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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5624_Библиотеки_им_академика_М_И_Перельмана.pdf
(DBU)[177] and then Wilson etal. using the phosphazine base 2-tert-butylimino-2-dieth-
(a)
(b)
ylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP)[178], enabling [
11
C]CO2 to
react rapidly under mild reactions conditions without the need for specialised laboratory
apparatus (Figure7.17b). This chemistry was applied to carbonylvia reaction of aliphatic primary[177] and secondary[178] amines with [
11
C-carbamate synthesis
11
C]CO2 in the
presence of an alkylating agent in good RCY. Anilines, however, proved to be more challenging substrates. Biologically active molecules, including the serotonin-receptor antag-
11
onist [
deacetylase inhibitor [
C]metergoline[177], the κ-opioid agonist [11C]GR103545[178], and the histone
11
C]MS-275[179], have been radiolabelled using this technique.
RNH
2
Q
Bases (Q):
N
N
DBU
11
[
–90
C]CO
NEt
11
[
N
2
3
o
C
C]CO
N
N
P
N
BEMP
Figure 7.17
Reaction of amines
with [
2 in the
tion agents.
O
R
N
*
H
2
Q
POCl
3
O
R3Y
*
N
C O
R
O
Y
O
Q
*
Path
O
O
*
1
R
NH
2
R
Path
O
1
R
N
*
2
R
RNH
2
3
R
I
R
R
II
R3Y
O
QH
R
symmetrical
11
1
NH
2
R
11
O
R
NHN
*
H
C-ureas
O
1
O
N
*
2
R
C-carbamates
3
R
(c)
POCl
3
O
XH
R
or
1
X
N
*
2
R
11
C-ureas,
11
C-carbamates
3
R
O
1
R
O
P
Cl
O
N
*
Cl
2
R
1
R
or
*
N
C O
3
R
X = NR
O
O
N
O
*
H
H
[11C]metergoline
32–40% RCY
<185 GBq/µmol
F
C
O
Cl
N
H
Cl
N
N
O
N
O
N
*
O
[11C]GR103545
24–35% RCY
108–162 GBq/µmol
H
N
O
*
O
[11C]CURB
19% RCY
93 GBq/µmol
3
OH
[11C]SL25.1188
12% ndc RCY
37 GBq/µmol
O
N
O
N
*
O
OMe
165
When evaluating DBU and BEMP as xation agents, Wilson etal. found that the latter
HPLC
MFC (N
MFC (N2, 2 Bar)
oered superior [
11
C]CO2 trapping and product yields, allowing 11C-carbamate formation
to proceed at room temperature in approximately one minute[178]. Mechanistically,
there are two possible reaction pathways following the formation of the base-[
11
C]carbamate intermediate, depending on the order of the subsequent reactions with the amine
and alkylating agent (Figure7.17b, Paths I and II). Investigating this, Wilson etal. obtained
optimal product yields when the order of reagent addition was tailored to Path II ([
11
C]CO2
xation in the presence of the amine, followed by addition of alkylating agent), and that
when this order was reversed, yields were very low[178].
In 2011, Wilson etal. extended this methodology to the synthesis of unsymmetrical
carbonyling agent POCl
11
C-ureas and carbonyl-11C-carbamates (Figure7.17c)[180] using the dehydrat-
to convert the 11C-carbamate intermediate into an 11C-isocyanate, which
3
can undergo reaction with a second amine or alcohol. Numerous PET tracers containing
11
[
C]carbamate[180–184] and 11C-urea[184–187] functional groups have been synthesized
using this approach, including the clinically validated fatty acid amide hydrolase (FAAH)
inhibitor [
previously only accessible in low yields from [
11
C]CURB[188] and the monoamine oxidase B (MAO-B) inhibitor [11C]SL25.1188,
11
C]phosgene[189].
This methodology was later transferred to an automated “in-loop” system consisting of three HPLC loops connected to an eight-port, two-way valve (Figure7.18)[190].
The loops are rst pre-loaded with reagent solutions: reactor loop A with amine and
xation base; the reagent loop with the dehydrating agent, POCl
; and reactor loop B
3
with the second nucleophile (alcohol or amine). The reaction then proceeds in stages:
11
rst, [
11
reagent loop to form the
reactor loop B, where it reacts with the nucleophile. The
C]CO2 is passed into and xed in reactor loop A to form the intermediate
C-carbamate ion, followed by the addition of POCl3 into reactor loop A from the
11
C-isocyanate. The 11C-isocyanate can then be eluted into
11
C-labelled product can then
Reagent
loop
[11C]CO2 from target
V1
, 2 Bar)
2
Liquid nitrogen
Detector
Figure 7.18 2
Waste
Lift
V2
V3
Waste
AB
Reactor loop
Detector
Receiving
vial
Vent
Detector
John Wiley & Sons.
