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molecules, including incorporation into biomolecules, transport across membranes, and
binding to receptors. From a patient-scanning perspective, the short half-life allows multiple PET studies to be performed in the same subject in one day, and also reduces the
radiation dose to the subject.
Substituting
12/13
C for 11C gives a structurally and biologically indistinguishable radiolabelled isotopologue (albeit for a negligible kinetic isotope eect), well suited for
studying in vivo properties of endogenous molecules. Carbon-11 is available in high
molar activitiy, enabling low masses of unlabelled compound to be administered, often
below pharmacologically active levels, resulting in minimal perturbation of the biological
system under investigation and minimizing the likelihood of any toxic eects.
The presence of multiple carbon atoms in most bioactive molecules oers a choice
of sites for radiolabelling with carbon-11. This is advantageous in the context of both
the radiochemistry used to incorporate the label and facilitates studies of in vivo
metabolism and biochemistry. For example, WAY100365, a 5-HT
antagonist, has
1
been radiolabelled with carbon-11 at the methoxy position and the carbonyl position.
[Methylbarrier and has an anity for the 5-HT
images. In contrast, the radiolabelled metabolites of [carbonyl-
11
C]WAY100635 is metabolized to a compound that crosses the blood-brain
receptor, confounding analysis of the resultant
1
11
C]WAY100635 do not
cross the blood-brain barrier, and this compound has been widely used to investigate
the serotonergic system[10]. Similarly, the rate of decarboxylation of
mine could be measured using
l-DOPA labelled with carbon-11 at dierent positions
l-DOPA to dopa-
(Figure7.1)[11, 12]. With the carbon-11 label in the methylene (β) position, decarboxylation gives [
However, decarboxylation of
11
C]dopamine, and radioactivity accumulates in the striatum (Figure7.1a).
l-[carbonyl-
11
C]DOPA gives unlabelled dopamine and
no accumulation of radioactivity in the striatum (Figure7.1b). Calculated inux rate
constants were used as a measure of the rate of decarboxylation of
l-DOPA. Similar
studies using dierential labelling to interrogate in vivo metabolism have also been
reported using [
11
C]pyruvate[12] and [11C]glutamate[13, 14].
PRECURSORS
7.2.1 Primary Precursors
The chemical composition of cyclotron-generated 11C is dictated by the choice of additive
gas within the [
dioxide ([
11
[
C]CO2 is the feedstock for the majority of 11C-labelling reactions, its susceptibility
to isotopic dilution from atmospheric CO
ucts (c. 50–500 GBq·μmol
(c. 500–2000 GBq·μmol
14
N]N2 target; trace amounts of O2 (0.05–1.0%) give rise to [11C]carbon
11
C]CO2), while H2 (5–10%) gives rise to [11C]methane ([11C]CH4)[15]. Although
is reected in the molar activity of prod-
−1
), which are usually lower than those obtained from [11C]CH4
−1
). A number of techniques may be adopted to minimize this, such
2
145
dopamine
(a)
(b)
Figure 7.1 Label
ling of
differential posi
tions allowed for
the determina
tion of the rate of
decarboxylation
to dopamine by
the accumulation
of [
C]dopamine
in the striatum.
Source: From
with permission of
John Wiley & Sons.
O
HO
HO
L-[β–11C]DOPA
HO
HO
β–11C]dopamine
[
HO
HO
L-[carbonyl–11C]DOPA
*
OH
NH
2
CO
2
*
NH
2
O
OH
*
NH
2
[
11C]CO
HO
NH
HO
2
as: (i) pre-conditioning the cyclotron target, (ii) ushing delivery lines with an inert gas
and preconditioning synthesis modules, (iii) maintaining leak-tightness throughout systems, and (iv) avoiding solution-phase reactions for further derivatisations or using highpurity, fresh reagents for these reactions. Radiochemical conversions of [
are also complicated by their delivery from the cyclotron at high dilution in an inert gas
stream, which may also contain trace amounts of hydrogen/nitrogen and nitrous oxide
impurities derived from the target gas mixture. Purication and preconcentration may
be achieved using a cryogenic[16, 17] or solid-phase[18, 19] trap-and-release process to
146 Handbook of Radiopharmaceuticals
2
11
C]CO2/[11C]CH4
capture [11C]CO2/[11C]CH4 from the gas stream and carry volatile impurities to exhaust.
