.916512 2 .1 s β−
100
Zr 99.91776 7.4 s β−
101
Zr 100.92114 2 . 3 s β−
102
Zr 101.92298 2 . 9 s β−
103
Zr 102.92660 1. 32 s β−, (β-n)
104
Zr 103.92878 0. 8 7 s β−, (β-n)
105
Zr 104.93305 16 7 ms β−, (β -n)
106
Zr 105.93591 180 m s β−
107
Zr 106.94075 14 6 m s β−
108
Zr 107.94396 7 7.4 m s β−
109
Zr 108.94924 56 ms β−
110
Zr 109.95287 37. 5 m s β−
111
Zr 2 4 ms β−
112
Zr 30 ms β−, (β-2n), (β-n)
(a.u.) Half-life Decay mode Daughter nuclides
78
Y
78
Sr or 79Y
80
Y
81
Y
82
Y
83
Y
84
Y
85
Y
86
Y
87
Y
88
Y
89
Y
587. 8 keV 4.16 min IT (93.8%), and β+
89
Zr and 89Y
(6.2%)
93
Nb
95
Nb
(2
. 3 5 × 10
19
ββ 2.80%
yr)
103
104
105
112
Nb,
abun
97
Nb
98
Nb
99
Nb
100
101
102
Nb,
Nb,
Nb,
106
107
108
109
110
111
111
Nb
Nb
Nb
102
103
104
Nb
Nb
Nb
Nb
Nb
Nb
Nb,
dance
Nb
Nb
Nb
110
Nb
O.S.=observationally stable.
Source: Data from the National Nuclear Decay Center (NNDC; Brookhaven National Laboratory,
Upton, NY; www.nndc.bnl.gov, accessed 17 January 2019). O.S. = observationally stable.
Chapter 11: The Radiochemistry ofZirconium 347
Notwithstanding the recent advances in zirconium-89 radiochemistry, the rst production and use of this radionuclide in both animal models and humans were reported
in the 1940s and 1950s[21–23]. Whilst working at the Massachusetts Institute of Technology cyclotron facility, Shure and Deutsch were among the rst to report the decay
properties of
89
Zr after production via the 89Y(d,2n) transmutation reaction[24]. Later
in 1957, Dr John Mealey reported the rst pharmacokinetic studies of zirconium-89
distribution in humans, which were performed at Massachusetts General Hospital and
Harvard Medical School (Boston, USA)[23]. Experiments used a citrate formulation
89
of
Zr ions produced after irradiation of 89Y solid targets and purication/isolation
by using classic ion-exchange methods (Dowex-1 resin, washing with HCl, and elution
with HNO
). Citrate was introduced to minimise colloid formation. Importantly, Mealey
3
reported that “In preliminary chemical toxicity studies in mice, 100–200 times the contemplated dose per kilogram in man was well-tolerated. No ill-eects were observed
in any of the animals.” After intravenous injection of “
89
Zr-citrate” formulations in
two patients undergoing neurosurgery, biopsy samples were taken at approximately
90 minutes and 3 hours post-administration. Concentrations of
89
Zr in bone, muscle,
normal brain tissue, and brain tumour tissue were measured at 0.9, 7.6, 0.8, and 4.6
%ID/kg, respectively. Temporal excretion studies found that most of the
89
Zr activity
was retained in the body with only 2.5 %ID/kg eliminated in the urine by 24 hours,
and a total of only 7.6 %ID/kg eliminated after seven days. Conclusions were that
“after intravenous injection of zirconium-89 in carrier-free dilute citrate solution, the
radiozirconium is only very slowly cleared from the plasma due to formation of metal
complexes with plasma proteins.” Although current knowledge of the pharmacokinetics of zirconium complexes in mammals is more detailed, these pioneering results
paved the way for future use of both
89
Zr and other metal-based positron-emitting
nuclides in humans.
From the 1970s onwards, many groups explored zirconium-89 radiochemistry[25–33],
but modern methods for the production of zirconium-89 in high quantities, purity, and
specic activity stem from the 1990s and the publications of Herscheid etal.[34–36].
Separation and radiolabelling chemistry was advanced further by Verel etal.[37, 38], and
standardised methods were reported in 2010[39].
Zirconium-89 for clinical use is now almost exclusively produced with small biomedical
cyclotrons (with c. 9–19 MeV incident proton beam energy) via the
89
Y(p,n)89Zr transmu-
tation reaction. Cyclotron solid target designs are not standardised. Most centres that
produce
89
Zr opt for custom-made solutions. Schematic diagrams and a photograph of a
custom-made solid target designed by Dr Bruce Wieland and co-workers (BTI Targetry, Cary,
North Carolina, USA) for irradiating metal foils using a GE PETtrace is shown in Figure11.4.