166 Handbook of Radiopharmaceuticals
be eluted into the receiving vial. [11C]SL25.1188 and two novel FAAH inhibitors were syn-
RN
2
R
2
R
1
20–80 oC
thesized using this method, and in all cases, non-isolated RCYs were higher than for the
corresponding vial reactions.
Dheere etal. reported an alternative pathway to access symmetrical[191] and unsym-
metrical[192] carbonyl-
11
C-ureas, utilising the Mitsunobu reaction to facilitate reaction
of poorly nucleophilic amines such as anilines (Figure7.19a). This reaction proceeds in
three stages: (i) DBU-mediated [
11
C]CO2 xation to form a 11C-carbamate intermediate,
(ii) addition of Mitsunobu reagents (tributylphosphine and di-t-butyl azodicarboxylate)
to form an oxyphosphonium species, and (iii) reaction with a second amine upon gentle
heating. This provides
was later extended to the production of
11
C-ureas in high RCYs of 69–94%. The scope of this methodology
11
C-amides via reaction of the oxyphosphonium intermediate with Grignard reagents (Figure7.19b) and applied to the synthesis
the hormone [
11
C]melatonin[193]. In 2018, Downey etal. performed a proof-of-concept
loop-based Mitsunobu radiolabelling reaction to synthesise the model compound
N,N′-[carbonyl-
11
C]dibenzylurea with a RCY of 72%, in a process lasting only three min-
utes[194].
─
Base-mediated [11C]CO2 xation chemistry has also been exploited for 11C─C bond
formation, providing a milder alternative to Grignard chemistry. This was rst reported
in 2012 by Riss etal. using boronic esters to form carbonyla copper(I)-mediated process (Figure7.20)[195]. Boronic esters can be incorporated
onto highly functionalised molecules and are less sensitive to moisture and oxygen
than Grignard reagents, allowing for easier handling and storage. Tetramethylethylenediamine (TMEDA), acting as both xation agent and chelating ligand for copper, was
identied as the optimal base, providing near-quantitative [
yields for a broad range of functionalised
11
C-carboxylic acids, with electron-decient
and amino-substituted aromatics being the most challenging substrates.
acids could be further derivatised in a one-pot process using alkylating, chlorinating, or
coupling agents (Figure7.20a–c), as exemplied by the synthesis an oxytocin receptor
ligand[195], the retinoic acid X receptor agonist [
agonist [
3-hydroxycyclopent-1-ene-[
11
C]AH-7921[197], and a ligand for γ-hydroxybutyric acid (GABA) binding sites
11
C]carboxylic acid[198].
11
C]bexarotene[196], the μ-opioid
11
C-carboxylic acids through
11
C]CO2 trapping and high
11
C-Carboxylic
Figure 7.19 [2
R
subsequent Mitsu
1
R
nobu reaction to
form [
[
C]amides.
1
C]ureas and
(a)
11
[
C]CO
H
2
2
DBU
O
R
N
O
*
H
PBu
DBAD
3
O
R
PBu
N
*
H
3
O
(b)
N
H
50 oC
R1MgBr
R
R
O
NHN
*
O
NHR
*
167
O
Figure 7.20
mediated
carboxylation of
boronic esters and
subsequent deriva
tisation reactions.
CH3I, TMEDA
(a)
R
O
B
O
R
[11C]CO
R
CuI, TMEDA
crypt–222, KF
100
2
o
C
R
O
OH
*
(b)
(c)
1.
SOCl
2
HN
2.
1. Diisopropylcabodiimide
2. DMAP, NHS
O
F
CH
3
O
*
O
N
*
O
O
O
N
O
*
O
O
OH
*
N
*
O
oxytocin ligand
20% RCY
56 GBq/µmol
O
N
*
H
O
F
[11C]AH–7921
~200 GBq/µmol
N
1–2% RCY
HO
[
831–1012 MBq
1. 5 GBq/µmol
11
C]HOCPCA
O
OH
*
11
[
C]bexarotene
15% RCY
>11 GBq/µmol
7.4.2 Reactions with [11C]CO
[11C]CO was one of the very rst 11C radiotracers to be investigated in humans[7]; yet
despite its ease of production and the prevalence of the carbonyl group in biologically relevant molecules, it was not exploited as a radiolabelling reagent until relatively
recently due to the challenges associated with its handling and reactivity. The poor solubility of CO in common organic solvents means conventional carbonylations are typically
performed using a large stoichiometric excess of CO and often require high temperatures, elevated pressures, and extended reaction times; conditions that are dicult to
achieve with low-mass, low-concentration [
the use of stoichiometric catalyst loadings, favouring increased reaction rates and fast
conversions.
