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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5624_Библиотеки_им_академика_М_И_Перельмана.pdf
IN
COLLIMATOR
TER
WATER
HELIUM
WATER
OUT
OUT
OUT
WASTE
BEAM
WA
IN
WATER
HELIUM
TARGET
IN/OUT
IN
Figure 6.3 Typical target design for the production of [13N]NH3-
tion with protons. Source: Based on the target Nirta® -N13 provided by IBA.
N]NO
As mentioned earlier, [13N]NO
−
is formed as the predominant species by proton irradia-
3
N]NO
N]N2O
2
tion of water in the absence of a scavenger, after a sucient dose has been imposed on
the target[24]. Usually, [
13
−
N]NO
and [13N]NH3 are also found in the irradiated solution,
2
eventually together with the radionuclides produced in the target chamber or target
window, e.g.
48
V if the target window is made of titanium. All cationic species can be eciently removed by passing them through a small column containing cation-exchange
resin, while [
13
decompose nitrous acid and expel it as NO
For the production of [
−
N]NO
can be eliminated by acidifying it with 10% H2SO4 and boiling it to
2
[34].
13
N]NO
−
, the most ecient route is the reduction of [13N]NO
2
x
−
3
produced by proton irradiation of water. The rsts methods reported in the literature[11]
exploited the reducing capacity of a freshly prepared cadmium-copper amalgam[35],
providing a maximal ratio of [
13
N]NO
−
to [13N]NO
2
−
of 6 with 95% of the activity recovered
3
from the column. Later, the reduction eciency could be improved by using a copperplated cadmium column, prepared by sequential treatment of cadmium with 2N HCl, 0.3N
HNO
, and 2N HCl, each lasting for 20 minutes, and with intercalating washing steps with
3
distilled water until the pH is neutral, followed by treatment with 0.08 M CuSO
and replacement of the solvent with 0.15 M NH
4
Cl before packing the column[36]. Under
solution
4
these conditions, radiochemical purity greater than 97% could be obtained in the eluent
of the cadmium column. This value could be increased to 99.2% by adding a subsequent
step consisting of rotatory evaporation at pH=11.0 to remove [
13
N]NH3. The reduction
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 115
with the use of copper-plated columns or variants of these has been successfully applied
(b
(c
N
13
2-Phenyl(13N)acetamide
by dierent research groups[37–45]. Recently, an enzymatic method for the ecient,
metal-free reduction of [
The production of [
NO
in sulfuric acid and in the presence of an excess of NH4NO3[47]. In both cases, the
3
formation of [
the presence of [
of (NH
4
)SO4.
13
N]N2O was achieved, although 30–40% of the radioactivity was due to
13
13
13
N]N2O has been achieved by pyrolysis of [13N]NH4NO3 or NH4[13N]
N]N2. This value could be decreased to c. 2% by addition of an excess
N]NO
−
to [13N]NO
3
−
has been reported[46] (see Section6.1.11).
2
6.1.5
Reactions typically used in classical organic chemistry have been applied to the prepa-
ration of
intermediates for the preparation of amines. One of the approaches for the preparation
of
to form the corresponding imine, which can then be reduced to the corresponding primary amine. This method was applied, for example, in the preparation of
amphetamine (Scheme6.1a) by reaction of [
13
N-labeled amines and amides, the latter usually not isolated and used just as
13
N-labeled amines was based on the reaction of [13N]NH3 with ketones or aldehydes
13
N-labeled
13
N]NH3 with phenylacetone in the presence
X
(a)
13
O
13
[
NH3]
+
ClO
13
[
N]NH3 / NH
3
NaOH
H
)
Cl
)
O
2
13
[
N]NH
O
Na2CO
Et2O
3
3
Al
HgCl
2
EtOH
13
NH
O
2
NaOBr
13
NH
2
O
LiAlH
4
NH
2
(d)
HO
13
NH
2
(e)
13
NH
2
OH
N
N
O
OH
N
N
[13N]NH
NaOH
X = Cl, F
3
BH
3
[13N]NH
NaOCl
HO
, THF
3
OH
N
N
O
OH
B
3
13
NH
2
Scheme 6.1 1313N]PEA
13
β
13
N-labeled alkylamines by amination of organoboranes (example shown for 1-[13
N]
NH
2
N
116 Handbook of Radiopharmaceuticals
of carrier ammonia and aluminum/mercuric chloride as the reducing agent[48]. Overall
radiochemical yields around 3.5% could be obtained; however, the molar activity of the
nal tracer was low (c. 300 MBq mmol
−1
) due to the presence of the carrier, which was
required to prevent the formation of the secondary amine, because under no-carrier-
added conditions the primary
13
N-labeled amine competes with [13N]NH3 to react with the
carbonyl compound.
