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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5903_Библиотеки_им_академика_М_И_Перельмана.pdf
RNH
(a)
H
11
CuTp*[
1
R
+
HN
2
2
R
or
11
[
C]CO / Xe
LnPd
C]CO
II
O
11
C
R R
N
N
H
1
R
F
2
H
3
O
N
*
N
C
[11C]GSK1034702
6% RCY
(non-isolated)
O
N
N
Ph
O
11
*
C-labelled sEH inhibitor
41% RCY
247–319 GBq/µmol
Cl
N
H
ClO
(b)
H
O
B
R
O
1
+
R
OH
[11C]CO / He
Pd(OAc)
PPh
, PBQ
3
2
O
11
R
1
C
R
O
N
[11C]tamibarotene
48% RCY
<44 GBq/µmol
O
OH
*
O
Figure 7.27
12
CO[245]. Using Pd(PPh3)2Cl2, homocoupling reactions of primary aliphatic amines pro-
duced the corresponding N,N′-disubstituted
11
C-ureas in good RCY. Secondary amines
were unreactive under these conditions. This dierence in reactivity allowed for the
formation of unsymmetrical N,N′,N′-trisubstituted
11
C-ureas using a mixture of a primary
and reactive secondary amines, as was used to prepare to the M1 muscarinic acetylcholine receptor radiotracer [carbonyl-
11
C-urea inhibitor of soluble epoxide hydrolase[246].
11
C]GSK1034702 and later by Roslin etal. to isolate a
Pd(II)-mediated oxidative carbonylation chemistry has also been used to couple aryl/
heteroaryl boronic esters and alcohols with [
6–80% RCY (based on trapped [
11
C]CO) (Figure7.27b)[247, 248]. These reactions were
11
C]CO to produce carbonyl-11C-esters in
performed at ambient pressure without additional complexation agents, with the cooxidant p-benzoquinone.
11
or
C-amides by reaction with NaOH or aqueous ammonia, respectively, as demonstrated
by the syntheses of [
A breakthrough in the handling of [
11
C-Esters could be further converted to the 11C-carboxylic acids
11
C]aspirin and the synthetic retinoid [11C]tamibarotene.
11
C]CO was made by Eriksson etal. in 2012 through
the use of xenon as a soluble carrier gas, obviating the need for chemical complexation
agents[22]. Since xenon is 160 times more soluble than helium in THF, it could be used
to sweep [
11
C]CO from a silica trap and into an unvented reaction vial lled with solvent.
While this does not increase the solubility of CO itself, it does enable it to be transferred quickly and quantitively into a small volume reactor without a signicant pressure
increase. This technically and chemically simple setup has been used for radiolabelling a
wide range of substrates via Pd(0)[22], Pd(II)[246], and Rh(I)[249] catalysed processes
with RCYs comparable to those obtained using high-pressure conditions or complexation
agents. Radiotracers prepared using the xenon-[
fonyl carbonyl-
11
C-carbamate as a non-peptide AT2 receptor agonist[249], benzovesami-
11
C]CO trapping method include a sul-
col analogues as potential tracers for the vesicular acetylcholine transporter[250], and
O
OH
*
OAc
[11C]aspirin
15% RCY
(non-isolated)
175
carbonyl-11C-acrylamides as transglutaminase inhibitor radiotracers (Figure7.26)[251].
C
O
*
(a)
(b)
In 2017, Filp etal. reported the synthesis of [
11
C]acrylamides from [11C]CO and their use
as Michael addition substrates with Schi base glycine derivatives to form amino acids
11
[
C]glutamate and [11C]glutamine[252].