The palladium(0)-catalysed Heck carbonylation[199, 200], which couples an electrophile and a nucleophile with CO, has been extensively investigated for
due to its compatibility with a wide range of nucleophilic substrates (Figure7.21).
Early attempts involved Stille-type coupling of organotin reagents and aryl halides to
generate carbonyl(Figure7.21a)[201–203]. While
11
C-ketones, following delivery of [11C]CO at atmospheric pressure
11
C-ketones were generally produced in high radiochemical
purity, RCYs were low (~10%), with the majority of [
solution. The principal challenge in
sucient quantities of [
11
C]CO into solution in order to react. Over the years, a number of
11
technological and chemical approaches have been developed to overcome this problem.
11
C]CO. These conditions, however, allow for
11
C-radiolabelling
11
C]CO passing unreacted through the
C-carbonylation chemistry, therefore, is to transfer
168 Handbook of Radiopharmaceuticals
Ar
R
(a)
*
*
(b)
R-SnMe
or R-B(OH)
R2NH
Figure 7.21 Scope
2
R
1
catalysed
Ar
O
*
3
2
R
1. R1R2NH
2.NaBH
3
CN
Ar
N
*
R
reactions.
O
Ar N
R
*
R
(c)
11
[
X
C]CO
L
n
Pd
0
(d)
(e)
(f)
Et3SiH
ROH
OH
–
Cl
–
O
Ar H
*
O
Ar
*
O
Ar
*
O
O
OH
R
–
Nu
Ar
Cl
Ar Nu
Preconcentrating [11C]CO on a liquid-nitrogen-cooled silica trap prior to delivery to
the reaction media has been reported to increase [
30–40%[204, 205]. A gas-handling system in which [
reagent solution leads to a further improvement, enabling
36–62% RCY[204].
11
C]CO incorporation to around
11
C]CO is recirculated through the
11
C-ketones to be obtained in
H
O
An alternative means of increasing [11C]CO solubility is to increase the gas pressure within
a sealed vessel. To achieve this, Långström etal. developed a micro-autoclave reactor
capable of performing
peratures (~200 °C) (Figure7.22)[207]. In this process, preconcentrated [
ferred into the micro-autoclave chamber; the coupling reagent solution is then added
using an HPLC pump that compresses the gas to <2% of the liquid volume, thus producing
a pseud one-phase system[208, 209]. An alternative high-pressure reactor was reported
11
C-carbonaylations at high pressures (~35 MPa, 350 atm) and tem-
11
C]CO is trans-
169
Figure 7.22
autoclave reaction
system. Source:
Wiley & Sons.
in 2002, in which the reactant solution is pushed through the [11C]CO trapping loop and
into the microreactor[210].
The micro-autoclave was initially used for the synthesis of carbonyl-
11
C-amides in good
RCY and with excellent molar activity via Pd(0)-catalysed reaction of aryl halides and
amines with [
11
C]CO[211], and has since been used to prepare 11C-radiolabelled ketones,
amides, aldehydes, esters, carboxylic acids, and derivatives such as amines, alkyl iodides,
and acyl chlorides (Figure7.21a–e)[23, 209].
In 2017, Dahl and Nordeman reported the direct synthesis of carbonyl-
chlorides via Pd(0)-catalysed
11
C-benzoyl chloride could undergo further reactions with various nucleophiles to form
the corresponding
11
C-labelled carboxylic acids, amides, esters, or aldehydes as well
11
C-carbonylation of aryl halides (Figure7.21f)[212]. The
11
C-benzoyl
as alcohols and ketones[213]. In 2017, Altomonte etal. reported that the use of reactive diaryliodonium salts in place of aryl halides in the Heck
11
C-carboxylic acids and 11C-amides to be formed at room temperature[214].
High-pressure
11
C-carbonylations have been used to radiolabel numerous drug-like
11
C-carbonylation enabled
molecules, as shown in Figure7.23[215], including the α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor modulator [
11
[
C]FIMX[216], the translocator protein 18 kDa (TSPO) receptor ligands 11C-PK11195[217]
11
and [
C]DAA1106[218], the AT1 receptor ligand [11C]eprosartan[219], the β-secretase 1
(BACE-1) inhibitor [
11
C]BSI-IV[220], histamine H3R ligands[221], the histone deacetylase
11
C]CX546[210], the mGluR1 ligand
170 Handbook of Radiopharmaceuticals
O
N
O
455 GBq/µmol
O
11
C]CX546
[
Pd(PPh
37% RCY
4–19 GBq/µmol
O
O
S
N
*
HN
O
[11C]BSI-IV
Pd(xantphos)Cl
29% RCY
4–19 GBq/µmol
Figure 7.23
radioligands
synthesised via
reactions.