*
R
2
2
**
3
11
[
C]CO2/[11C]CH4 can then be released as a more concentrated bolus by heating the trap
under a controlled ow of sweep gas.
7.2.2 Secondary Precursors
Primary 11C-labelling reagents may be converted into more reactive or synthetically
useful species to provide access to a broader range of functional groups. For example,
11
[
C]CH4 has limited scope for direct incorporation into biologically relevant molecules
but can be readily converted into the useful radiolabelling reagent [
11
([
C]CH3I). A summary of well-known 11C reagents that can be derived from [11C]CO2 and
11
[
C]CH4 is shown in Figure7.2, and their synthesis is described in the following sections.
C]Carbon Monoxide
Although [11C]CO can be produced directly from the cyclotron as a by-product of
11
[
C]CO2 formation, it is more commonly formed via gas-phase reduction of [11C]CO2 over
zinc or molybdenum at elevated temperature (Figure7.3a). Recently, solution-phase
(Figure7.3b) and electrochemical (Figure7.3c) methods to produce [
been reported.
Reduction of [
chemical yield (RCY)[20, 21]. This method has been reported to suer from declining RCY
over successive runs, necessitating regular replacement of the zinc[22], which in itself
may be problematic due to inconsistent conversion yields following replacement[23]. The
limited reproducibility is due to (i) zinc deactivation arising from reaction with oxygen
and/or nitrogen oxides derived from the target[24–26], (ii) adsorption of [
11
C]CO2 over zinc at 400 °C produces [11C]CO in near-quantitative radio-
11
C]methyl iodide
11
C]CO have also
11
C]CO/CO2 at
X
R
OH
11
C
O
11
CCl
4
O
Cl Cl
*
Figure 7.2
Common
secondary
reagents derived
O
R
OM
*
O
R
Cl
*
11
[
11
CH
C]CO
3
O
H H
OH
11
[
11
CHF
C]CH
11
CH
4
I
3
11
N N
CH
2
11
H
C
11
C
S
11
CH3OTf
11
CH
3
N
S
NO
from [
and [
2
C]CH4.
147
(a) Gas phase:
C]CO
C]CO
(b) Solution phase:
(c) Electr
C]CO
−
Figure 7.3
Methods for
reduction of
[
2 to [
850
400
o
C
o
C
o
485
C
,
2
11
[
11
[
C]CO
Mo,
or Zn,
or Zn-SiO
2
(i) LiEt
BH (ii) PPh3, (Cl3C)2CO
3
SiLi (ii) TBAF
2
Si-SiR3, TBAF
3
11
[
11
[
C]CO
or (i) RPh
or (i) R
2
ochemical:
+
1.8
2
, KCl
V
11
[
11
[
C]CO
2
Zn(cyclen)
the metal surface[25], and (iii) technical issues arising from the reduction temperature
being close to the melting point of zinc (420 °C)[27]. In 2017, Dahl etal. reported a modied method in which the zinc reductant is supported on fused silica particles, allowing for
a higher reduction temperature of 485 °C, achieving RCYs of 93% ± 3% over 20 runs[28].
Gas-phase reduction using molybdenum at 850 °C provides a reliable route to [
11
C]CO,
albeit with lower RCYs (~70 to 80% using molybdenum powder[23] or mesh[27]). Yields
are consistent throughout ~100 production cycles, which may in part be attributable to
the conversion temperature being signicantly below the melting point of molybdenum
(2623 °C). Furthermore, the molybdenum(IV) oxide formed by reaction of [
molybdenum is itself able to reduce [
11
C]CO2, which may improve the performance of the
11
C]CO2 with
converter[27].
