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(a)
2
(d)
O
2
O
NH
2
triphosgene
N
C
O
[13N]NH
3
NH13NH
2
O
13
NH
N
2
O
13
NH
O
O
13
O
NH
2
N
(b)
(c)
NH
triphosgene
Cl
N
[13N]NH
3
O
Cl
OH
triphosgene
N
O
N
O
2
H
N
triphosgene
2
O
[13N]NH
[13N]NH
3
N
O
2
3
O
O
Cl
N
chloride (Scheme6.6b), or chloroformate (Scheme6.6c), respectively. This strategy was
also applied to the preparation of [
chemical yield (56–74%, decay corrected and based on [
(22–33 GBq μmol
−1
).
The same group reported the use of anhydrous [
thalidomide[77] and [
13
[
N]NH3 was reacted with N-phthaloylglutamic anhydride to produce [13N]ammonoly-
13
N]dantrolene[78] (Scheme6.7). For thalidomide (Scheme6.7a),
13
N]carbamazepine (Scheme6.6d) with high radio-
13
N]NH3) and high molar activity
13
N]NH3 for the radiosynthesis of [13N]
sis. Under no-carrier-added conditions, low yields were achieved in this step (20%),
although a signicant improvement was achieved by the addition of i-Pr
NEt (76%). This
2
step was followed by cyclization with carbonyldiimidazole to yield the desired tracer.
After purication by HPLC, 570–780 MBq of pure (98%) tracer could be obtained, resulting in a decay-corrected radiochemical yield of 56% ± 12% and molar activity values of
49 ± 24 GBq μmol
−1
. For the preparation of [13N]dantrolene (Scheme6.7b), the authors
reacted ethyl 2-{2-[5-(4-nitrophenyl)furfurylidene]hydrazino} acetate with triphosgene in
Scheme 6.6 One-
pot synthesis of
13
[
13
[
analogs using noncarrier added [
NH
3
13
of [
N]carbamaze-
13
N]
pine following a
parallel strategy.
(a)
O
N
O
O
O
O
13
[
N]NH
iPr2NEt
o
130
C,
/DMF
min
2
3
O
N
O
13
OH
O
carbonyldiimidazole
O
NH
2
130
O
Cl
N
(1)
(2)
O
(b)
N
NH
O
O
N
O
2
O
DCE
iPr
NEt
2
o
75
min
30
C,
N
O
N
O
O
Scheme 6.7 Synthesis of [1313
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 125
DMF
o
min
2
C,
13
N]NH
[
purification
N
O
O
3
N
O
2
O
O
13
N
H
N
N
13
N
H
O
the presence of i-Pr2NEt to produce the corresponding carbonyl chloride. After removal
of excess COCl
to induce [
and without further purication, the mixture was reacted with [13N]NH3
2
13
N]ammonolysis. In this process, controlling the initial amount of triphosgene
was essential to achieve good yields under no-carrier-added conditions, as the excess of
COCl
reacted with [13N]NH3, thus preventing the desired [13N]ammonolysis. Final cycliza-
2
tion to yield [
13
N]dantrolene was achieved by purication using HPLC followed by heating
of the collected fraction. The process was fully automated, resulting in non-corrected
radiochemical yields close to 5% and molar activities around 30 GBq μmol
The preparation of
13
N-labeled peptides is the nal example in which [13N]NH3 is used
−1
.
as the labeling agent. The only study in the literature in which the preparation of the
opioid tetrapeptide H-Tyr-D-Met(O)-Phe-Gly-[
13
N]NH2 is described is the study by Saji
etal.[79]. This preparation was achieved by amidation of the activated p -nitrophenol
ester with [
13
N]NH3, with a decay-corrected radiochemical yield of 48% in an overall pro-
duction time of 25 minutes.
