Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5382_Библиотеки_им_академика_М_И_Перельмана.pdf
S8/sand
400
°C
70 oC, 2 min
11
Mo-Fe-O
(a)
(b)
H
C]CO
or Ag
or XeF
LiAlH
1.
2
2.
4
11
H
O
2
[
C]CH
OH[
3
2
or enzyme
H H
Figure 7.9 Radio
synthesis of
O
[
C]formaldehyde.
*
11
[
C]CH3I
Me3NO
DMF
O
11
H
NMe
C
3
3
O
H
*
The production of [11C]CS2 was rst reported in 1984 by Niisawa and co-workers via
microwave discharge of [
11
C]CO2 in hydrogen sulde gas[96]; however, [11C]CS2 did not
receive further attention until Miller etal. reported new methods (Figure7.10) for its
production from [
phase reaction of [
malodourous P
ing for the rapid, quantitative formation of [
11
C]CH3I in 2012[97]. In their rst report, [11C]CS2 was generated by gas-
11
C]CH3I with P2S5 at 400 °C. An improved method in which the toxic and
was replaced with elemental sulfur was subsequently reported, allow-
2S5
11
C]CS2 at 500 °C[98].
11
7.2.2.9.1 [
The CF3 group is present in many pharmaceuticals; however, existing radiolabelling
approaches using uorine-18 suer from poor molar activities, leading Haskali and
Pike to develop a novel carbon-11 radiolabelling approach using high molar activity
11
[
C]uoroform ([11C]CF3H)[99]. In this process, [11C]CF3H can be produced in 53% RCY by
passing [
oric acid side product is removed from the gas stream using an in-line MeCN/dry ice trap,
allowing [
(Figure7.11b).
C]Fluoroform
11
C]CH4 through a column containing CoF3 at 270 °C (Figure7.11a). The hydrou-
11
C]CF3H to be collected in chilled ethanol or N,N-dimethylformamide (DMF )
Figure 7.10 Radio
2
synthesis of
[
2
[
11
C]CH
11
[
11
[
C]CS
C]CS
°C
500
I
3
P
/sand
2S5
155
trap
(a)
(b)
trap
or DMF
oolant
11
11
from cyclotron
trap
[
C]CH
CoF
3
4
[11C]CF3H
Pressure
regulator
CH4 in N2-10% H
Liq. ArLiq. Ar
2
Guard
He
supply
Removable
11
CH4 trap
To
waste
Porapak
Q trap
Furnace
(270 °C)
P
2O5
CoF
3
MeCN-
dry ice
(≈ 41 °C)
HF
11
CHF
EtOH
C
3
Figure 7.11 C]CHF3 from [C]CH4 and CoF3
7.2.2.9.2 [11C]Nitromethane
The solution-phase synthesis of [11C]nitromethane ([11C]CH3NO2) was rst reported by
Schoeps etal.[100] in 1988 via reaction of [
phase process using a AgNO
column at 80 °C, as shown in Figure7.12a[101]. The reaction
2
is fast and typically uses an additional NaHCO
outlet to help remove nitrogen oxide by-products of pyrolysis. Longer-chain
iodides could also be converted to the respective nitro species in 50–70% RCY (based on
11
C-alkyl iodide).
11
C]CH3I with AgNO2, and a year later as a gas-
column, which is attached to the AgNO2
3
11
C-alkyl
7.2.2.9.3 [11C]Diazomethane
In 1986, Crouzel etal. reported the radiosynthesis of [11C]diazomethane ([11C]CH2N2) in a
two-step process from [
partial chlorination at 310 °C, giving rise to [
of hydrazine and KOH in ethanol. [
of up to 130 GBq· μmol
7.2.2.9.4 [11C]Methyl Azide
[11C]Methyl azide ([11C]CH3N3) can be formed in one step from [11C]CH3I, as shown in
Figure7.12c, providing the opportunity to perform Huisgen cycloaddition reactions with
alkynes to form
Schirrmacher etal. in 2008 through reaction of [
ing the 18-crown-6 cryptand[103] and was later performed on a cartridge containing
+
Na
/15-crown-5/N
156 Handbook of Radiopharmaceuticals
−1
11
C-labelled 1,2,3-triazoles. [11C]CH3N3 synthesis was rst reported by
−
in acetonitrile[104].