The xenon-[
11
C-carbonylation to produce alkyl carbonyl-11C-amides. In a parallel to the high-pressure
11
C]CO method has also been used to develop a thermally initiated radical
UV-initiated radical reactions performed by the Långström group, Chow etal. used
the radical initiator azobisisobutyronitrile (AIBN) to promote the
of alkyl iodides and amines at ambient pressure to form a range of alkyl
including the 11β-HSD1 inhibitor [carbonyl-
11
C]adamantan-1-yl(piperidin-1-yl)methanone
11
C-carbonylation
11
C-amides
(Figure7.28a)[253]. Using isopropanol instead of an amine allowed the formation of
11
C-esters via an initial radical dehalogenation of the alkyl halide to form an alkyl and
then acyl radical after the addition to [
11
C]CO. This species could be either quenched by
the starting alkyl iodide to form an acyl iodide, or oxidized to an acylium ion, which then
reacts with an amine to produce the
Alternatively, Rahman etal. used Ni(cod)
bathophenanthroline to couple non-activated alkyl iodides with amines and [
at ambient pressure at 100 °C (Figure7.28b)[254]. Model
11
C-labelled alkyl amide.
in the presence of the supporting ligand
2
11
C]CO
11
C-amides were obtained in
33–72% RCY highest being for weaker nucleophiles and sterically hindered electrophiles,
in contrast to the usual reactivity observed in Pd(0) catalysis.
In 2006, Buchwald etal. showed that aminocarbonylation reactions could be performed at low CO pressures in the presence of a Pd(0) catalyst supported by the wide
bite-angle bidentate phosphine ligand xantphos[255]. This led Dahl etal. to explore
the synthesis of [carbonyl-
11
with [
C]CO. A series of Pd reagents were screened, showing that xantphos and
(Pd(π-cinnamyl)Cl)
2
11
C]N-benzylbenzamide and optimize this method for use
was a particularly ecient catalyst system, allowing exceptional
Figure 7.28
R
3
+
AIBN
(TMS)
H2NR
H2NR
3
SiH
3
3
bonylation
reactions of alkyl
iodides to form
[
C]amides.
R
R1I
1
2
R
R1I
2
R
O
N
*
H
2
R
176 Handbook of Radiopharmaceuticals
1
R
R
[11C]CO
Ni(cod)
1
R
2
R
O
I
*
2
1
R
2
NN
O
1
R
*
2
R
1
I
R
2
R
O
3
R
N
*
H
2
R
O
N
*
H
*
O
O
N
*
H
O
N
*
H
N
N
N
Via radical
20% RCY
101 GBq/µmol
11ß-HSD
via radical
18% RCY
Via nickel
72% RCY
(non-isolated)
Via nickel
57% RCY
(non-isolated)
inhibitor
1
[11C]CO incorporation and high RCY (13–98%) for substituted 11C-N-benzylbenzamides,
11
C-carboxylic acids, 11C-aldehydes, 11C-ketones, and 11C-lactones[256]. A subsequent
report described a further improvement in RCY through microwave irradiation[257].
The eciency of the Pd-xantphos system has seen it become increasingly adopted
as a rst-choice reagent for
the synthesis of a histamine type-3 receptor radioligand[256] and the D
[carbonyl-
11
C]raclopride (Figure7.26)[258].
In 2015, Anderson etal. reported an ecient
11
C-carbonylation reactions, as exemplied by its use in
radioligand
2
11
C-aminocarbonylation strategy
designed to optimise RCYs for structurally demanding motifs[259]. Since oxidative
addition can be a slow step, it was reasoned that pre-formed aryl-palladium-xantphos
complexes might undergo more ecient reaction with [
reagents. PET radiotracers [carbonyl-
11
C]raclopride, [11C]olaparib, and [11C]JNJ-31020028
11
C]CO as stoichiometric
were successfully radiolabelled at low pressures using this approach (Figure7.29a).
This methodology was applied to the
peptides [carbonyl-
11
C]acetyl-LULUPhol, [carbonyl-11C]acetyl-cRGDfK, and [11C]lacos-
11
C-N-acetylation of peptides, allowing native
amide to be synthesised in good RCY and with high molar activity under mild conditions
(Figure7.29b)[260].
Cornilleau etal. used an alternative strategy for
11
C-labelling complex biomolecules,
whereby a 2-iodobenzylalcohol moiety was appended via click chemistry, making it amenable to radiolabelling via Pd(0)-catalysed intramolecular cyclisation with [
11
C]CO [261].
Following the high-yielding radiosynthesis of the unconjugated test substrate, a bioconjugated glucose derivative and a cyclo-RGD peptide bioconjugate were radiolabelled
(Figure7.29c) in good RCY.