The irradiation target typically uses 100% naturally abundant
89
Y solid metal foils, although
solution targets[40, 41], thick targets[42], and powdered/pressed targets[43] have been
considered. When irradiating a solid
must be considered. Excitation functions for the
89
Y foil with protons, three principal reaction channels
89
Y(p,n)89Zr, 89Y(p,pn)88Y, and 89Y(p,2n)88Zr
transmutation reactions are shown in Figure11.5 and Eq.(11.4).
Handbook of Radiopharmaceuticals
Zr
39
89
39
6
Energy/MeV
25
Cross-section (mb)
1
4
5
2
8
7
4
3
Figure 11.4 Figure
showing design
schematics and a
photograph of a
water-cooled solid-
metal target
assembly for use
.25
2
on a GE PETtrace
cyclotron. Source:
Design and sche-
matics courtesy of
10
9
11
Dr. Matthew Stockley, BTI Targetry.
1000
89
Y(p,n)89Zr
89
Y(p,pn)88Zr
89
Y(p,2n)88Zr
800
600
400
200
0
05
(p,n)89Zr
40
1
+
Y +
p
1
(p,2n)
(p,pn)88Y
Calculated threshold energies for the transmutation of
10 15 20
88
40
11.4
89
Y to 89Zr, 88Y, and 88Zr
are 3.65, 11.60, and 13.08 MeV, respectively. In practice, proton beam energies in the
range of approximately 13–15 MeV are used to ensure a balance between ecient
production of clinically useful quantities and minimising the formation of long-lived
88
Y (t
=106.626 d h) and 88Zr (t
1/2
experimental data on the irradiation yields of
=83.4 days) radionuclide impurities. Representative
1/2
89
Zr with dierent irradiation energies and
time are presented in Table11.2 and Figure11.6.
Figure 11.5 Exper-
imentally measured excitation
functions showing
the cross-sections
for the formation
89
of
Zr (blue), 88Y
(green), and
88
Zr
(red) during irradiation of a thin
89
Y foil
with protons in the
energy range ~ 7
to ~22 MeV.
Chapter 11: The Radiochemistry ofZirconium
Activity (EOB)/MBq
300
µ
30
Table 11.2
Ex
perimental data on the
irradiation yields
89
of
Zr using an 89Y
foil target.
Irradiation
number
Approximate
current (mA)
Duration
(min)
Charge
(mA h)
End of bombardment
activity (MBq)
1 5 25 2.03 23.98
2 5.5 60 5.42 51.80
3 7 153 17.38 163 .17
4 8 172 22.40 225.70
5 9 175 25.50 253.08
6 9 120 17.67 178.34
7 9 176 25.81 268.62
8 10 153 25.04 261. 59
Figure 11.6 Plot
of the activity
yield (MBq) versus
the incident
charge (mA h)
giving an activity
at saturation of
1145 ± 14 MBq.
Activity = 10.12 ± 0.1236
250
200
150
100
50
0
x Charge
2
R
= 0.995
501015
Charge/
A(sat) = 1145 ± 14 MBq
20 25
A.h
Although not perfect, 89Zr possesses favourable nuclear decay characteristics for use
in the preparation of radiotracers that exhibit prolonged circulation and uptake times
in vivo. Experimental data showing the γ-ray emission spectrum of
Figure11.7, and nuclear decay schemes for radioactive decay of
excited state
plexity of the
89m
Zr are shown in Figure11.8a,b, respectively. In spite of the moderate com-
89
Zr decay scheme, only two γ-ray lines at 511 and 909.2 keV have signicant
emission intensities. Nevertheless, when compared with the emission spectra of other
common radionuclides like
11
C, 13N, 18F, and 64Cu for PET imaging, the additional radiation burden imposed by the ~99% intensity emission of photons at 909.2 keV has important implications regarding radiation protection for nuclear medicine clinicians, patient
dosimetry, and patient management. It also places stringent limitations on the maximum
administered doses of
89
Zr-based radiopharmaceuticals (which is typically in the range
37–185 MBq in human trials). In spite of the excellent clinical performance reported for
many dierent
89
Zr-radiolabelled antibodies, some members of the nuclear medicine
community remain concerned about dosimetry. Improved patient management strategies
89
Zr are presented in
89
Zr and the metastable
350 Handbook of Radiopharmaceuticals
Normalised intensity
909 keV
2000
Energy/keV
(a)
(b)
V
Z
511 keV
1713 keV
0 500 1000 1500
Figure 11.7
Experimental
γ-ray emission
spectrum of
89
Zr.