3
11
C]CH4 (Figure7.12b)[102]. In the rst step, [11C]CH4 undergoes
11
C]CHCl3, which is then delivered to a solution
11
C]CH2N2 was obtained in 30% RCY and molar activities
.
11
C]CH3I with NaN3 in a solution contain-
*
2
(a)
(b)
(c)
(d)
(e)
R I
80
2
°C
*
R NO
2
AgNO
R = H, alkyl
11
[
11
[
C]CH3I
11
[
11/12
[
C]CH
C]CO
C]CO
CuCl
Cl
,
2
2
11
[
4
310 °C
,
cryptand.
NaN
3
N
2
Li
SiMe
3
– N
2
barium,
2
– H2O
C]CHCl
11
CH
O
*
•
Li
SiMe
o
H
900
C
,
2
NH2NH
3
N N N
3
3
11
H H
KOH
,
2
EtOH, 60 °C
Me
Si
3
C
*
11
[
C]CH
OLi
7.2.2.9.5 [11C]Ynolates
Ynolates are triple-bond analogues of enolates, which may be promising reagents for
ketenylation reactions in radiotracer synthesis. The synthesis of lithium [
ynolate (Figure7.12d) has been reported by reaction of [
11
C]CO with in situ-prepared lithi-
ated silyldiazomethane[105].
11
C]trimethylsilyl
Figure 7.12 Radio
syntheses of
secondary
precursors.
C]diazometh
N
2
[
C]trimeth
C]acetylene.
C]methyl
7.2.2.9.6 [11C]Acetylene
Acetylene is a useful reagent in organic synthesis; however, its complex synthesis with
11
C has limited its use a radiolabelling reagent. In 2005, Nazih etal.[106] reported a simplied synthetic procedure based on the method described by Madsen etal.[107]. In this
process, [
tube and then heated to 900 °C under hydrogen ow to produce [
RCY and with molar activities of up to 6 GBq· μmol
11/12
C]CO2 is trapped at room temperature on barium within a quartz reaction
11
C]acetylene in 50–75%
−1
(Figure7.12e).
Early 11C-methylation reactions involved trapping the labelling agent in a solution containing the precursor within a small reaction vial. This technique remains widely used and
157
is regularly incorporated into automated processes. Since this method involves multiple
time-consuming transfers of reagents to and from the reactor, intermediate vials, and
the purication system, it is susceptible to incomplete transfer of materials and hence
diminished RCYs.
Eorts to streamline these processes led to the development of reactions that take
place on an inert solid support, known as “on-cartridge” reactions. Three variations of
such on-cartridge reactions have been described. First, the precursors for radiolabelling
may be loaded onto an inert solid support, such as polymer resins[108, 109], silica[110],
C
-modied silica[111], or stainless steel powder[112]. After loading with precursor,
18
a small volume of solvent, gaseous [
owed over the solid support, where the reaction then takes place. Second, [
11
[
C]CH3OTf can be trapped on the solid support and a solution of the precursor owed
over the trapped
11
C-methylating agent. Third, the precursor may be covalently attached
11
C]CH3I or [11C]CH3OTf in N2 carrier gas, is gently
11
C]CH3I or
to a solid support, which is then released after reaction with the labelling agent[113].
This strategy is attractive as unreacted precursor remains resin bound, and purication
11
of the
C-labelled product is greatly simplied. For all methods, once the reaction is
complete, the entire reaction mixture can be eluted into the purication system to isolate the
11
C-labelled product.
