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64. Srivastava, S.C., Atkins, H.L., Krishnamurthy, G.T. etal. (1998). Treatment of metastatic
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67. Abel, E.P., Avilov, M., Ayres, V. etal. (2018). Isotope harvesting at FRIB: additional
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68. Loveless, C.S., Blanco, J.R., Diehl, G.L. SE Cyclotron Production and Separation of
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J Nucl Med. 2020.
Chapter 5: Production ofTherapeutic Radionuclides 105
PART III
Synthetic Methods for
Radiopharmaceuticals
Chapter 6
13
Synthesis of
N-
15
and
O-Labeled
Radiopharmaceuticals
Krishna R. Pulagam1, Vanessa Gómez-Vallejo1,
Fernando López-Gallego
1
Radiochemistry and Nuclear Imaging Group, CIC biomaGUNE,
Basque Research and Technology Alliance (BRTA), 20014, Donostia San Sebastián, Spain
2
Heterogeneous Biocatalysis Laboratory, CIC biomaGUNE, Basque
Research and Technology Alliance (BRTA), 20014, Donostia San
Sebastián, Spain
3
IKERBASQUE, Basque Foundation for Science, 48013 Bilbao,
Spain
4
Faculty of Chemistry and Chemical Technology, University of
Ljubljana, SI-1000, Ljubljana, Slovenia
2,3
, Luka Rejc
1,4
, and Jordi Llop
1
Nitrogen-13 was discovered more than 80 years ago when Irene Curie and Frederic
Joliot irradiated boron nitride with α-particles to produce nitrogen-13 via the
nuclear reaction[1]. After treatment of the irradiated sample with sodium hydroxide, the
authors detected the distillation of a radioactive compound that produced a radioactive
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.
10
B(α,n)13N
white precipitate when contacted with a paper soaked in hydrochloric acid. This precipitate was identied as ammonium chloride, and Joliot and Curie concluded that the
radionuclide formed was nitrogen-13 and estimated its physical half-life to be close to
14 minutes. Within the same year, the rst production of nitrogen-13 using a cyclotron
was reported by Cockcroft etal.[2]. The authors irradiated either
13
C-enriched graphite
with accelerated protons or natural graphite with accelerated deuterons to produce, in
both cases, nitrogen-13. The half-life was determined to be 10.5 ± 0.5 minutes, a value
that better resembles the currently accepted physical half-life of nitrogen-13 (9.97 minutes). Joliot and Curie got the Nobel Prize in 1935 for “their synthesis of new radioactive elements,” while Cockcroft and Walton received the Nobel Prize in 1951 for “their
pioneer work on the transmutation of atomic nuclei by articially accelerated atomic
particles.”
After these pioneering studies, nitrogen-13 has progressively been incorporated in the
toolbox of positron emission tomography (PET) chemists, who have developed strategies
for the in-cyclotron production of dierent
13
N-labeled species, which have been used
directly in dierent applications or further employed to prepare more complex labeled
molecules. This chapter will cover the main alternatives for the production of nitrogen-13
and the application of this radionuclide to the preparation of labeled molecules.
Nitrogen-13 can be produced in biomedical cyclotrons using dierent nuclear reactions
(see Table6.1), the most commonly used reactions being those rst described by Cockcroft etal.[2], i.e.
accelerated ion-induced nuclear reactions, nitrogen-13 can also be produced by neutron
irradiation of natural nitrogen via the
requires the use of a neutron source, which is not widely available; additionally, because
the irradiated material and the radionuclide are isotopes of the same element, low molar
activity values are achieved. Because of this, neutron irradiation has barely been applied
to produce
12
C(d,n)13N and 13C(p,n)13N together with 16O(p,α)13N. In addition to
14
N(n,2n)13N nuclear reaction. This nuclear reaction
13
N.
Table 6.1 Methods
Target material Nuclear reaction In-target product
for the production
13
of
N using nuclear
reactions.