Alternatively, amines can also be produced by Hofmann rearrangement. For example,
13
N-labeled β-phenethylamine was prepared by the reaction of phenylpropionyl chloride
with an aqueous solution containing [
to yield, initially, [
13
N]phenylpropionamide, which in the presence of sodium hypobromide
13
N]NH3, carrier ammonia, and sodium hydroxide[49]
underwent rearrangement to produce the corresponding amine (Scheme6.1b). When
the reaction was carried out in the absence of the carrier ammonia, yields dramatically
decreased from 50% to 5%, since the appropriate molar ratio of sodium hypobromite/
amide, which is essential for obtaining good yields, is dicult to achieve under no-carrieradded conditions. High specic activity values under no-carrier-added conditions can be
obtained by using an alternative strategy based on the reduction of the corresponding
13
N-labeled amide (Scheme6.1c). In the rst step, phenylacetyl chloride was reacted with
13
[
N]NH3 to yield the corresponding amide, which was reduced in the presence of lithium
aluminum hydride to yield the corresponding amine with a good radiochemical yield (60–
70%) even without the addition of a carrier[50]. The main disadvantage of this method is
that the reaction needs to be conducted in LiAlH
-compatible solvents and under an inert
4
atmosphere.
The third reaction that has been applied to the preparation of
13
N-labeled amines is
aminolysis, by replacement of a halogen atom by ammonia. This method was applied to
the synthesis of
13
N-labeled adenosine starting from two dierent substrates: 6-chloro9-β-D-ribofuranosylpurine and 6-uoro-9-β-D-ribofuranosylpurine (Scheme6.1d). The
reaction resulted in good yields in the presence of carrier ammonia (close to 25% for the
uoro derivative under optimal conditions), while the yields were slightly lower (around
10%) in no-carrier-added conditions. In the latter, the addition of NaOH was required to
maintain a basic pH, while the addition of a base was not necessary under carried-added
conditions, where the concentration of ammonia was sucient to keep appropriate
pH values.
Finally, the preparation of
tion of organoboranes[51]. Experimentally, [
13
N-labeled alkylamines has also been achieved by amina-
13
N]NH3, produced by proton irradiation followed by reduction with Devarda’s alloy, was distilled into a solution of tetrahydrofuran
(THF) containing the corresponding tri-n-alkylborane, which was prepared by reaction of
the corresponding terminal alkene with borane/THF solution (Scheme6.1e). This was followed by the addition of carrier ammonia and sodium hypochlorite. The formation of the
amine, which presumably proceeds via the in situ formation of chloramine, oered good
yields (40–60%) in an overall time of 25–30 minutes, and the mild reaction conditions
allowed the extrapolation of the method to functionalized amines such as γ-aminobutyric
acid[52]. This method was later optimized by using polymeric borane reagents, which
facilitated the purication of the amines[53, 54].
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 117
6.1.6
The synthesis of [13N]nitrosothiols was rst reported in 1995[44]. In this pioneering
13
study, [
resulting
−
N]NO
was reduced to [13N]NO
3
13
N-labeled nitrite was trapped in an anion exchange column, which was eluted
−
using an activated cadmium column. The
2
with a solution of dierent thiols in acidic media (citric acid) to yield the corresponding
13
N-labeled thiols in close to quantitative amounts and ready for injection after ltration
(in an overall production time of ve minutes). The methodology was further extended,
following a similar approach, to the preparation of S-nitrosoglutathione[55], although
in this case the nitrosation reaction was conducted in a vial, and later to the preparation
of a small library of both hydrophilic and hydrophobic
13
N-labeled nitrosothiols in a fully
automated process that included reactions in solid phase and purication using highperformance liquid chromatography (HPLC)[41]. Decay-corrected radiochemical yields
in the range 33.8–60.6% were reported, with molar activity values above 5 GBq μmol
and overall preparation times <13 minutes. The preparation of [
13
N]nitrosothiols was later
−1
assayed under microuidic conditions[37]. Radiochemical purities (so-called radiochem-
ical conversion in the original publication, as they were determined from chromatographic
proles) clearly exceeding those obtained in solid-phase reactions could be achieved
in three out of ve cases (compounds 2–4; see Table6.2), while equivalent results were
obtained for compounds 1 and 5.