The principal advantage of using the on-cartridge method lies in the speed with
11
which
minimized, as are losses of the volatile
C radiopharmaceuticals can be produced. Transfers of the reaction mixture are
11
C-methylating agents into the headspace of
the reactor, all contributing to improving both RCY and molar activities, whilst being
amenable for transfer into a simple “kit” form[114]. The on-cartridge method has been
used for the synthesis of a number of radiopharmaceuticals, including [
nate[115], [methyl-
11
[
C]Pittsburgh compound B ([11C]PIB)[114].
11
C]-l-methionine[116, 117], [N-methyl-11C]choline[116, 118, 119], and
11
C]methyl jasmo-
Wilson etal.[17, 120, 121] described the “loop” method for radiosynthesis, where the precursor in a suitable solvent was coated as a thin lm onto the inner surface of a high-performance liquid chromatography (HPLC) loop connected directly to an HPLC purication
system. [
the thin solvent lm, where it underwent rapid reaction with the precursor. The reaction
mixture could then be directly eluted onto the HPLC system for purication. At the same
time, Iwata etal.[122, 123] described a similar procedure using a dedicated polytetrauoroethane (PTFE) loop. The large surface area presented by the thin lm of precursor/
solvent on the inner surface of the loop ensures ecient trapping of the labelling agent,
while the resultant high concentration of precursor in the lm ensures a rapid reaction
even in the absence of heating.
be easily incorporated into existing commercial synthesis systems (Figure7.13)[50, 124,
125] or used with cheaper dedicated automated systems[126, 127]. The use of EtOH as
158 Handbook of Radiopharmaceuticals
11
C]CH3I was then passed through the loop in a stream of inert gas and trapped in
The loop method is particularly attractive due to its operational simplicity, and it can
11
CH3I
HPLC LOOP
(g)
2
1
3
6
4
5
GammaDet.
N2 PRESSURE
HPLC Pump
load
inject
VIAL
iso.
NaCl
V7 V8
VIAL8VIAL
7
EtOH H2O
V9
Figure 7.13 Mod
“loop” synthesis.
9
John Wiley & Sons.
V17
C18
V22
VENT.
V22/21
UV Detector
Auto Zero
UV lamp
WASTE
TO FINAL
V18
V16
BOTTLE
V15
V21
DILUTION
FLASK
MIXING
FLASK
on
N
2
off
PRODUCT
a solvent for both trapping and purication has made the process practically simpler
by eliminating the reformulation step[128]. A number of radiotracers, including [
raclopride, [
nitrile ([
11
[
C]methylphenidate[132], and [11C]metomidate[133], have all been prepared using the
11
C]rolipram, [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzo-
11
C]DASB), [11C]PIB[129], [methyl-11C]-l-methionine[130], [11C]carfentanil[131],
11
C]
loop method, in generally greater RCY compared with vial-based methods.
159
There have been numerous eorts to adapt more PET radiosyntheses for operation using
microuidic devices. The advantages include inherent compatibility with small masses
and volumes of reagents, improved heat transfer, and facile automation[134–137]. The
rst application in
11
C synthesis of 11C-methyl esters from carboxylic acids was accomplished in 65% RCY using a 0.2 μl T-shaped microreactor. The precursor and a base in DMF
(5 mM) were infused by syringe pump though one arm of the T, and [
though the other arm[138]. Similarly, [
11
C]DASB[139] and [11C]raclopride[140, 141] were
11
C]CH3I was infused
prepared using microuidic methods.
The time taken to purify and perform quality control of the resultant 11C radiopharmaceutical contributes to the total synthesis time, and time savings at these steps can lead to
signicant improvements in RCY and molar activity of the nal product[142].