Solution-phase techniques are an alternative means of generating [
11
C]CO without
the need for high-temperature ovens and associated apparatus. Roeda etal. report a
two-step process using lithium triethylborohydride and triphenylphosphine-hexachloroacetone to convert [
in near-quantitative yield[29]. In 2015, two groups published separate reports of [
11
C]CO2 to [11C]formyl chloride, which decomposes to give [11C]CO
11
C]
CO production through the use of lithiated silyl reagents[30, 31]. These reagents,
which must be prepared in advance, capture [
corresponding
a uoride source such as tetra-n-butylammonium uoride (TBAF). Near-quantitative
11
[
C]CO conversions within 10 minutes were reported when using tBuPh2SiLi[30]. A sim-
11
C-silacarboxylic acid, which can then release [11C]CO upon addition of
11
C]CO2 through the formation of the
plied method using commercially available disilane reagents allows the uoride source
to be added before [
11
C]CO2 delivery and is capable of producing [11C]CO in 74% RCY
within 10 minutes[32]. A proof of principle electrochemical methodology has also been
reported, which uses a screen-printed electrode immersed in a solution of Zn(cyclen)
2+
148 Handbook of Radiopharmaceuticals
electrocatalyst and is able to reduce cyclotron-produced [11C]CO2 to [11C]CO in up to
10% RCY[33].
7.2.2.2 [C]Methyl Iodide
In 1973, Comar and co-workers rst reported the synthesis of [11C]CH3I by LiAlH4
reduction of [
acid, as shown in Figure7.4a[36]. [
reaction with amines, phenols, and other suitable nucleophiles. [
cursor to other useful reagents for radiolabelling with
11
[
C]HCHO, and [11C]CS2. The versatility of [11C]CH3I has led to the extensive development
11
C]CO2 to [11C]CH3OH followed by iodination with concentrated hydroiodic
11
C]CH3I is a potent electrophile that readily undergoes
11
C]CH3I is also a pre-
11
C, including [11C]CH3OTf,
of reliable and repeatable automated methods, the radiosynthesis of the most widely
used intermediate in carbon-11 radiochemistry.
7.2.2.2.1 [11C]CH3I by the “Wet Method”
The rst reported method for producing [11C]CH3I[37] was further optimized by Långström and colleagues[38] and has since evolved from a multi-reactor, manual process to
a simple, semi-automated, single-reactor process (Figure7.4b)[34]. The “wet method”
involves the cryogenic trapping and concentration of [
a solution of LiAlH
11
[
C]CO2 is reduced to [11C]CH3O−. The organic solvent is evaporated before the addition
in tetrahydrofuran (THF) or Et2O (hence the “wet method”), where
4
of concentrated aqueous HI, hydrolysing any salts and releasing [
undergoes substitution with HI to give [
through a P
/NaOH trap (for drying and scrubbing of excess HI) into a second reactor
2O5
and used for further reaction. Alternatively, P
ation of [
11
C]CH3OH. These reagents are less corrosive than HI, improving the lifetime of
11
C]CH3I. The [11C]CH3I is distilled from the solution
2I4
the synthesis apparatus and reducing failure rates.
The wet method reliably produces [
activity of [
11
C]CH3I varies between 0.55–222 GBq·μmol−1, often lower than that pro-
11
C]CH3I in >80% RCY from [11C]CO2[41]. The molar
duced using alternative methods[42], likely due to (i) [
and delivery gases; (ii) ingress of [
12/13
C]CO2 into the target system during target lling,
bombardment, or emptying[42–44]; (iii) absorption of [
12/13
[
C]CO2 dissolved in the solvents used for synthesis; or (v) iodination of residual volatile
organic materials to give contaminating [
12/13
C]CH3I[46, 47].