EnergyEnergy
9/2+
11/2+
7/2+
5/2–
9/2+
1/2–
3/2–
1/2–
γ 1713 keV
EC (6.23%)
γ 1507.4 keV
89
Y
γ 1657.3 keV
γ 1620.8 keV
γ 1744.5 keV
0.07%0.11%0.75%
89
Y
99.0%0.12%
89m
Zr
IT (93.77%)
89
Zr
EC
γ 909.2 keV
1/2–
9/2+
Q-value
2.833 MeV
89
Zr
I
= 22.74%
β+
Kβ+(max) = 902 keV
9/2+
Q-value
2.833 Me
Z
Figure 11.8 Nuclear
energy level decay
schemes for (a)
89
Zr (ground state)
and (b)
89m
Zr meta-
stable excited state
(t
=4.16 minutes)
1/2
formed during
89
Y(p,n)89Zr pro-
duction using a
cyclotron.
and increased clinical experience are still required before 89Zr-immuno-PET can receive
more widespread acceptance in nuclear medicine.
Most radiochemists working on
radionuclide. However, cyclotron production of
89
Zr-radiotracers only encounter the 89Zr ground state
89
Zr typically produces high quantities
Chapter 11: The Radiochemistry ofZirconium 351
89m
of the
hour prior to removing the
Zr excited state. For this reason, targets are usually left to “cool” for at least an
89
Y-foil and commencing the purication chemistry.
The comparatively low mean kinetic energy of the positrons emitted during the decay
89
of
Zr (395.5 keV) means PET image resolution is essentially limited only by the physical
resolution of the preclinical and clinical cameras used to record data sets and not by
the nuclide itself. This means the spatial resolution of most reported
comparable to data reported using radiotracers labelled with
89
Zr-PET images is
18
F or 64Cu[10, 39, 44].
An overview of the manual steps involved in the purication of 89Zr from the 89Y target
material is shown in Figure11.9. The procedure has several important features. First,
89
the
Y target (which is cheap and does not need recycling) is dissolved carefully by
using a solution of 6 M HCl. This step generates copious amounts of heat and hydrogen
gas, and the mixture is liable to boil. Hence, care should be taken to ensure that the
solution is vented to prevent pressure buildup and that the mixture is sealed from
ignition sources. While some research groups have opted for cooled reaction vessels
to manage the heat produced from dissolution, this adaptation is not essential, and
the temperature of the solution can be reduced eectively by controlled (stepwise or
portion-wise) addition of the acid and later by diluting the mixture with cold water. It
is essential to ensure that the nal concentration of HCl is <2 M; otherwise, the separation chemistry will be compromised. It should be noted that all solutions should
be prepared from the highest purity reagents. In addition, 18.2 MΩ⋅cm water is puri-
ed further by pretreatment using Chelex resin to ensure that other metal ions that
may compete with Zr
particular, Fe
3+
4+
ions during the separation and radiolabelling chemistries (in
ions) are removed.
Figure 11.9
Schematic owchart showing
the steps and
approximate timing involved in the
manual separation
89
of
Zr from the bulk
89
Y target material.
Wash 2 M HCl(aq.) (4 × 2.5 mL)
<5 min
352 Handbook of Radiopharmaceuticals
89
Y(s) target dissolution
(2 mL 6 M HCI, 5 mL H
Hydroxamate column (100 mg)
<10 min
Elute 1 M oxalic acid
(4 × 0.5 mL fractions)
O)
2
5 min
5 min
<5 min
Wash H
O (4 × 2.5 mL)
2
<30 min processing time
>98% recovery
>90% in first 1 mL fraction
After dissolution, the mixture has a clear appearance, but some black precipitate/
mn
Po
particulates remain. Although the black material has not been characterised, it is
presumably a form of Y
that precipitates during the addition of acid. The presence
2O3
of the black precipitate does not impact the eciency of the separation chemistry,
and during the solid-phase extraction (SPE) step, it is completely removed by ltration.