Solid-phase extraction (SPE) has proven useful for radiotracers such as
[N-methyl-
11
([
C]β-CFT), where large dierences in polarity between the precursor and the
11
C-labelled product exist[143]. Owing to the large dierence in the amount of precursor
and radiolabelled product (mg vs. μg), the precursor peak often tails into the product
peak using conventional reverse-phase HPLC. To circumvent this problem, modied
reverse-phase HPLC stationary phases[144] or hydrophilic interaction chromatography
(HILIC)[145] has been used to develop methods where the
before the precursor. Such an approach has been used for the purication of [
11
[
C]FLB457, [11C]carfentanil, [11C]DASB, [11C]WAY1000635, and [11C]SCH23390.
include: (i) use of shorter columns packed with smaller particles, where analysis times can
be reduced to as little as one minute[145]; (ii) use of ultra-high performance liquid chromatography-based methods where analysis times are 2–3 minutes[146]; and (iii) use of
liquid chromatography with tandem mass spectrometry methods, as reported by Shetty
etal.[147], which allows for the simultaneous determination of radiopharmaceutical
identity, molar activity, and half-life.
11
C]choline and 2β-carbomethoxy-3β-(4-uorophenyl) [N-methyl-11C]tropane
11
C-labelled product elutes
11
C]raclopride,
Additional improvements toward reducing the time taken for quality-control testing
7.4.1 Reactions with [11C]CO
CO2 is a centrosymmetric molecule with no overall dipole, rendering it a weak electrophile with poor solubility in organic solvents. To compensate for its low reactivity, large
stoichiometric excesses and/or high pressures are often employed during reactions with
160 Handbook of Radiopharmaceuticals
2
CO2; however, this is not feasible for radiolabelling experiments due to the small quantities of [
11
C]CO2 available. Consequently, the direct use of [11C]CO2 was initially limited to
Grignard-type chemistry involving highly reactive nucleophiles. In the last decade, however, new synthetic methodologies have been developed using non-nucleophilic bases as
xation agents, which serve to dramatically enhance [
11
C]CO2 solubility and reactivity.
11
7.4.1.1.1
Grignard reagents react rapidly with [11C]CO2 and are trapped in solution through the
rapid formation of the corresponding magnesium
quenched or further derivatised as required using a variety of methods (Figure7.14a–d),
including: (a) aqueous workup to produce the corresponding carbonylacid[148], e.g. [
boxylate with primary or secondary amines to produce carbonylcan be subsequently reduced using NaBH
reaction with activating agents such as thionyl chloride or phthaloyl dichloride to produce carbonyl155],
are used as
amines or alcohols; and (d) reduction of the carboxylate intermediate using LiAlH
lowed by halogenation, to give access to 1-
11
C-alkylating reagents in subsequent reactions[64, 160].
Organolithium reagents are more reactive than Grignard reagents and can undergo
double addition with [
of reaction conditions is required to avoid side reactions. For example, [
may be obtained via reaction of methyl lithium with [
(Figure7.14e)[161–163]. [
N-isopropyl groups via reductive alkylation[163] and has been used to radiolabel tracers
such as [
lithium [
azole[166].
C─C Bond Formation
11
C-carboxylate species. These may be
11
C-carboxylic
11
C]acetate[149, 150] and [11C]palmitate[108, 150]; (b) heating the car-
11
C-amides[151], which
to yield 11C-labelled tertiary amines[152]; (c)
4
11
C-acid chlorides, e.g. [11C]acetyl chloride[153], [11C]propionyl chloride[154,
11
C-cycloalkanecarbonyl chlorides[156–158], and [11C]acryloyl chloride[159], which
11
C-acylating reagents to generate 11C-amides or 11C-esters via reaction with
, fol-
11
C-alkyl halides, which can then be used as
11
C]CO2 to form carbonyl-11C-ketones; however, careful control
11
C]acetone
11
C]CO2, followed by hydrolysis
11
C]Acetone is a useful building block for the introduction of
11
C]practolol[164] and [11C]pindolol[165]. 11C-Carboxylation of tBuLi produces
11
C]pivalate, which has been used to radiolabel a tBu-substituted benzimid-
4
7.4.1.1.2 11C─H Bond Formation
11
C─H bond formation can be achieved by reaction of metal hydrides with [11C]CO2:
LiAlH
gives rise to [11C]methanol (Figure7.15a), which forms the basis of the wet method
4
11
for [
C]methyl iodide production[16] (see Section 7.2.2.2.1). LiEt3BH partially reduces
11
[
C]CO2 to give lithium [11C]formate, which can then be alkylated, providing 11C-formate
esters (Figure7.15b)[29]. These can be used as
by the synthesis of [
11
C]benzimidazole[167].