13
[
far. Very recently, the preparation of
−
N]NO
has also been reported in other applications than those presented so
2
13
N-labeled polysubstituted triazoles has been
achieved via Huisgen cycloaddition following a four-step process[70]. First, cyclotronproduced [
step,
13
13
N-labeled diazonium salts were formed by reaction of [13N]NO
amines under acidic conditions. These were reacted with NaNO
in acidic media to yield the corresponding
−
N]NO
was reduced to [13N]NO
3
−
using a cadmium column. In the second
2
13
N-labeled azides, which were nally
−
with aromatic
2
and hydrazine hydrate
2
reacted with alkynes or aldehydes in the presence of a catalyst to yield the labeled triazoles (Scheme6.8). Full automation of the process was reported for only one triazole
(compound 6 in Scheme6.8), which could be obtained in decay-corrected radiochemical
yields of 11% ± 2% and molar activity of 4.6 ± 0.2 GBq μmol
−1
in an overall production time
of 25 minutes. In a dierent study, and by incorporation of the label into two dierent
positions, either in the diazonium salt or in the hydrazine, the same authors demon-
strated that the formation of the aryl azides proceeds under a stepwise mechanism via
acyclic zwitterionic intermediates[42]. More recently, the formation of
zoles was achieved by reaction of
13
N-labeled azide (by reaction of [13N]NO
13
N-labeled tetra-
−
with hydra-
2
zine hydrate in acid media) with a nitrile in the presence of a Cu-Cr-Al catalyst. Despite
the conrmation of the presence of the desired labeled compound by chromatographic
co-elution with the reference standard, the isolation of the compounds was not carried
out in this work [43].
13
[
and nitrosoureas[80] (Scheme6.9).
−
N]NO
has also been used for the preparation of 13N-labeled nitrosocarbamates[45]
2
13
N-labeled 1,3-bis(2-chloroethyl)-1-nitrosourea ([13N]
BCNU, Scheme6.9) was prepared by treating a solution containing cyclotron-produced
13
[
−
N]NO
and carrier HNO3 with bis(2-chloroethyl)urea in the presence of acetic acid and
3
copper dust. The desired labeled compound was obtained by extraction with chloroform
and subsequent evaporation, in decay-corrected radiochemical yields of 20–40% and
overall times of 15–20 minutes. By means of a parallel procedure, its carbamate analog
N-nitroso-N-chloroethyl-1-chloroethyl carbamate ([
13
N]BCNC) was also successfully pre-
pared a few years later with radiochemical yields in the range 4–11%[81].
126 Handbook of Radiopharmaceuticals
–
1
3
1
[
13
[
[
[
[
[
Cl
O
O
(b)
13
13
13
13
13
NH
R
1
N]1R
N]2R
N]
3
N]
4
N]5R
N]6R
13
H5or R
H
-CH
5
-CH
2)3
-CH
2)5
)-COOCH
2
-p-N(CH
N
+
N
R
1
=
-C
H
5
3
6
3
3
3
3
3)2
–
N+HN
N
R
2
a
13
N
N
R
N
2
–
[13N]NO
[13N]NO
H; R
2
H; R
2
R
H;
2
R
H;
2
H;
R
2
R
H;
2
Cd
3
–
2
=
-C
6
=
-C
6
=
-(CH
=
-(CH
=
-(CH
=
-C
6H4
2
=
1
=
1
=
R
1
=
R
1
=
1
=
1
N
+
13
N
N
O
R
1
H
R
3
b
13
N
N
N
Scheme 6.8 Syn-
thesis of [
azoles by reaction
13
of
N-labeled aryl
azides with alkynes
and aldehydes.
R
13
N]tri-
R
–
Cl
13
N
H
N
N
O
O
13
–
Cl
N
O
N
Cl
O
(a)
Cl
Cl
HNH
O
O
R
[13N]NO
N
Cl
H
N
Cl
dust
Cu
AcOH,
[13N]NO
dust
Cu
AcOH,
3
RT
3
RT
The application of 13N-labeled tracers in the clinical eld requires the presence of a cyclotron on site. Additionally,
and due to the short half-life of the radionuclide, image acquisition beyond one hour
after administration is unfeasible. Hence, the use of this radionuclide in clinical applications is severely restricted.