11
C]CO2, followed by its release into
11
C]CH3OH, which rapidly
[39] or PPh3I2[40] can be used for iodin-
12/13
C]CO2 present in the target
12/13
C]CO2 by the LiAlH4[45]; (iv)
7.2.2.2.2 [11C]CH3I by the “Gas-Phase” Method
The “gas-phase” synthesis of [11C]CH3I was developed independently by Link etal.[48]
and Larson etal.[49] in an eort to improve the molar activity of [
the use of LiAlH
thesis involves a reduction of [
solutions and highly corrosive HI. The reported gas-phase radiosyn-
4
11
C]CO2 to [11C]CH4 by H2 over a nickel catalyst at c. 400 °C,
followed by a radical iodination[21]. The radical iodination is performed in a quartz
tube in a furnace between 700 °C and 720 °C, where [
gaseous [
11
C]CH3I (Figure7.5a). Link etal. described a single-pass process where the
11
C]CH4 reacts with I2 vapour to give
149
11
C]CH3I by avoiding
aq.HI/P
I
/
MeI
+
–
II
Waste
HI
4
2
2
I
3
PPh
4
O/THF
LiAIH
Et
(a)
I
C]CH
11
[
⊝
O
3
C]CH
11
[
2
2
C]CO
11
[
3
4
Reactor
LiAIH
sieve
Molecular
I can then be trapped in reactor II. Source: From Lång
3
C]CH
Waste
3
NH
NaOH
2
N
Waste
I
3
CH
11
O
NaOH/P
NaOH
5
2
Cooling
bath
–78 °C
Heating
bath
Heating
50 °C
block
4
3
C]CH
I
3
3
Waste
(b) (c)
150 Handbook of Radiopharmaceuticals
C]CH
2
N
11
Trap
CO
2
Heating
device
Figure 7.4
for producing [
would be added into the reactor from the syringe. The resultant [
C]CH
production of [
(c)(a)
(b)
Figure 7.5 C]CH3I from [C]CH4 and molecular iodine by radical iodination in the
thesizing [
C]CH3I from [2
C]CH3I
sion of John Wiley & Sons.
[11C]CH4 passes once through the heated iodination furnace and [11C]CH3I is condensed
in a cooled glass trap upon exit. [
11
gave
C-methylated products with a molar activity of 451 GBq·μmol−1 at the end of bom-
11
C]CH3I was obtained in <55% RCY from [11C]CH4 and
bardment (EOB)[48], representing a signicant improvement in molar activity over the
wet method. Some of the highest molar activities for carbon-11 labelled compounds,
averaging 4700 GBq·μmol
−1
and as high as 9700 GBq·μmol−1, have been prepared using single-pass gas-phase methods[46, 51, 52]. These ultra-high molar activity productions start
from cyclotron-produced [
inants that can react to form [
11
C]CH4 rather than [11C]CO2. Introduction of organic contam-
12/13
C]CH3I is also limited, as the gas bolus passes through
the apparatus only once.
Larsen etal. described a similar process but including a pump that recirculates [
through the iodine furnace, improving the yield of [
11
C]CH3I (Figure7.5b). A Porapak-N
11
C]CH4
cartridge (a porous divinylbenzyne polymer bead-bed) was incorporated into the
151
recirculation loop, which traps [11C]CH3I from the gas stream and allows any unreacted
11
[
C]CH4 to circulate back into the iodine furnace. Once radioactivity is trapped on the
cartridge plateaus, conversion of [
11
C]CH4 to [11C]CH3I is complete and recirculation is
stopped. Heating of the Porapak-N cartridge in an inert gas ow releases the trapped
11
[
C]CH3I, which can then be transferred to the reaction vessel. The average non-decay
corrected RCY of [
method had a molar activity of >550 GBq·μmol
11
C]CH3I from [11C]CH4 was 66%, and the [11C]CH3I produced by this
−1
[49]. The eciency, reproducibility, ease
of automation, and high molar activities that can be achieved have made this recirculation-based method the most widely used in radiochemistry facilities for the production of
11
[
C]CH3I. Several manufacturers oer commercially available systems that automate the
entire [
11
C]CH3I process (Figure7.5c).