Once dissolved, the crude solution is passed onto a prepacked SPE cartridge containing
~100 mg of ‘hydroxamate resin.’ Commercial sources are now available, but during the
early-to-late 2000s, research groups prepared these SPE cartridges manually. The
‘hydroxamate’ resin actually consists of a poly(acrylamide-acrylic acid) block co-polymer
backbone in which the carboxylic acid groups have been transformed into hydroxamic
acid groups via standard activated ester formation and amide bond formation using
hydroxylamine in acetonitrile (Scheme11.1)[39]. Loading the ‘hydroxamate’ resin takes
<5 minutes with essentially >99% of the radioactivity retained on the SPE cartridge. Then,
the resin is washed with dilute HCl to ensure the eective removal of the soluble fraction
3+
of Y
ions (and other metal ion impurities), followed by further washing with high-purity
water. It should be noted that the resin remains white in colour with the exception of the
top few millimetres, which trap the black particulate material. If the colour of the resin
changes to orange/brown, this is a positive indication that the solutions are contaminated
with Fe
3+
ions. Ferric ions form strong dative covalent bonds with hydroxamate donors
and give rise to intense metal-based electronic absorption at ~430 nm (molar absorption
coecient, ε ~2200 M
eective separation of
−1
cm−1). At present, no methods have been reported for the
89Zr4+
ions from Fe3+ ions, and hence, if contamination is evident,
it is best to abandon radiolabelling experiments, perform a full clean of the lab space to
remove dust particles (which often contain rust), and prepare all solutions fresh.
OH
NH
O
O
NH
ly(acrylamide-acrylic acid)-copolymer
OOH
2
mn
After the washing steps, puried
EDAC, TFP
MeCN
Hydroxylamine HCI
89Zr4+
ions are eluted from the SPE cartridge by
O
NH
Hydroxamic acid resin
2
washing with 1 M oxalic acid solution. The nal product is obtained in <30 minutes
processing time with high recovery of the activity and in high chemical and radiochemical purity. Measurements of the specic-activity using the aforementioned separation
procedure gave a value in the range 195–496 MBq mg
of 17.39–44.22 GBq μmol
is 1478.74 GBq μmol
factors (IDFs) for clinical-grade
−1
)[39]. Given that the theoretical maximum molar activity of 89Zr
−1
(449 056 Ci g−1; or 39.97 Ci μmol−1), the estimated isotopic dilution
89
Zr are in the range 33–87. This means the 89Zr produced
−1
of Zr (equivalent to a molar activity
via this route is of comparable or even higher purity than standard productions of most
18
F- and 64Cu-radiolabelled compounds[39, 45]. With such high molar activities (low IDF
values), it is essential that the radiochemical kinetics of
89
Zr labelling reactions occurs
Chapter 11: The Radiochemistry ofZirconium 353
Scheme 11.1
Chemical synthesis
of the ‘hydroxa-
mate resin.
extremely fast to ensure ecient complexation and high radiochemical yields[45]. Radiolabelling eciency depends strongly on the nature of the radiochemical species present in
solution and on the thermodynamics and kinetics of the complexation reaction.
In the elution step, the oxalate anions eectively displace the didentate hydroxamate
donors under conditions of low pH (~1–2). Hydroxamate groups have pK
range 5.5–7.0, and thus are protonated under the elution conditions, making them weak
donors. An underappreciated feature of this separation chemistry is that the
activity is eluted as ‘
[Zr(C
]4−[46]. One of the major challenges of performing Zr chemistry is aqueous con-
2O4)4
ditions is preventing the highly polar Zr
89
Zr-oxalate’ whose speciation is likely of the chemical formula [89Zr]
4+
ions from hydrolysing[47, 48] or forming multi-
nuclear hydroxylate complexes[49]. Oxalate anions have the eect of both solubilising
4+
Zr
ions and stabilising the complex against hydrolysis up to pH values over 7[46].
Interestingly, Baggio etal.[50] have reported that Zr
4+
in the presence of oxalate anions gives crystals showing a bridged dimeric structure in which both Zr
are 8-coordinate and one of the oxalate anions acts as a η
(Figure11.10). Although the precise nature of the
89
4
–,μ2–C2O4 bridging ligand.
Zr species in the oxalate solution
remains uncertain, a wealth of empirical data has shown that the ‘
tion is a suitable starting material for radiosynthesis.
In 2009, a method for the preparation of ‘
89
Zr-chloride’ was reported by myself and
co-workers[39]. The rationale behind accessing a dierent formulation of
do not contain oxalate ligands/oxalic acid was that powerful didentate ligands in high
concentration can be thermodynamically and kinetically dicult to displace with some
multidentate ligands (typically macrocyclic chelates) that have less accessible cavities.
Our original method involved an initial (two-step) trap and release using a quaternary
methyl ammonium ion (QMA) SPE cartridge followed by a practically cumbersome
thermal hydrolysis step in which the ‘
89
Zr-oxalate’ mixture was boiled to dryness under
values in the
a
89
Zr-radio-
4+
ions
89
Zr-oxalate’ formula-
89Zr4+
ions that
Figure 11.10 Single
crystal X-ray
structure of the
bridged dimer
K
[{Zr(C2O4)3}2
6
(μ-C
)][50]. Note:
2O4
potassium ions and
water molecules
incorporated inside
the crystal are
omitted for clarity.
354 Handbook of Radiopharmaceuticals