6.1.7
The synthesis of 13N-labeled nitrosamines was also rst reported in 1995[44], following
a parallel strategy to that applied to the synthesis of
ever, in this case, a solution of a secondary amine was used to elute the resin-trapped
13
[
−
N]NO
at pH 2–4.5. The authors reported decay-corrected radiochemical yields
2
>30% and observed variations in the reaction rate depending on the secondary amine,
although individual values for specic compounds were not provided. In an attempt to
extend the methodology to the preparation of other
Vallejo etal. reproduced the experimental conditions to perform the
reaction with dierent secondary amines, but the formation of the labeled nitrosamines could not be observed[40]. The authors postulated that the lack of reactivity
was due to the low nucleophilicity of the secondary amines, especially under acidic conditions. Good radiochemical yields could be achieved by the previous activation using
Ph
P/Br2 to form in situ bromotriphenylphosphonium bromide, which slowly reacts with
3
the secondary amine to yield triphenyl(amin-1-yl)phosphonium bromide, which can then
undergo the nitrosation reaction (see Scheme6.2). With this methodology, four dier-
13
ent
N-labeled nitrosamines were prepared with decay-corrected radiochemical yields
in the range 34–40.7% and overall production times <10 minutes, including purication
by HPLC[40].
13
N-labeled nitrosothiols. How-
13
N-labeled nitrosamines, Gómez-
13
N-nitrosation
118 Handbook of Radiopharmaceuticals
Table 6.2 Radiochemical purity for the preparation of different 13N-labeled nitrosothiols by solid-phase-
HBr
Ph
3
2
3
2
Entry
13
N-labeled nitrosothiol
Radiochemical purity
(solid support)
a
Radiochemical purity
(microuidics)
1 72 .5 ± 3. 9 53. 6 ± 8. 8
2
3
4
5
60 .3 ± 5. 5 99. 5 ± 0. 2
74 .5 ± 2.1 98 .4 ± 1.1
48 .7 ± 6. 3 99. 6 ± 0. 3
66 .2 ± 5. 8 5 7.3 ± 6. 5
b
a Source: Obtained from Gómez-Vallejo, V., Kato, K., Oliden, I. et al. [41].
b Source: Obtained from Gaja, V., Gómez-Vallejo, V., Cuadrado-Tejedor, M. et al. [37].
Scheme 6.2 Syn-
13
N]
13
N]
PBr
3
-CH2-(CH
-CH
(CH
3
(CH
+
2
R
1
-(CH
2
-CH-, (CH
)
2
)-CH
+
R
1
NH
R
2
R
,
2
−
-CH
)
2
2
3
−
-CH
2)2
2
-CH-
)
2
3
(CH
)-CH
−
-,
P
R
N
1
R
2
[13N]NO
(solid
13
NO
R
N
1
R
2
+
–
2
support)
thesis of N-[
nitrosamines
by following
the combined
approach (resinsupported [
NO
3
2
Br
2
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 119
6.1.8
R
–
2
Aromatic azo compounds can be readily synthesized by azo coupling involving an electrophilic substitution reaction of an aryl ring, which is usually substituted with electrondonating groups on an aryl diazonium cation. The latter can be easily prepared by the
reaction of an aromatic amine with sodium nitrite in acidic conditions. This ecient reaction has been employed in the preparation of
−
NO
produced by proton irradiation of puried water was reduced into [13N]NO
3
activated cadmium. The resulting [
the corresponding
13
N-labeled diazonium salts, which were nally coupled with aromatic
amines and phenols to yield
13
N]NO
13
N-labeled diazonium salts (Scheme6.3).
13
N-labeled azo compounds[39]. First, [13N]
−
using
−
was reacted with aromatic amines to generate
2
2
Scheme 6.3 Syn-
thesis of
13
N-labeled
azo compounds.