A number of ow-based approaches to performing 11C-carbonylations have been investigated, making use of micro-reactors that are well suited to the small scale of radiolabelling reactions. The microtube system developed by Miller etal. uses a heterogeneous
silica-bound Pd catalyst packed into a PTFE tube[262]. The 45 cm tube (internal diameter
[i.d.]=1 mm) is rst loaded with a solution of aryl halide and amine, and then [
delivered into the tube and heated at 75 °C for 12 minutes, after which the crude product
mixture is eluted into a vial under a ow of THF. Model [carbonyl-
11
C]-N-benzylbenzamides were obtained in 33–79% RCY with excellent reproducibility. The same group later
reported the use of a glass-microuidic device to perform gas-liquid aminoion reactions inside a 5 m channel (i.d. ≈ 200 μm) using an annular ow of [
co-infused with a solution of cross-coupling reagents[263]. In a 7–8 minute reaction performed at 150 °C, the same model carbonyl-
11
C-amides were this time obtained in 56–88%
RCY. In an alternative approach, Kealey etal. performed liquid-liquid aminoation reactions using a preformed CuTp*-[
11
C]CO solution rather than [11C]CO gas, within
a 2 m silica glass capillary (i.d.=100 μm) in a commercially available microuidic device,
as exemplied in the synthesis of [
ics to perform amino-
11
C-carbonylation reactions in a gas-liquid segmented microuidic
11
C]MK-0233[244]. In 2015, Dahl etal. used microuid-
process[264]. Using a 5 m fused silica capillary (i.d.=200 μm) at 100 °C, 12 dierent
11
C]CO is
11
C-carbonyat-
11
C]CO gas
11
C-carbonyl-
177
Ph
(a)
Ph
P
O
R
Pd I
+
P
Ph
Ph
2
R
N
1
R
H
[11C]CO
o
95
C
R
O
2
R
N
*
1
R
(b)
L
Pd
L
(c)
O
O
Cl
*
OH
Cl
11
[
C]raclopride
38–44% RCY
333–407 GBq/µmol
CH
Cl
N
1
3
+
R
H2N
O
H
N
N
H
2
R
O
[11C]CO
xantphos
o
40–80
CH
3
C
OH
I
O
N
N
11
[
C]CO
(dba)
Pd
2
xantphos
70–90
3
o
C
N
N
1
R
O
N
*
H
O
H
N
N
H
2
R
O
O
*
O
O
N
= peptide or biomolecule
Ph
O
NH
NH
O
[acetyl-
HN
HN
H
N
O
11
C]cRGDfK
O
HO
O
O
N
N
H
37% RCY
281–404 GBq/µmol
HN
H
N
*
NH
CH
O
NH
3
HO
HO
2
HO
O
N
OH
11
[
C]glucose derivative
O
O
*
NN
O
75% RCY (non-isolated)
Figure 7.29
11
C-labelled compounds were produced in 38–99% RCY, including the D2 receptor ligands
[carbonyl-
11
C]raclopride and [carbonyl-11C]FLB 457.
11
Methyl groups are common motifs in both natural and synthetic products providing potential sites for labelling with carbon-11. The rapid adoption of [
as “go-to” reagents for labelling with carbon-11 led to signicant market forces to develop
commercially available automated systems for the production of [
178 Handbook of Radiopharmaceuticals
11
C]CH3I (and later [11C]CH3OTf)
11
C]CH3I and [11C]CH3OTf
as well as the radiolabelling, purication, and reformulation of radiopharmaceuticals
labelled with these agents[50, 265]. “Kit” setups[266] have further spurred the growth of
PET imaging in the clinic by simplifying radiopharmaceutical manufacture.