7.2.2.2.3 Other Methods
Alternative methods for the generation of [11C]CH3I are based upon the recoil synthesis
11
of [
C]CH3I by the 14N(p,α)11C reaction in an N2/HI ow target system[53], giving [11C]
CH
I in 25% RCY over 40 minutes. Single-pass iodination of [11C]CH4 by iodine radicals in a
3
glow-discharge helium plasma, rather than a high-temperature furnace, was reported to
11
give [
C]CH3I in 13% RCY[54]. These alternate methods are rarely used as their yields are
lower than those obtained using the gas-phase method, and the equipment used is not
commercially available.
7.2.2.3 [
[11C]Methyl triuoromethylsulfonate ([11C]methyl triate, [11C]CH3OTf) is inherently
more reactive, less volatile, and more eciently trapped in the reaction solvent than
11
[
C]CH3I. Reactions can therefore be conducted at lower temperatures and with less precursor[55, 56]. The synthesis of [
a column of silver triate-impregnated graphitized carbon at 200 °C was reported by
Jewett in 1992[57]. This gas-phase synthesis system is easily appended to the outlet of a
gas-phase system for [
11
C]CH3I production (Figure7.5c) and provides [11C]CH3OTf in nearquantitative conversions. The synthesis of [
reported[58, 59].
11
C]CH3OTf by a single pass of gaseous [11C]CH3I through
11
C]CH3OTf from [11C]CH3Br has also been
[11C]CH3Br has also been used as a 11C-methylating reagent, requiring the use of lower
furnace temperatures (550 °C vs. 720 °C) for radical bromination compared to iodination[58]. The synthesis of [
95%/5% N
reported[60].
The longer-chain 1-
11
[2-
C]isopropyl iodide[63, 69], and [2-11C](2-iodoethyl)benzene[70] have also been
152 Handbook of Radiopharmaceuticals
mixture) for investigation of in vivo kinetic isotope eects has also been
2/D2
11
C-alkyl halides[61–64], α -11C-benzyl iodides[63, 65–68],
11
C]CD3I from [11C]CD4 (produced by bombardment of a
reported as 11C-alkylating agents. These are most often prepared using processes analo-
1.
LiAlH
O
I
H
THF
(a)
(b)
(c)
C]HCN
H2, Ni
NH
,
Pt
[
400 oC
gous to the wet method for [
prepared alkyl- or phenyl-Grignard reagents to generate a
and then reduced with LiAlH
corresponding
11
C-alkyl halides (Figure7.6a).
Långström and co-workers have also reported the radiosyntheses of [2-
iodide[71], [1-
11
[
C]CO2 in an eort to obtain 11C-alkylated products with higher molar activities.
11
[
C]Ethyl iodide was formed in 55% RCY via Pd(0)-catalysed 11C-carbonylation reaction
with CH
and methyl [2-
11
C]propyl iodide, and [1-11C]butyl iodide[72] from [11C]CO rather than
I, followed by hydride reduction of the intermediate mixture of [2-11C]acetic acid
3
11
C]acetate (Figure7.6b). [1-11C]Propyl and [1-11C]butyl iodide were obtained
11
C]CH3I radiosynthesis. [11C]CO2 is rst reacted with freshly
11
C-carboxylate species,
and iodinated with concentrated aq. HI to produce the
4
11
C]ethyl
in 58% and 34% RCY, respectively, via Pd(0)-catalysed formylation of ethene or propene
11
with [
C]CO and H2, followed by hydride reduction and iodination of the intermediate
alkyl aldehyde/carboxylic acid mixture (Figure7.6c). Sterically more hindered 1-iodo-2-
11
[
C]methylpropane was prepared in 59% RCY over three steps from [11C]CO2 using a Grignard reaction as a key transformation.
C]Hydrogen Cyanide
[11C]Hydrogen cyanide ([11C]HCN) production was rst reported by Cramer and Kistiakowsky in 1940 via high-temperature reaction of [
ammonia within a sealed tube reactor[73, 74]. Today, it is usually synthesized via the
platinum catalysed reaction of [
11
C]CH4 with ammonia at ~1000 °C (Figure7.7)[74–76].
11
C]CO2 with potassium metal and
11
[
11
[
11
[
R
C]CO
C]CO
+
CH
C]CO
+
H
R I
*
H
2.