[13N]NO
NH
H
3
, OH, NH
3)2
2
2
1
=
R
H,
SO
1
=
R
N(CH
2
2
+
H
1
1
+
NR
13
N R
NR
13
N
R
2
In the rst study that reported this synthesis method[39], the formation of the
13
N-labeled diazonium salt was carried out in an anionic exchange resin-lled cartridge,
while the subsequent reaction for the formation of the labeled azo compound was carried out in a vial. Chromatographic purities (so-called radiochemical conversion, or RCC,
in the original publication) in the range 40.0–58.3%, overall non-decay-corrected radiochemical yields in the range 7.7–19.1%, and molar activity values close to 5 GBq μmol
−1
were obtained in an overall synthesis time of 13–16 minutes, including purication.
The reaction was later assayed under microuidic conditions[37], resulting in slightly
improved chromatographic purities (49.3–93.9%), although in this case, radiochemical
yields after purication and specic activity values were not reported.
Selected
13
N-labeled azo compounds were evaluated as β-amyloid markers in a mouse
model of Alzheimer’s disease[38]. One of the compounds assayed showed increased
binding potential values in the cortex of Tg2576 animals when compared with agematched littermates.
120 Handbook of Radiopharmaceuticals
Amino acids can be readily synthesized using biocatalysis (see the next section). However, attempts to radiolabel amino acids at the R group have been carried out. These
methods are time-consuming and oer poor radiochemical yields, so they have barely
O
O
OH
2
been explored. In one of the few examples found in the literature, the synthesis of
13
L-[
N]aspargine was performed by reaction of L-α-N -Boc-aspartate with [13N]NH3, followed by hydrolysis (Scheme6.4)[56]. First, the β-carboxylic group of the protected
L-aspartic acid was activated with N-hydroxysuccinimide to yield α-N-t-Boc-α- t- Bu-β-Nhydroxysuccinimidyl aspartic ester, which was reuxed for 10 minutes with [
13
N]NH3. After
one-minute hydrolysis with 1 M HCl solution, the labeled aspargine was puried by cation
exchange. Unfortunately, no yields were reported in this study. Another example is the
preparation of a γ-amino acid, reported by Kabalka etal., although a completely dierent
approach was used in this case (see Section6.1.5)[52].
Scheme 6.4
Synthesis of L-[
aspargine by a
synthetic chemistry method.
13
N]
HN
13
NH
2
Hydrolysis
O
13
NH
O
O
O
O
O
NH
2
O
O
N
O
HN
O
O
O
[13N]NH
13
L-[
N]aspargine
O
3
Biocatalysis, although surprisingly underutilized in radiochemistry, constitutes a pow-
erful tool for organic chemistry. The excellence of enzymes to catalyze chemical reactions
lies in their exquisite chemical selectivity and high turnover numbers. Due to the tightly
regulated cell metabolism, enzymes have evolved to work under rather low substrate
concentrations with high eciency. This substrate-limiting situation resembles the conditions in radiochemical reactions, where the concentration of the radioactive precursors is
extremely low.
The enzymatic synthesis of amino acids labeled with nitrogen-13 is a paradigmatic
example of the success of biocatalysis in radiochemistry. A battery of
acids have been enzymatically produced using ammonia ([
cursor. Up to now, [
13
N]NH3 has been enzymatically incorporated into amino acids through
13
N]NH3) as a radioactive pre-
three main biosynthetic schemes (Scheme6.5): (i) using amino acid dehydrogenases that
catalyze the reductive amination of α-ketoacids using nicotinamide adenine dinucleotide
(NADH) as redox cofactor and [
synthetases that catalyze the insertion of [
13
N]NH3 as the amine source[57–63]; (ii) using amino acid
13
N]NH3 into the ω-carboxylic group of acidico-
sphate (ATP)[56, 58, 64]; and (iii) using a bi-enzymatic system integrated with an amino
13
N-labeled amino
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals 121
O
O
OH
(c)
2
Scheme 6.5 Main
enzymatic routes
to incorporate [
NH
into amino
3
13
N]
amino acid dehy-
amino acid syn-
a bi-enzymatic
system formed
by an amino acid
dehydrogenase
and a
transaminase.