The mainstay of
istered intravenously, [
the form of [
13
N]NH
branes, and hence [
equilibrium between [
single-pass extraction of the tracer into the extravascular space of the dierent tissues,
and this also occurs in the myocardium. Once inside the cells, [
13
[
N]glutamine or diuses back into the vascular space (Figure6.4). Because the metabo-
lism of glutamine is very slow in the myocardium, there is apparent metabolic trapping of
13
[
N]NH3 within the cells[82, 84]. Hence, the amount of [13N]NH3 trapped is proportional
to the activity of the enzyme glutamine synthetase, which catalyzes the synthesis of glutamine. This entrapment can be clearly visualized with PET thanks to the fast clearance of
13
N-labeled tracers cannot be distributed to remote centers,
13
N-radiopharmaceuticals is and has been [13N]ammonia. When admin-
13
N]NH3 is in equilibrium with [13N]NH
+
at physiological pH[82, 83]. [13N]NH3 freely diuses across mem-
4
13
N]NH3 has a high single-pass extraction fraction[83]. Because the
13
N]NH3 and [13N]NH
+
is attained rapidly, there is a nearly complete
4
+
, with 95% of the 13N in
4
13
N]NH3 is converted into
Scheme 6.9 Syn-
thesis of [
13
N]
13
[
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 127
EXTRAVASCULAR
Figure 6.4 Sche-
matic display of
the physiological
behavior of [
13
N]NH3
in the myocardium
following intravenous injection. [
NH
freely diffuses
3
13
N]
across cellular
membranes and
is metabolically
trapped in the form
13
of [
N]glutamine.
BLOOD
[13N]NH
[13N]NH
13
N activity from the vascular space[85] and can be interpreted in terms of tissue perfu-
3
+
4
COMPA RTMENT
[13N]NH
[13N]NH
3
+
4
METABOLIC COMPARTMENT
[13N]NH
[13N]NH
3
4
+
Glutamate
Glutamine
sinthetase
13
[
N]glutamine
sion. In this scenario, PET with ammonia has become an accurate and well-validated tool
for the assessment of myocardial perfusion and blood ow in coronary artery disease
(CAD) or suspected CAD and their eects on ventricular function. A description of the
acquisition protocols, image interpretation, and a detailed overview of all the medical
applications fall beyond the scope of this chapter. For recent reviews on these topics, the
reader is referred to[16, 86, 87].
Because [
13
N]NH3 is widely used as a radiopharmaceutical tool in the clinical arena,
there are precise guidelines for its quality control in both the European and US Pharmacopeia. Tests to be performed during the quality control on the injectable solution
include (data from European Pharmacopeia): (i) determination of the pH, which should be
between 5.5 and 8.5; (ii) presence of aluminum <2 mg l
−1
, as determined by a colorimetric
test; (iii) radionuclide purity, with a determined half-life in the range 9–11 minutes and
< 1% of gamma-emitting impurities; and (iv) radiochemical purity >99%, as determined
by liquid chromatography. Additionally, the solution should comply with sterility criteria
and bacterial endotoxin limits like any other PET radiopharmaceutical. Major radiochemical impurities are usually [
−
F
produced during irradiation via the 18O(p,n)18F nuclear reaction (note that the natural
abundance of
18
O is close to 0.2%), and [15O]H2O formed due to the 16O(p,pn)15O nuclear
13
reaction. The anionic species can easily be eliminated by trapping [
exchange resin, while the
15
N]NO
−
and [13N]NO
2
−
produced during the irradiation, [18F]
3
13
N]NH
+
in a cation
4
O-labeled water is eliminated by simple radioactive decay
(half-life=122.2 seconds).
128 Handbook of Radiopharmaceuticals
Oxygen-15 is an unstable isotope of oxygen. It decays through the emission of a positron
and has a half-life of 2.07 minutes (Table6.3). It was discovered in 1934 when Livingston
and McMillan irradiated nitrogen gas with deuterons[88]. The resulting gas mixture was
found to be radioactive, with an estimated eciency of activation of one nitrogen atom
Isotope Half-life E
15
O 2.07 min 1.732 0.735 8.4
max
(MeV )
a
E
mean
(MeV )
b
R
max
(mm)
c
a Maximum energy of the emitted positrons.
b Mean energy of the emitted positrons.
c Maximum range in water.
per million incident deuterons. The identity of the radioactive nuclide was conrmed
by mixing the irradiated gas with O
asbestos, and nally leading it through a CaCl
and H2, passing the mixture over heated platinized
2
drying tube. The activity was trapped
2
entirely in the drying tube, thereby indirectly conrming the formation of radioactive isotope oxygen-15.