4
aq. HI
R-MgX
2
R
OMgX
*
Figure 7.6 Syn
thesis of longer
chain [
C]alkyl
iodides from
[
(dba)
Pd
2
3
PPh
3
I
3
H
2
THF
O
Pd2(dba)
PPh
3
TsOH
O
OH
*
3
R
O
*
11
C]CO
O
+
O
*
+
H
R
2
LiAlH
1.
O
*
2.
[
OH
11
aq. HI
C]CH
4
1.
2.
4
153
LiAlH
aq. HI
~
1000
H
H
I
*
4
H
R
3
11
[
o
C
2 or [
*
Figure 7.7 Radio
synthesis of [
Residual NH3, which interferes with subsequent reactions, is removed through an in-line
Cl
,
hν
2
(a)
P
trap. The synthesis is reproducible and gives yields of over 95%[74, 76]. Direct pro-
2O5
duction of [
11
C]HCN in a cyclotron target lled with nitrogen and hydrogen (1%) has also
been reported[77].
7.2.2.6 [
[11C]Phosgene ([11C]COCl2) is a versatile labelling reagent; however, its synthesis requires
specialized apparatus that has restricted its widespread use. Initial methods to access
11
[
C]COCl2 utilised [11C]CO as a starting material, via reaction with PtCl4 at 280 °C[78, 79], or
direct reaction with chlorine gas under UV irradiation[80–82]; however, low molar activities were observed due to [
In 1987, Landais etal. reported an alternative synthesis starting from [
method, [
11
C]CH4 is reacted with Cl2 in the presence of a CuCl2 catalyst to give [11C]CCl4,
which is then oxidised by an iron catalyst to [
ities (<40 GBq· μmol
removing the CuCl
−1
and increasing the temperature of the chlorination oven[85]. An
2
improvement in yield for the second step was subsequently reported through the use of
an Fe/Fe
catalyst for the oxidation of [11C]CCl4[86] and, in a further iteration, in the
2O3
absence of catalyst at 750 °C[87]. In 2010, Ogawa etal. reported the room-temperature
conversion of [
and fuming H
11
C]CCl4 to [11C]COCl2 using a Kitagawa gas detector tube lled with I2O5
(Figure7.8b)[88].
2SO4
12/13
C]CO contamination arising from PtCl4 or Cl2 (Figure7.8a).
11
C]CH4. In this
11
C]COCl2[83]. Moderate molar activ-
) were reported[83, 84], which could be signicantly improved by
Figure 7.8 Radio
synthesis of
[
C]phosgene.
7.2.2.7 [C]Formaldehyde
[11C]Formaldehyde ([11C]HCHO) is usually produced through the reduction of [11C]CO2 to
11
[
C]CH3OH followed by partial re-oxidation in the presence of a catalyst such as ferric
molybdenum oxide[89], silver[90, 91], or XeF
been used to convert [
11
C]CH3OH to [11C]HCHO[93, 94]; however, the product is obtained
as an aqueous solution, which may limit its subsequent reactivity.
The solution-phase reduction of [
11
C]CO2 using LiAlH4 is likely to contribute to low
molar activities, leading the Fowler group to develop an alternative method utilizing
high molar activity [
N-oxide was used to convert [
11
C]CH3I as the starting reagent[95]. In this approach, trimethylamine
11
C]CH3I to [11C]HCHO in 89% RCY in a reproducible and
robust process, with no erosion of molar activity (Figure7.9b).
2
, 280 °C
4
, 560 °C
2
[
[
(b)
11
[
11
[
C]CO
C]CH
or, PtCl
Cl2, CuCl2, 380 °C
or, Cl
4
[92] (Figure7.9a). Enzymatic oxidation has
2
11
C]COCl
2
Fe, 30 0 °C
11
C]CCl
or, Fe/Fe
or, no catalyst, 750 °C
or, I
4
O3, 320 °C
2
, H2SO4, 25 °C
2O5
11
[
C]COCl
154 Handbook of Radiopharmaceuticals