(a)
(b)
HO
HO
R
O
NH
O
2
O
O
O
OH
O
O
R
OH
13
NH
L-glutamate dehydrogenase
OH
L-glutamine synthetase
OH
L-glutamate dehydrogenase
[13N]NH
Glutamate-pyruvate
aminotransferase
NADPH
13
N]NH
[
13
N]NH
[
NADPH
R
OH
13
NH
2
13
HO
2
O
O
N
NH
2
O
O
OH
13
NH
2
3
3
3
H
O
R
OH
O
acid dehydrogenase (usually glutamate dehydrogenase) that catalyzes the reductive
amination of α-ketoglutarate to produce L-[
13
N]glutamate, which is concurrently used by
a transaminase that transfers the radiolabeled amine group to the target α-ketoacid to
form the desired L-[
13
N]-amino acid[58, 64].
These biosynthetic strategies have often been performed with soluble enzymes, which
may turn into a potential source of pyrogenic proteins; the presence of such contaminants consequently requires a time-consuming purication process[65]. This problem
is smartly solved by immobilizing the enzymes on solid carriers through covalent and
irreversible bonds that avoid protein lixiviation. Several immobilized enzymes, including
multi-enzyme systems, have been successfully applied to the heterogeneous synthesis
13
of
N-labeled glutamine, glutamate, asparagine, citrulline, aspartate, alanine, serine,
and glycine[57–59, 62–64, 66]. These amino acids have been obtained with dierent
radiochemical yields, ranging from 10% for L-[
thetase[67] to 70% for L-[
tamate dehydrogenase is very versatile since it is able to synthesize a plethora of L-[
13
N]glutamate using a glutamate dehydrogenase[59]. The glu-
13
N]asparagine using an asparagine syn-
13
N]
amino acids beyond glutamate[57, 66]. Some of these enzymatically synthesized amino
acids were tested for in vivo studies (both in animals and in humans) to assess their biodistribution and metabolism[59, 66]. In 1983, Lambrecht etal.[68] synthesized L-[
13
N]
glutamate through a semi-automatic approach. To this end, the authors used a glutamate
dehydrogenase immobilized on porous glass beads for a short time (10 minutes). As a
result, this system yielded the labeled amino acid with high purity and high molar activity
(1.11 GBq μmol
13
β-[
N]aminobutyric acid ([13N]GABA)[69]. Finally, the system was fully automatized to
yield pure L-[
−1
). Later on, the same group expanded this methodology to manufacture
13
N]glutamate[61].
122 Handbook of Radiopharmaceuticals
In the past ve years, a fruitful collaboration between biotechnologists and radiochemists has materialized for the construction of more ecient biocatalytic systems
to synthesize L-[
13
N]-amino acids in one pot through only one enzymatic step. Herein,
L-alanine dehydrogenase from Bacillus subtilis catalyzed the non-carrier-added syn-
thesis of L-[
α-ketoacids and using NADH as the redox cofactor and [
13
N]alanine, [13N]glycine, and L-[13N]serine, starting from their corresponding
13
N]NH3 as the amine source[60].
This one-pot methodology shows superior performance compared with other enzymatic
methods previously published[64], since it enables the preparation of up to three dierent enantiomerically pure L-[
13
N]amino acids with chromatographic yields >98% in only
15 minutes. This setup enabled the manufacturing of sucient amounts of dierent
radiolabeled amino acids to perform in vivo studies in small rodents. Following this study,
L-amino acid dehydrogenase was immobilized on dierent carriers and through dierent chemistries to search for the optimal immobilization protocol that maximizes both
activity and stability of the nal heterogeneous biocatalysts. These immobilized biocatalysts eciently operated ve separate batches with chromatographic yields of L-[
13
N]
alanine >95%.
One of the limitations of this system is the necessity of an exogenous cofactor, which
is usually added in large excess in the reaction mixture. In situ recycling of the cofactor
is therefore mandatory to enhance the purity of the radiotracers and the eciency of
the radiochemical reaction. With a formate dehydrogenase (FDH) from Candida boidinii
added to the reaction tube, NADH was in situ recycled, allowing a 50-fold decrease in the
cofactor concentration without compromising radiochemical yields.