The high abundance of oxygen in molecular species involved in biological processes
presents an opportunity for radioactive oxygen-15 to be used as a radiomarker of biologically active molecules without changing their original structure. A possible role of
15
O as a
radiotracer was rst recognized in the middle of the twentieth century; however, its short
half-life and low availability at the time led early investigators to divert their research
interests to other radiotracers[89, 90]. It was not until Ter-Pogossian and Powers, of
Washington University, St. Louis, used [
murine experimental neoplasms that the idea of
15
O]O2 to assess the distribution of oxygen in
15
O as a radiotracer was revived[91]. This
encouraged the development of new strategies for the faster and more ecient incorporation of
opening new avenues for the exploitation of
15
O into new 15O-labeled radiotracers and gave a breath of fresh air to the eld,
15
O in biomedical research.
Table 6.3 Main
properties of
15
O.
Storage or transportation of oxygen-15 is unfeasible due to its short half-life
(t
=2.07 minutes); hence, the production of 15O-labeled species is limited to fast nuclear
½
and radiochemical reactions and the performance of the reactions on site.
Oxygen-15 is produced in low-energy proton and deuteron accelerators. By carefully
selecting the target material and the type of irradiation, one can produce the radionuclide in dierent chemical forms (Table6.4).
Target material Nuclear reaction In-target product
N
2
N2/O
N2/CO
N2/H
N
/CH
2
O
2
H2O
15
[
N]N2/H
2
2
2
4
2
14
N(d,n)15O [15O]O2 + [15O]N2O + [15O]NO2 + [15O]O
14
N(d,n)15O [15O]O
14
N(d,n)15O [15O]CO
14
N(d,n)15O [15O]H2O
14
N(d,n)15O [15O]CH3OH + [15O]C2H5OH + [15O]H2O
16
O(p,pn)15O [15O]O
16
O(p,pn)15O [15O]H2O
15
N(p,n)15O [15O]H2O
2
2
2
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 129
3
Table 6.4
Nuc
reactions used
for the production of
15
O.
lear
Three main strategies are used: irradiation of 15N or 16O-bearing targets with protons
and irradiation of
tion of [
15
O]N2O, [15O]O2, [15O]CO2, [15O]H2O, [15O]alcohols, or [15O]O3, depending on the
14
N-bearing targets with deuterons. This, in turn, leads to the produc-
strategy used. On the downside, undesired chemical and radiochemical impurities form in
the target during the irradiation. The full spectrum of the crude
15
O-labeled mixture has
rarely been fully characterized, but evidence suggests that careful control of the irradiation energy and the specic chemical composition of the initial target improve the purity
15
of the
to produce
O-labeled product. Nevertheless, impurities need to be removed post-irradiation
15
O-labeled species that can be injected into patients or used as reagents in
further radiochemical reactions.
6.2.2.1 Early Beginnings: [15O]N2O
Early reports on the production of 15O-bearing molecules date from 1958[92]. Irradiation
of an air target with deuterons initiated the
wide energy range of the deuterons used for bombardment caused the production of
radiology-based chemical and radiochemical impurities, such as [
15
[
O]O3. The development of low-energy deuteron accelerators (3–4 MeV) enabled the
production of 99.95% pure [
15
O]N2O gas upon irradiation of N2 target gas at a low (0.5 μA)
beam, and purication through a zeolite column[93]. Regardless of these improvements,
15
[
O]N2O has no reported applicability in biomedical research and is mostly considered an
unwanted side product of in-target radiolysis in the production of [
14
N(d,n)15O reaction to produce [15O]N2O. A
15
O]O2, [15O]NO2, and
15
O]O2[94, 95].