11
[
C]CH3I is the simplest alkyl iodide, and the lack of steric hindrance at the electrophilic site makes it the ideal electrophile for use in nucleophilic substitution reactions
with amines, amides, alcohols, thiols, or enols. Polar aprotic solvents like acetonitrile,
DMF, acetone, 2-butanone, and dimethyl sulfoxide (DMSO) are most commonly used,
although protic solvents such as ethanol have also been reported[267]. Forcing conditions may be used to accelerate radiolabelling reactions; however, precursor decomposition or undesired side reactions with the solvent may occur[268, 269]. Bases (e.g.
hydrides, hydroxides, and carbonates) can be used to either deprotonate the substrate
to increase nucleophilicity or quench acidic by-products. The choice of base is dictated by
the pK
of the substrate and the stability of the precursor. To overcome the challenges in
a
controlling the stoichiometry of the base in the reaction due to the limited solubility of
inorganic bases in organic solvents, TBAF has been shown to be a suitable base for both
N- and O-alkylation with [
11
C]CH3I in DMSO[270, 271].
C]Methyl Iodide vs. [
[11C]CH3OTf is a more reactive methylating agent with a higher boiling point than that of
11
[
C]CH3I (94–99 °C vs. 41–43°C) being frequently employed for labelling less nucleophilic
substrates. While the synthesis of [
11
[
C]CH3I, its production via in-line gas-phase synthesis from either [11C]CH3I or [11C]CH3Br
adds minimal time to the process but dramatically improves RCY as well as molar activities (Figure7.30a–e). Further advantages include improved trapping in the reaction solvent; shorter reaction times, allowing for lower reaction temperatures; and a reduction in
the mass of precursor required as well as by-products formed. Head-to-head comparisons
of the application of [
11
C]CH3OTf or [11C]CH3I for labelling of amines, anilines[55], thiols,
amides[282], phenols, and carboxylic acids[56, 283] have been reported.
11
C]CH3OTf requires an additional step compared to
7.4. 3 .2 N
N-alkylation with [11C]CH3I or [11C]CH3OTf is the most widely used strategy for radio-
labelling with carbon-11 due to the abundance of methylated aliphatic amine motifs
amongst bioactive molecules. The excess of desmethylamine precursor and minimal
amounts of
the intermediate [
the reaction, as the parent amines are often suciently nucleophilic, and the excess
precursor can function as the base. For example, [
transporter ligand, is synthesised by selective
matic) of the desmethyl precursor using [
66% ± 6.9% (n=60) RCY[284].
using [
PIB (Figure7.31b)[272]. When the aromatic amine is particularly electron-decient and
11
C-methylating agent ensure that poly-11C-methylation is negligible despite
11
C]methylamine being more nucleophilic. A base is not needed in
11
C]DASB (Figure7.31a), a serotonin
11
C-methylation (aliphatic over aro-
11
C]CH3I in DMSO at 100 °C for ve minutes in
11
C-Methylation of an aromatic amine is often achieved
11
C]CH3OTf, exemplied by the synthesis of an amyloid-β PET radiotracer [11C]
179
2
NH
S
N
0.4 mg
N
N
H
OH
O
O
0.1 mg
OH
O
N
N
O
0.5–1 mg
11
11
OTf Route
3
C]CH
[
I Route
3
C]CH
[
HO
2-butanone
25 °C, 1 min
3
CH
NH
11
S
HO
+
min, then H
5
KOH, DMSO
125 °C,
2
NH
S
11
11–16% RCY
N
11
12% RCY
N
)
2
C]CCO
(EOS, [
30–60 GBq.μmol–1
C]PiB
11
[
I)
–1
3
C]CH
[
85 GBq.μmol
(EOS,
1.5 mg
(EOS)
(EOS)
min
3
°C,
70
NaOH, acetone
O
TBAOH, DMF
O
F