Besides amino acids, [13N]NH3 has been incorporated into other biological molecules
by means of carbamyl phosphate synthase and carbamoyl transferases. Following this
scheme, Gelbard etal. co-immobilized carbamyl phosphate synthetase with either aspar-
−
N]NO
, which, as men-
2
13
N]carbamyl phos-
tate transcarbamylase or ornithine transcarbamylase to synthesize [
phate, L-[ω-
sequence, the carbamyl phosphate synthetase uses [
13
N]citrulline, and [carbamyl-13N]-l-aspartate[58]. In this multi-enzymatic
13
N]NH3 as the ammonia source,
carbamic acid as substrate, and ATP as the cofactor to synthesize radiolabeled carbamyl
phosphate, whose carbamyl group is concurrently transferred to either ornithine or the
aspartate using the corresponding transcarbamylase to achieve the corresponding car-
bamylated amino acid. These amino acid derivatives were obtained with moderate radiochemical yields of around 15%.
Biocatalysis has also been applied to the preparation of [
13
tioned in other sections, has been employed in the preparation of nitrosothiols[41, 44,
55], nitrosamines[40, 44], azo derivatives[38, 39], triazoles[70], and tetrazoles[43] (for
the last two, see the later discussion). Typically, [
of cyclotron-generated [
13
−
N]NO
. This reduction can easily be performed by chemical
3
13
−
N]NO
is produced from the reduction
2
methods using cadmium-copper activated columns, albeit with potential toxicity issues.
To increase the safety of the process, da Silva etal. have recently reported an innovative
Chapter 6: Synthesis of 13N- and 15O-Labeled Radiopharmaceuticals
methodology to quantitatively reduce [13N]NO
−
to [13N]NO
3
−
under innocuous conditions
2
by using a nitrate reductase immobilized on agarose activated with diethyl-aminoethyl
groups[46]. With this heterogeneous biocatalyst, quantitative reduction of [
13
N]NO
−
is
3
achieved in four minutes, and the immobilized enzyme can be reused up to seven reaction
cycles without activity loss. The potential of this heterogeneous biocatalyst was conrmed by applying enzymatically prepared [
13
−
N]NO
to the synthesis of S-[13N]nitrosoglu-
2
tathione in a two-step/one-pot process.
6.1.12
Nanoparticles (NPs) have recently emerged as key tools in a wide range of applications. This has raised serious concerns about their potential toxicological eects after
administration to or incorporation into living organisms. Incorporation of a positron
emitter into the NP structure followed by in vivo imaging has been postulated as a suit-
able imaging tool for the evaluation of the biodistribution pattern and biological fate of
dierent types of NPs. In a pioneering study, Pérez-Campaña etal. reported the radiolabeling of Al
nanoparticles by proton irradiation to induce in situ the 16O(p,α)13N nuclear
2O3
reaction. Despite the short half-life of the radionuclide, this approach provided valuable
information about the biodistribution of NPs with dierent sizes after intravenous
administration in rodents[71].
Nitrogen-13 has sporadically been used for the preparation of radiotracers that do not
fall into any of the categories mentioned previously. One of the most interesting examples is the preparation of [
K
PtI4 was produced by reaction of K2PtCl4 with potassium iodide. This compound was
2
reacted with aqueous [
which, after the addition of AgNO
NH
. After purication by HPLC, the radiochemical yield and molar activity were
3)2Cl2
27.1% and 11 GBq μmol
modestly to 31.8% by directly sparging [
increase (80%) was obtained by using a solid-support synthesis method[74].
13
N-labeled carbamates and ureas have also been prepared using [13N]NH3 as the
labeling reagent. [
13
[
N]NH3[75]. After purication in a solid-phase extraction cartridge, decay-corrected
13
radiochemical yields of 56% could be achieved in an overall time of 10 minutes. In this process, carrier urea was added before the purication, resulting in a very low molar activity
of the nal tracer (c. 2.6 × 10
urea and dierent [
years later, using as the labeling reagent anhydrous [
with a primary amine, a secondary amine, or an alcohol previously treated with triphos-
gene; this reaction step yields the intermediate isocyanate (Scheme6.6a), carbamoyl
13
N]cisplatin[72], which was synthesized in three steps. First,
13
N]NH3 under carrier-added conditions to form cis-Pt([13N]NH3)2I2,
, ltration, and collection in NaCl, yielded cis-Pt([13N]
3
−1
(EOB), respectively. The radiochemical yield could be improved
13
N]NH3 into K2PtI4[73]; a more substantial
N]urea could be synthesized by reaction of ammonium cyanate with
−5
GBq μmol−1). The preparation of non-carrier-added [13N]
13
N]carbamate analogs using one-pot synthesis was reported many
13
N]NH3[76], which was reacted
124 Handbook of Radiopharmaceuticals