6.2.2.2 [15O]O
2
One of the most widely used nuclear reactions for the production of 15O radioisotopes has been the irradiation of O
14
N(d,n)15O reaction to produce [15O]O2[96]. The lower content of oxygen in the target,
compared with the air-lled target used by Dyson etal.[92], resulted in the formation of
fewer impurities. Primarily [
N
O. Beam intensity clearly determined the selectivity of irradiation, producing 96.7% or
2
99.3% pure [
15
O]O2, the rest being [15O]N2O, at 5 or 50 μA beam, respectively.
With the development and widespread distribution of proton-only cyclotron accelerators, alternative methods for the production of [
explored by exploiting the
The use of [
15
O]O2 is not limited to oxygen biodistribution studies; [15O]O2 has also
been used as a radioactive precursor for the synthesis of [
CO[100, 101], and [
15
O]butanol[102–105].
15O]CO2 and [15O]CO
There are two main strategies to produce [15O]CO2: (i) in-target production of [15O]
CO
, which entails the irradiation of N2 gas mixtures containing 0.25–5% of CO2 with
2
Handbook of Radiopharmaceuticals
(0.1–4% of O2) mixtures with deuterons via the
2/N2
15
O]O2 was formed in the presence of trace amounts of [15O]
15
O]O2 using proton irradiation have been
16
O(p,pn)15O and 15N(p,n)15O reactions[97].
15
O]CO2[98], [15O]H2O[99], [15O]
deuterons[95]; and (ii) post-irradiation treatment of [15O]O2 with activated charcoal at
600 °C[98]. The choice of the methodology will depend mainly on the type of cyclotron
available. However, one might consider dierent limitations of the two strategies. The
post-irradiation treatment involves an additional step, diminishing the yield of production due to the fast radioactive decay of
instigates the
12
C(d,n)13N nuclear reaction, producing [13N]N2, which is sometimes impos-
sible to remove. Fine-tuning of the reaction conditions by adding low amounts of CO
(0.25%) in the N
gas target and increasing the strength of irradiation from 5 to 40 μA
2
resulted in 98% and 99.5% purity, respectively, but the problem of [
15
O. On the other hand, in-target production
13
N]N2 removal
2
remained[95]. As an alternative for the two previously mentioned approaches, a method
based on the metal-oxide-catalyzed isotopic exchange between [
15
O]O2 and CO2 has been
described[106].
Unlike that of [
amount of oxygen. The rst report on the production of [
15
O]CO2, the production of [15O]CO requires careful control of the
15
O]CO described the irradiation of oxygen-free nitrogen in a recirculating target system with an active carbon tube
heated to 900 °C[96]. While the major product observed was indeed [
15
O]CO, the product
was most likely predominantly a result of radiolysis-driven exchange reactions between
15
[
O]O2 and CO in the target. Attempts to optimize in-target conversion involved an introduction of a source of hot carbon within the target volume[107] and post-irradiation
modication of [
the O
carrier in the target is crucial for reducing the nal content of non-radiolabeled
2
CO. This is especially important when [
15
O]O2 with carbon at 900–950 °C[100, 101]. In both cases, the control of
15
O]CO is considered for biological applications
because of its potential toxicity.
15O]H2O
[15O]Water is by far the most used 15O-labeled radiotracer in biological applications. The
nontoxic nature of water and its large abundance in biological systems are exploited in
preclinical and clinical studies to measure blood ow throughout the living organism.
Similarly to
ation with deuterons (
The rst attempts to produce [
lyzed reactions of [
ication uses an in-ow system, in which [
hot cell, where it is mixed with H
to produce [
in biological studies[99]. Other early reports describe the isotopic exchange of [
with water[109] and the irradiation of 5% H
turn predominantly produce [
More recently, the
from 5% H
passed through a cold trap at −40 °C to capture [
unreacted [
with an inert gas, after which the activity is transferred to the radiochemistry lab.
15
O-labeled species described earlier, [15O]H2O can also be produced by irradi-
14
N(d,n)15O) or protons (16O(p,pn)15O).