CO2 (trace N2)
Graphite
Charcoal
13
C-enriched charcoal
H
O/ethanol
2
H2O
NaNO3 (aq)
Al4C
3
CH
(owing)
4
110 Handbook of Radiopharmaceuticals
12
C(d,n)13N [13N]N
12
C(d,n)13N [13N]CN
12
C(d,n)13N [13N]N2 + trapped [13N]CN
13
C(p,n)13N Trapped [13N]CN
16
O(p,α)13N [13N]NH
16
O(p,α)13N [13N]NH3 + [13N]NO
14
N(n,2n)13N [13N]NH
12
C(d,n)13N Matrix-trapped 13N
12
C(d,n)13N [13N]NH3 + [13N]H CN + [13N]CH3NH
2
3
3
−
+ [13N]NO
3
−
2
2
N]N
TER
WATER
HELIUM
2
Dinitrogen is an inert gas, and its chemical modication for conducting radiolabeling
reactions is challenging. Because of this, the main applications of [
13
N]N2 have been
limited to nitrogen xation experiments[3, 4] as well as ventilation studies both in animal
species[5, 6] and in human subjects[7].
13
[
N]N2 is unintentionally produced in biomedical cyclotrons worldwide on a daily basis
when N
tion. In addition to the formation of [
O
, [15O]O2, [11C]CO, and [13N]N2; the last is as a result of the 14N(p,pn)13N nuclear reaction,
2
which produces recoil
ultimately resulting in the in situ formation of [
oxygen isotopes by simple radioactive decay and of [
the rst and subsequent trappings of [
mixtures are irradiated to produce [11C]CO2 via the 14N(p,α)11C nuclear reac-
2/O2
13
N atoms that can undergo isotopic exchange reactions with N2,
11
C]CO2, this process leads to the formation of [14O]
13
N]N2. After elimination of short-lived
11
C]CO and [11C]CO2 by oxidation of
11
C]CO2, pure [13N]N2 can be produced in sucient
amounts to conduct ventilation studies (c. 10 GBq in 30-minutes irradiation of the target
at 20 μA; Figure6.1)[8].
Before the development of this convenient and straightforward approach, more
sophisticated methods had been developed. The rst paper that specically mentioned
WATER
OUT
OUT
OUT
COLLIMATOR
BEAM
[13N]N
WATER
IN
2
HELIUM
IN
SODA
LIME
TARGET
GAS IN
CuO
SODA
LIME
N
/ 0.1% O
2
TARGET
GAS OUT
2
WA
IN
Figure 6.1 Schematic representation of the system used for the production of [13N]N2 by irradiation
of an N
mixture, as used for the production of [11C]CO2. Source: Based on the target Nirta® -C11
2/O2
provided by IBA.
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 111
the production of [13N]N2 and its use in plant xation experiments was published in
1940[9]. In this study,
13
N was produced via the 12C(d,n)13N nuclear reaction by irradia-
tion of charcoal using 8-MeV deuterons. Combustion of the irradiated material under a
stream of O
taining [
and in the presence of CuO resulted in a mixture of radioactive gases con-
2
13
N]CN, [13N]NH3, [13N]NO, and [13N]N2, which could be isolated by purication over
dierent chemical and cryogenic traps. With the same nuclear reaction, a continuous
ow production of [
13
N]N2 could be achieved by ushing the irradiated granulated charcoal with argon gas and passing the gas mixture through combustion tubes packed with
copper at high temperature (750 °C) and then through diluted H
solutions[10]. With this procedure, a continuous ow containing
1–2 GBq min
−1
using a deuteron current of 40 μA in the target could be produced.
Liquid targets have also been applied to the production of [
and alkaline sulte
2SO4
13
N activity in the range
13
N]N2. By proton (18 MeV)
irradiation of 0.1 M aqueous ammonia solutions at 10 μA, Parks and Krohn demonstrated
that 75% of the radioactivity was due to the presence of [
13
N]N2, which could be recov-
ered with a spirometer and stored in a specially designed reservoir outside the cyclotron
vault[11] (see Figure6.2 for the scheme of the production system). [
−
NO
(6%), and [13N]NH
2
+
(3%) were also formed. Of note, this method leads to low molar
4
13
N]NO
−
(16%), [13N]
3
activities, because the radiolytic oxidation of ammonia results in the formation of nonradioactive N
The direct production of [
13
C-enriched charcoal with protons (energy=19 MeV). In this case, the 13C-enriched char-
(up to 3 mmol under the experimental conditions assayed by the authors).