50–60% RCY
N
N
H
F
20–40% RCY
50–55 °C, 6 min
N
N
H
)
2
C]CO
11
(EOB, [
O
I)
3
C]CH
11
(EOB, [
OH
3
CH
11
O
O
(EOS)
185–555 GBq.μmol–1
C]fallypride
11
[
(EOS)
15–30 GBq.μmol–1
1 mg
CN
3
80 °C, 3 min
NaH, CH
3
CH
11
O
O
25 °C, 3 min
TBAOH, DMF
OH
O
)
2
C]CO
11
70–80% RCY
(EOB, [
185–555 GBq.μmol–1
N
N
O
)
2
C]CO
11
26% RCY
(EOS, [
85–330 GBq.μmol–1
N
N
O
(EOS)
C]PBR28
11
[
(EOS)
mg
1
MOMO
(a)
(b)
180 Handbook of Radiopharmaceuticals
F
(c)
Figure 7.30
4
(d)
ONH
N
O
O
N
N
O
O
1 mg
H
N
0.5 mg
O
O
TBAOH, DMSO
O
C
11
3
H
DMF
ONa
16% RCY
25 °C, trapping time
N
N
O
30% RCY
35 °C, 5 min
N
N
O
O
O
11
)
2
C]CO
11
(EOS, [
)
2
C]CO
(EOB, [
–1
–1
(EOS)
GBq.μmol
130
C]carfentanil
11
[
(EOS)
85 GBq.μmol
1 mg
acetone
O
/KF, MeCN
3
O
2
Al
O
O
(e)
120 °C, 10 min
O
110 °C, 10 min
OTf)
3
C]CH
11
66% RCY
5–30 GBq.μmol–1
(EOB, [
N
3
CH
N
11
O
O
)
2
–1
C]CO
11
16% RCY
>11 GBq.μmol
(EOB, [
N
H
N
O
O
(EOS)
C]verapamil
11
[
(EOS)
0.5 mg
3
C]CH
3
C]CH
[
181
11
11
3
(a)
(b)
(c)
[
C]flumazenil
Figure 7.31
N
used to synthesise
[
and [
HO
NC
S
N
NH
H
2
N
S
[
C]CH3I
DMSO
NH
2
5 min, 100 °C
CH
3
N
S
NC
11
[
C]DASB
11
[
C]CH3OTf
NH
2
2-butanone
1 min, RT
HO
S
N
11
[
C]PIB
11
NH
CH
11
[
O
NH
F
O
N
O
N
C]CH3I
DMSO, KOH
F
5 min, RT
11
O
CH
3
N
N
11
O
O
N
poorly nucleophilic, [11C]CH3OTf may not be suciently reactive. To address such cases,
Pike etal. showed that solid, inorganic bases like Li
CH
I in DMF eectively 11C-methylated a range of nitroanilines and pyrroles at room tem-
3
N and Li2O in combination with [11C]
3
perature with ultrasonication in moderate RCYs[269]. Carbon-11-methylated secondary
and tertiary amides are also common targets, in which case the presence of a base is
required. [
11
C]Flumazenil (Figure7.31c), a GABAA receptor antagonist, was radiolabelled
on a solid-supported thin lm of KOH in DMSO, in 5–10% RCY, with a molar activity of
520–600 GBq· μmol
11
[
C](CH3)2NH has been reported as a precursor for introducing 11C-methyl groups using
electrophilic precursors. [
−1
(End-of-synthesis [EOS])[112].
11
C](CH3)2NH is prepared by 11C-methylation of CH3NH2 and has
been used in nucleophilic substitutions with primary benzyl bromides in N,N-dimethylacetamide (DMA) in the presence of Hunig’s base (Figure7.32a)[284]. Unlike benzyl
bromides, allyl and simple alkyl bromides react sluggishly under these conditions.
Palladium-mediated N-methyl-
11
using [
C]CH3I in the presence of Cp2Fe2(CO)4 as a CO source has been reported by Norde-
man etal.[285]. N-methyl-
11
11
C-acetylation of alkyl and benzylamines and anilines
C-acetylated products were obtained in good RCYs at 160 °C for
10 minutes in THF; however, sterically hindered substrates performed poorly (Figure7.32b).
7.4.3.3 O
11
C-Methylated phenols and esters are also common radiolabelled motifs. Their precursors are poor nucleophiles when protonated. However, their conjugate bases, phenolates,
and carboxylates, respectively, are potent nucleophiles and react rapidly with [
11
C]CH3I
182 Handbook of Radiopharmaceuticals
3
(a)
(b)
[
C]Melatonin
11
HN
H
CH
3
C]CH3I
[
THF/DMSO
5 min, 45 °C
HN
11
CH
3
CH
3
N
O
2
iPr
dimethylacetamide
2
EtN
Br
N
O
2
11
N
CH
CH
3
10 min, 40 °C
H2N
OMe
N
H
Pd(XantPhos)Cl
[CpFe(CO)
11
[
C]CH3I
2
2]2
THF, 10 min, 160 °C
H
11
H
C
N
3
O
11
OMe
N
H
and [11C]CH3OTf. Thus, tetra-n -butylammonium hydroxide or an alkali hydroxide is usually
required in the reaction mixture unless preformed salt is being used.