15
O]H2O were based on palladium- or platinum-cata-
15
O]O2 with H2 at elevated temperatures[95, 101, 108]. The latest mod-
15
O]O2 is rst produced and transferred to the
and circulated through a palladium catalyst-lled oven
15
O]H2O. The product is trapped in a saline solution and is then ready for use
15
N(p,n)15O nuclear reaction for the in-target production of [15O]H2O
in [15N]N2 has been exploited[97]. In this procedure, the irradiated mixture is
2
15
N]N2 gas. For the extraction of [15O]H2O, the cold trap is heated and ushed
2
15
O]H2O[110 –112].
15
O]CO2
in an N2 mixture with deuterons, which in
2
15
O]H2O, followed by the recovery of the
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals
15O]O
(CH
15
O
THF
OH
3
Like [15O]N2O, [15O]O3 has mainly been described as an impurity produced during the production of
benet of [
15
O-labeled species in several 15O-production systems[113]. The potential
15
O]O3 in the investigation of environmental exposure to ozone has encouraged the development of a heterogeneous target-based method that produces highspecic-activity [
15
[
O]O3 in the reaction between a matrix of silica micro-bers irradiated with high energy
(22–27 MeV) protons, and a low concentration of oxygen (0.5% O
15
O]ozone[114]. In this study, the authors describe the production of
) in Ne. The product is
2
nally puried by cryopurication.
Most of the oxygen-15 radiochemistry involves in-target production of 15O-labeled
species or post-irradiation treatment of primary in-target produced products. As mentioned earlier, its short half-life limits
the involvement of the radionuclide in radiochemical conversions and its incorporation
into organic molecules, to produce highly specic and high-yielding products, extremely
dicult. Nevertheless, a few attempts of such reactions have been described in the
literature.
6.2.3.1 Synthesis of [15O]Butanol
The reaction of [15O]O2 with tri-n-butylborane in THF to synthesize [15O]butanol was rst
described by Kabalka etal.[105] (Scheme6.10). Further improvements involved the use
of solid-support-immobilized tri-n-butylborane on alumina Sep-Pak cartridges, which
enabled the automation of multi-dose preparation systems[103, 104, 115].
15
O to extremely fast modications. This makes
3CH2CH2CH2)3
B
Scheme 6.10 Synthesis of 15O-labeled butanol.
6.2.3.2 Synthesis of [15O]H2O
Another successful example of the use of solid-support synthesis in radiochemical
reactions is the conversion of [
ously reported redox-reaction-based preparation of [
of 2-ethylantrahydraquinol with [
droquinone and consequently [
conditioned with a solution of 2-ethylantrahydraquinol, the reaction can be performed by
simply passing [
a saline solution.
Handbook of Radiopharmaceuticals
15
O]O2 through the cartridge and nally eluting the [15O]H2O2 product with
2
15
O]O2 into [15O]H2O2[116]. The method is based on a previ-
15
O]H2O2 (Scheme6.11). When a C-18 Sep-Pak cartridge is
CH3CH2CH2CH
2
15
O]O2, resulting in the formation of 2-ethylanthrahy-
15
2
18
O]H2O2 and involves autoxidation
OH
15
O
2-Eth
2-Ethylanthrahydroquinone
HO
OH
O]H
2
O]H2O
16O15
OH)
15
H
2
O
2
2
O
Scheme
6.11
nthesis
Sy
15
of
O-labeled
hydrogen peroxide.
OH
O
ylanthrahydroquinol
6.2.3.3 Synthesis of [15O]DG
A few years ago, the single-step synthesis of 6-[15O]-2-deoxy-d -glucose ([15O]DG) from
2,6-dideoxy-6-iodolenges related to the short half-life of oxygen-15, a specially adapted hot-air-jacketed
reaction vessel, equipped with a sintered glass bottom through which
introduced as ne bubbles, was implemented. Additionally, a non-protected iodinated
sugar precursor was used to reduce the reaction time from several hours to a few minutes
and make the reaction possible even under mild conditions. The iodo-activated precursor
was rst reacted with cold O
(AIBN), and tributyltin hydride, which initialized the formation of DG, hydroperoxide,
and 2,6-dideoxy-D-glucose, before introducing radioactive [
The addition of triphenylphosphine in triuorotoulene instantaneously converted any
remaining hydroperoxide to obtain [
Sep-Pak cartridges to obtain the nal solution containing [
chemical purity, while [
and short production (only eight minutes from the start of the bombardment to the injection) allowed the authors to demonstrate the applicability of [
new strategy expanded the toolbox of
metabolite studies with [
duction of a variety of
d-glucose was reported (Scheme6.12)[117]. To overcome the chal-
15
O-oxygen gas was
in the presence of peruorodecaline, azobisisobutyronitrile
2
15
O]O2 gas (Scheme6.12).