2
13
N]N2 in the target has also been achieved by irradiation of
coal (ca. 0.8 g, 97% enriched) was packed into a carbon (natural abundance) cylinder that
was spring-loaded into a quartz tube, preheated at 800 °C, and irradiated at 10 μA[12].
EFFLUENT
RESERVOIR
4-WAY VALV E
PUMP
[13N]N2 COLLECTION/STORAGE
BEAM
TARGET
He
2
O
H
GAS
COLLECTOR
Figure 6.2 Schematic representation of the liquid recirculation system for the production and
accumulation of [
active [
13
N]N2
13
N]N2. All components except the target were outside the cyclotron vault. The whole
by using a variable-speed pump. Radio-
solution without interrupting irradiation.
112 Handbook of Radiopharmaceuticals
The target was ushed with helium gas to transfer the radioactive species into a liquidcooled charcoal trap. As much as 99.7% of the generated radioactivity under these conditions was [
NO and [
Strategies to generate [
13
N]N2. When lower target-intensity values were used, other species, i.e. [13N]
13
N]N2O, were majorly formed (22.6% and 44.9%, respectively).
13
N]N2 from other radioactive precursors produced in the cyclo-
tron have been reported. The clearest example is the oxidation of cyclotron-produced
13
[
N]NH3 (see the next section) with NaOBr in the presence of NH4Cl to give [13N]N2[13,
14]. The addition of NH
could be slightly improved by increasing the amount of both NH
Cl resulted in low molar activity values. The molar activity values
4
Cl and NaOBr, which also
4
resulted in an increase in radiochemical yield[4].
N]NH
Ammonia is the most widely used 13N-labeled radiotracer, and it has been widely applied
as an accurate noninvasive diagnostic tool for the quantication of myocardial perfusion
in clinical settings[15, 16] and to explore dierent phenomena in preclinical studies[17–
19]. Additionally, it is used as the precursor for a wide range of more sophisticated tracers
(discussed later).
13
N-labeled ammonia was the rst 13N-labeled compound ever reported, and it was
rst produced by Joliot and Curie in an attempt to prove the identity of the radionuclide
that they had produced by irradiation of boron nitride with α-particles[1]. They treated
the irradiated sample with sodium hydroxide and distilled a radioactive compound that
produced ammonium chloride when contacted with hydrochloric acid. After this pioneering work, other attempts to successfully produce [
13
N]NH3 using solid targets were
reported, all based on the same principle but using particle accelerators for the production of the radionuclide. For example, Hunter and Monahan produced
ation of Al
of KOH and distilled [
with 8–12-MeV deuterons. The authors treated the target with a solution
4C3
13
N]NH3 that was trapped in an acidic solution[20]. Although no
13
N by irradi-
details about irradiation time and the amount of target material were reported, 740 GBq
of carrier-free [
simultaneously, Welch and Lifton reported the formation of
13
N]NH3 could be produced using a target intensity of 30 μA. Almost
13
N-labeled compounds
produced during irradiation of dierent carbides with deuterons, with the relative
amounts depending on the integrated current on the target material[21]. They found
that by varying the carbide and irradiation conditions, dierent chemical species could
be obtained, including [
13
[
N]NH3 was obtained after irradiation of Al4C3, with relative values in the range 75–90%
13
N]NH3, [13N]CH3CN, and [13N]CN−. The maximum percentage of
depending on the integrated current in the target. It is noteworthy that this irradiation
results in the formation of the short-lived β
27
Al(d,p)28Al nuclear reaction (maximum cross-section at around 5 MeV)[22].