phenols and carboxylic acids[286] can also be accomplished using [
[Methyl-
11
C]Raclopride, a D2-selective dopamine receptor antagonist, was labelled
11
C-Methylation of
11
C]CH2N2[102].
using the loop method at the phenolic position of preformed desmethylraclopride tetran-butylammonium (TBA) salt with [
11
C]CH3OTf in 2-butanone (Figure7.33a)[125]. A nucleophilic tertiary amine and a secondary amide within the molecule remain unreacted.
Similarly, an oestrogen receptor ligand (Figure7.33b) can be methylated at the carboxylic
acid in the presence of an unprotected phenol[288]. This is a result of the dierence in pK
between acids and phenols (c. 2–4 vs. 7–11, respectively). [
imaging of adenoma, was esteried in DMF with [
(Figure7.33c). Instead of using [
11
C]CH3I, Ackermann etal. employed either BF3·Et2O[289]
11
11
C]Metomidate, an agent for
C]CH3I from the carboxylic acid TBA salt
and 1,3-dichlorodibutylstannoxane[290] as mediators to accomplish esterication with [
CH
OH in moderate RCY thorough addition-elimination or transesterication, respectively.
3
O-alkylations of other functional groups are less common.
usually prepared using [
bamic acid, made either by bubbling CO
by transcarboxylation from the DBU-CO
receptor agonist, was achieved in 8.2% RCY using [
ve minutes (Figure7.33d)[292]. The use of [
11
with [
C]CH3I required heating, resulting in partial decarboxylation of the carbamic acid
and production of the N-
11
C]methyl chloroformate[291] or via 11C-methylation of a car-
through a solution of the amine precursor or
2
adduct. Labelling of [11C]GR103545, a κ-opioid
2
11
C-methylated compound as a byproduct[293]. The 11C-meth-
11
C]CH3OTf at room temperature in
11
C]CH3OTf proved critical, as the reaction
11
C-Methyl carbamates are
a
11
C]
ylation of the hydroxyl group of an oxime has also been reported, illustrated by the synthesis of [
and [
11
C]ABP688 and similar compounds as mGlu5 antagonists in the presence of NaH
11
C]CH3I at 90 °C for ve minutes (Figure7.33e)[294, 295].
Figure 7.32
Radiolabeling
of amines using
[
C]dimethylamine
N
source and [
C]CH3I.
7.4.3.4 S
The most widely used radiopharmaceutical labelled at sulfur is [methyl-11C]-l-methionine,
which is used for imaging of the rate of amino acid transport and protein biosynthesis.
183
11
(a)
(c)
11
Cl
TBA
(d)
Cl
(e)
(b)
[
C]ABP688
O
Cl
H
Cl
C
3
O
O
N
H
N
OH
O
OH
[
C]CH3OTf
N
H
N
DMSO
90 s, RT
Cl
11
[
C]raclopride
O
OH
N
O
11
[
C]CH3OTf
CN,
CH
3
NaOH
O
O
11
CH
3
O
N
HO
F
N
3 min, 80 °C
F
N
HO
11
[
C]CH3I
DMF
min,
4
DBU·CO
min,
5
130
0
°C
,
2
–25
DMF
°C
11
[
C]metomidate
N
O
N
O
HN
O
OTBA
N
N
N
O
N
Cl
Cl
11
[
OH
N
N
I, NaH
C]CH
3
DMF
5 min, 90 °C
N
11
CH
O
3
O
N
N
O
N
11
[
C]CH3OTf
5 min, 25 °C
Cl
H
Cl
11
CH
3
O
N
O
N
N
O
O
11
C
3
Cl
11
[
C]GR103545
N
11
Figure 7.33 O
oestrogen receptor ligand.
184 Handbook of Radiopharmaceuticals