11
C-formylating reagents, as exemplied
161
C]formate esters
[
O
+
1
(e)
(a)
O, H
H
2
R
OH
*
R MgX
CH
3
R
R
R I
O
R
N
*
1
R
O
Cl
*
*
2
X = R2N or O
R
NaBH
R1XH
1
R2NH
4
O
3
*
R1R2NH
heat
thionyl chloride/
[
11
C]CO
(b)
2
O
R
OMgX
*
(c)
phthaloyl chloride
(d)
(i) LiAlH
4
(ii) H2O, HI
11
[
C]CO
Li
2
LiO
H
C CH
3
*
OLi
3
+
H
H
O,
2
H
C CH
3
*
R N
O
R
*
*
R
R
2
R
1
R
X
R
2
N
R
1
[11C]acetone
O
OH
*
O
N
N
N
N
*
O
HO
N
*
O
NH
OH
H
O
N
*
11
C]palmitic acid
[
via path A
20–40% RCY
11
C]WAY100635
[
via path C
2.3% RCY
133 GBq/µmol
11
(+)-[
C]PHNO
via path C
16% RCY
84 GBq/µmol
Figure 7.14 Reactions of [2 with organometallic reagents.
Figure 7.15
Reaction of
[
2 with metal
(a)
LiAlH
4
H
*
OAlH
H
H
hydride reagents.
11
C]CO
2
(b)
LiEt3BH
O
H
OLi
*
162 Handbook of Radiopharmaceuticals
3
H
ROH, H
11
[
C]pindolol
via path E
18% RCY
22–37 GBq/µmol
O
2
[11C]methanol
SO
4
2
11
[
H
*
OH
H
H
O
R
H
O
*
7.4.1.1.3 11C─N Bond Formation
Deprotonated amine bases can react directly with [11C]CO2 at room temperature, as
demonstrated by Chakraborty etal. in their synthesis of [carbonylbis(trimethylsilyl)amide (LiHMDS) (Figure7.16a)[168]. This reaction proceeds via a
11
C-carbodiimide intermediate, which is subsequently hydrolysed to produce [11C]urea;
however, the scope of this methodology cannot be extended to the formation of substi-
11
tuted
C-ureas.
Van Tilberg etal. showed the viability of the aza-Wittig reaction for
using commercially available phenyl triphenylphosphinimine[169]. Quantitative [
CO
trapping was observed at −60 °C, and the resultant phenyl [11C]isocyanate under-
2
went reaction with various amines to produce unsymmetrical carbonylisolated RCYs of 8–49% (Figure7.16b). In 2018, Del Vecchio etal. used this methodology
to form cyclic carbonyl-
11
C-ureas in 25–85% non-isolated RCY from in situ generated phosphinimines, synthesised by reaction of o -azidoanilines with dimethylphenylphosphine
(Figure7.16c)[170]. A variety of aliphatic unsymmetrical
maceutically active
34–48% and molar activities of 32–75 GBq· μmol
The ability of silylated amines to react with [
has been exploited for
the method developed by Ram etal., [
11
C-ureas were labelled using this procedure, with isolated RCYs of
−1
.