−
-emitter 28Al (half-life=2.24 minutes) via the
An alternative method using a gas-phase target was developed one year later, and
it was based on the deuteron irradiation (8 MeV) of methane continuously owing in
a Pyrex glass-lined target chamber[23]. Ten minutes of irradiation at 5 μ A resulted
in 740 MBq of [
13
N]NH3, which could be trapped in an isotonic saline solution. Minor
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals
impurities were [13N]CH3NH2 (2%), [13N]C2H5NH2 (<0.2%), and [13N]HCN (<3%), as determined by gas chromatography.
The use of liquid targets for the production of [
13
N]NH3 was described one year later[24],
to overcome the limitations of the low molar activity obtained using the methane target
(0.2–0.4 GBq μmol
10–20 mCi). Following suggestions by Tilbury that the
−1
or, as reported in the original publication, 30 μg of carrier ammonia in
16
O(p,α)13N reaction proceeded with
a high yield, Krizek etal. investigated this nuclear reaction in liquid targets by irradiating
water with protons. With 15-minutes irradiation at 10 μA, they could produce 7.9 GBq of
13
N (end-of-bombardment [EOB]) mainly as [13N]NO
hydroxide to yield 3.5 GBq of [
13
N]NH3 with a molar activity close to 8 GBq μmol−1, clearly
−
, which was reduced with titanium
3
superior to the activity obtained using the methane target. Other reducing agents[25],
such as Devarda’s alloy in the presence of NaOH and TiCl
in the presence of NaOH, were
3
successfully assayed, and a fully automated process was rst described in 1973[26].
A few years later, Tilbury and Dahl showed that the integrated dose in the target
played a pivotal role in the formation of [
generated during beam delivery, i.e. [
major species at high doses (>80% for doses >3 μAh)[27], but with [
13
N]NH3 relative to the other two major species
13
N]NO
−
and [13N]NO
3
−
, with [13N]NO
2
13
N]NH3 ammonia
−
being the
3
accounting for ca. 40% of the radioactivity at low integrated doses (0.01 μAh). This is
due to the fact that the nitrogen-13 nuclei produced by the
16
O(p,α)13N nuclear reaction
rst pick up hydrogen atoms, either by hydrogen abstraction from water or by reaction
with other hydrogenous species. These reactions produce OH radicals, which can induce
the radiolytic oxidation of [
13
N]NH3 to its oxoanions. If we assume that this mechanism is
correct, it is clear that the formation of the oxoanions could be prevented by “inactivating” or “removing” the radicals formed during hydrogen abstraction. This was achieved
by using a cryogenic target containing frozen water[28]. The authors irradiated water in
the solid state using protons with an eective energy of 15.7 MeV and found that nearly
all nitrogen activity was in the form of [
range 1–20 μA, with only traces of [
13
N]NH3, irrespective of the beam current in the
13
N]NO
−
and [13N]NO
3
−
present, because the low tem-
2
perature decreased radiolysis.
The use of frozen targets has major inconveniences. Hence, the addition of radical
scavengers to liquid water to prevent the formation of the oxoanions was investigated.
The major breakthrough was reported by Wieland etal.[29], who demonstrated that the
addition of a small amount of ethanol (5–10 mM concentration) to the irradiated water
resulted in more than 96% of the radioactivity being produced as [
13
N]NH3, irrespective
of the beam intensity (15–30 μA) and irradiation time (8–20 minutes). Similar results could
be achieved with the addition of acetic acid, which at concentrations >5 mM also yielded
more than 95% of the radioactivity as [
achieved after the addition of ethanol. Currently, the production of
13
N]NH3, with equivalent saturation yields to those
13
N by proton irradia-
tion of ethanol/water solutions is widely established worldwide, using a target conguration similar to that shown in Figure6.3.
Other, less convenient strategies to prevent the formation of [
−
NO
include the pressurization of the water target with (i) hydrogen with[30] and
2
13
N]NO
−
and [13N]
3
without[30–32] addition of ethanol in the irradiated solution, and (ii) methane[33].
114 Handbook of Radiopharmaceuticals