15
O]DG. The crude was puried through a series of
15
O]DG in around 70% radio-
15
O]water accounted for the rest of the radioactivity. An ecient
15
O]DG in PET imaging. The
15
O-radiochemistry and created a possibility for
15
O]DG and eventually the expansion of this method to the pro-
15
O-labeled alcohols.
OH
1.
cat. AIBN/
2.
15
[
PhCF
PPh
O]O
,
3
2/N2
n-Bu
SnH
3
10F18
o
C
/2-C
H
OH,
4
9
/C
3
80
I
HO
O
HO
HO
15
[
15
OH
O]DG
15
[
O
O
OH
+
15O16
OH
HO
+
HO
16
[
Bu
PPh
SnH
3
O
+
OH
and
situ)
(in
3
HO
H
HO
(
Scheme 6.12 Syn-
thesis of 6-[
2-deoxy--glucose.
O
15
O]-
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals
15
The only 15O-labeled tracer currently included in the European Pharmacopeia is [15O]H2O.
Tests to be performed during the quality control of the injectable solution include the
determination of (i) the pH, which should be between 5.5 and 8.5; (ii) the radionuclidic
purity, with a determined half-life in the range 1.9–2.2 minutes and <1% of gammaemitting impurities; (iii) the chemical purity, with a limit for main impurities, ammonia,
and nitrate of 10 mg l
−1
each; and (iv) the radiochemical purity, which should be >99%, as
determined by liquid chromatography. For this assay, the injected radioactivity is circulated through the radioactivity detector before and after being eluted through a 250-mm
aminopropylsilylated silica column with a phosphate buer (pH=3) at 1 ml min
−1
. The
area under the second radioactive peak (i.e. the amount of radioactivity exiting from
the column) should be at least 99% of the amount of radioactivity before it entered the
column. Additionally, the solution should comply with sterility criteria and bacterial endotoxin limits like any other PET radiopharmaceutical.
In biomedical research, the success of administration is as important as the quality
of the radiotracer; hence, research focuses on the development of reliable and safe
administration methods. The choice of administration method will depend on the
aggregate state of the radiotracer.
For gaseous
is performed continuously[118–121] or as a bolus[119] via a medically accepted breathing
system. When the activity is administered continuously, a steady-state delivery system
capable of regulating the target beam current, target gas ow, and air dilution ow to
maintain a constant delivery of radiotracer is used. The radioactivity can be administered
through a facemask, nasal tubes, or a ventilator.
In bolus administration of gaseous products, a exible vessel is lled with a dose of
radiotracer and administered via a mouthpiece and a one-way non-rebreathing valve or
a ventilator. In this case, the activity is prepared before inhalation and has a much higher
concentration than the one used in the steady-state method.
In contrast, [
steady-state infusion. The rst biological studies with [
aration of doses[95, 122, 123], posing a higher exposure risk for the personnel involved
in the experiments. Together with the rise in functional brain PET studies that demanded
multiple-dose deliveries per subject, this encouraged the development of automated systems for [
15
O-labeled tracers, inhalation of a regulated mixture of radiotracer in air
15
O]water is injected intravenously as a bolus solution in saline or as a
15
O]H2O required the manual prep-
15
O]H2O delivery[124–126], which made the experiments safer and more reliable.
Only a few groups in the world are working on the development of new strategies for the
preparation of
Handbook of Radiopharmaceuticals
13
N-labeled compounds, and probably nobody dedicates eorts to the