11
C]CO2 to give carbonyl-11-carbamic acids
11
C-methylation as an alternative to [11C]CH3I/CH3OTf labelling. In
11
C]CO2 is delivered at −80 °C to a solution of tri-
11
C-ureas as well as ve phar-
methylsilyl amine, heated to form an O -silylcarbamate, and then reduced using LiAlH
produce the corresponding
approach has been used to synthesise radiotracers [
zine[172], and [
Direct one-pot
11
C]tamoxifen[174].
11
C-methylation of aliphatic and aromatic amines using [11C]CO2 has also
11
C-methylated tertiary amine (Figure7.16d)[171–174]. This
11
C]imipramine[171], [11C]chlorproma-
been achieved using phenylsilane as a reductant in the presence of a zinc-N-heterocyclic
carbene complex (Figure7.16e)[175]. In this process, [
11
C]CO2 is delivered at 0 °C to a
diglyme solution containing the reducing reagents and heated at 150 °C for 20 minutes
to yield
11
C-methylated amines in 24–75% RCY. The amyloid-β imaging agent [11C]PIB was
radiolabelled under these conditions, but with lower molar activity than that obtained via
11
[
C]CH3OTf labelling (15 GBq· μmol−1 vs. 50 GBq· μmol−1, respectively).
11
C]urea using lithium
11
C-carboxylations
11
C]
11
C-ureas in non-
4
to
In 1999, Coenen etal. reported that in the presence of a tertiary amine base, nonactivated amines such as aniline could react with [
carbonylSubsequent treatment of the
gave symmetrical
improve [
phinimine
11
C-carbamate salts, albeit using low-temperature trapping (Figure7.17a)[176].
11
C-carbamate with POCl3 and reaction with excess amine
11
C-ureas via an intermediate 11C-isocyanate. The use of amines to
11
C]CO2 capture was also observed by van Tilburg etal. in their study on phos-
11
C-carboxylation (vide supra)[169].
These ndings, as well as advances in “green” CO
work for what is arguably the most signicant breakthrough in
11
C]CO2 to form the corresponding
capture chemistry, laid the ground-
2
11
C chemistry since the
163
(a)
TMS
Li
N
TMS
–5
o
11
[
C]CO
C – 25 oC
2
TMS
TMS
N
*
C
N
NH4Cl, H2O
o
25
C – 65 oC
O
H2N NH
*
2
(b)
(c)
(d)
(e)
1
R
R
N
X
PMe2Ph
N
NHR
TMS
N
2
R
1
H
N
2
R
3
PR′
H
11
[
C]CO
3
RNH
–60
2
2
o
C
*
N
C
O
X
RNH2, X = H
60 oC
X = NHR
o
C – 90 oC
20
11
[
–80
11
[
C]CO
o
C
C]CO
0 oC
2
2
O
1
R
N
OTMS
*
2
R
O
1
R
−
N
O
*
2
R
PhSiH
150 oC
i
LiAlH
Pr
60
3
ZnCl
,
Pr
i
4
o
C
2
R
R
1
N
R
1
N H
R
H
N
N
*
R
O
H
N
*
O
N
R
*
CH
3
2
O
*
2
*
1
R
CH
3
N
2
R
NN
iPr
iPr
O
O
N
N
*
H
H
tryptamine-containing urea
via path B
45% RCY
(non-isolated)
N
H
O
NHN
*
[11C]oxatomide
75 GBq/µmol
N
via path C
45% RCY
N
Ph
Ph
Figure 7.16 Reactions of activated amines with [2.
advent of [11C]CH3I in the 1970s–the use of strong non-nucleophilic bases as [11C]CO2 xation agents to promote
11
C-carboxylation reactions with less reactive substrates. This was
rst described by Hooker etal. using the amidine base 1,8-diazabicyclo[5.4.0]undec-7-ene
164 Handbook of Radiopharmaceuticals
Ph
Ph
[11C]tamoxifen
via path D
65–84% RCY
9–15 GBq/µmol
O
*
N
HO
S
*
NH
N
[11C]PiB
via path E
38% RCY
15 GBq/µmol