N
O
*
C]MK-0233
Pd(PPh
NH
N
F
3)4
N
O
N
*
N
O
S
N
*
F
11
C]FIMX
[
3)4
Pd(PPh
37% RCY
3)4
NH
N
O
11
[
Human PET study
100 GBq/µmol
O
OH
S
N
3)4
HN
HO
NH
Ph
O
[
2
393 GBq/µmol
N
11
C]PK11195
Pd(PPh
55% RCY
O
N
*
Cl
O
*
OH
N
[11C]eprosartan
3)4
Pd(PPh
37–54% RCY
360 GBq/µmol
O
N
O
Histamine H3R ligand
(dba)3/P(o-tol)
Pd
2
9% RCY
398 GBq/µmol
O
*
F
O
F
*
N
N
O
O
F
3
OPh
[11C]DAA1106
Pd(PPh
3)4
30% RCY
[11C]tubastatin A
Pd
N
(dba)3/xantphos
2
16% RCY
8 GBq/µmol
OH
N
*
H
6 inhibitor [11C]tubastatin-A[222], and the neuropeptide Y5 receptor antagonist [11C]
MK-0233[223, 224], which has been studied in humans[225]. Aberg and Långström used
this approach to synthesise a library of 12 potential irreversible epidermal growth factor
receptor (EGFR) inhibitors from 4 substituted vinyl iodides and 3 dierent amino-quinazolines through Pd(0)-catalysed
11
C-carbonylation reactions using a single set of reaction
conditions[226]. A semi-automated dispensing system for performing multiple carbonylation reactions with a single batch of [
and may facilitate combinatorial
11
C]CO has been developed by Van der Wildt etal.
11
C-radiolabelling strategies[227].
171
The scope of the micro-autoclave system has been explored beyond Pd(0)-catalysis.
O
Nu
11
C-Labelled ureas[228–231] and carbamates[228] have been produced by Rh(I)catalysed
radiolabelling (Figure7.24). This reaction is thought to proceed via an
11
C-carbonylation of azides, providing an alternative to [11C]CO2 or [11C]COCl2
11
C-isocyanate
intermediate, which can then react with a nucleophile to generate the corresponding
11
C-carbonyl compound. A carbonyl-11C-malonate has been produced using a diazo starting
material instead of an azide. This could be further functionalised at the α-carbonyl
position by deprotonation and reaction with an alkylating agent[232]. Rh(I)-catalysed
11
C-carbonylations have been used to synthesise bioactive molecules such as the cytotoxic sulfonylurea [
11
C]LY-181984[231], the Pgp substrate [11C]phenytoin[24], and a dual
vascular endothelial growth factor receptor-2/platelet-derived growth factor receptor β
(VEGFR-2/PDGFRβ) inhibitor[230].
The transition metal-catalysed reactions described so far are limited to methyl,
benzyl, aryl, and vinyl halides as the electrophilic coupling partner to avoid competing
β-hydrogen elimination at the metal centre following oxidative addition. To extend the
labelling of aliphatic substrates, Långström etal. explored metal-free photoinitiated
11
radical
with a sapphire window to allow irradiation of UV light to prepare
C-carbonylations of alkyl iodides using a modied micro-autoclave equipped
11
C-labelled aliphatic
amides[233, 234], esters[234–236], and carboxylic acids[208, 236–238] (Figure7.25a).
Reactions generally proceeded in good RCY, although in some cases photosensitisers such as acetone, benzophenone, or di-t-butyl peroxide were added to improve
yields[234, 236].
Selenium-catalysed high-pressure
11
C-carbonylations have also been investigated
for the conversion of amines, amino alcohols, and alcohols into cyclic and acyclic
carbonyl-
11
C-ureas, carbonyl-11C-carbamates, and carbonyl-11C-carbonates, respectively
(Figure7.25b)[239]. These reactions are thought to proceed via initial formation of
11
[
C]carbonyl selenide, which can then undergo reaction with an amine to produce an
intermediate
11
C-isocyanate. Subsequent nucleophilic attack of the isocyanate yields the
Figure 7.24
alysed
bonylation to
[11C]CO
N
3
RhL
n
– N
2
form carbamyl
derivatives.
H
N
*
S
O
O
O
[11C]LY- 181984
[Rh(cod)Cl]
68% RCY
H
N
, PPh
2
172 Handbook of Radiopharmaceuticals
11
C
III
Rh
N
Cl
3
L
n
HN
*
O
[11C]phenytoin
Rh
(OAc)4, DPPE
2
22% RCY
277 GBq/µmol
O
NH
VEGFR-2/PDGFR inhibitor
O
11
C
N
N
O
O
O
F NHN
[Rh(cod)Cl]
O
*
, PPh
2
78% RCY
92 GBq/µmol
Nu
F
H
3
O
11
C
N
H
RI
′
(a)
11
[
C]CO
hv
H
O
2
R′-OH
O
R
OH
*
O
R′
R
O
*
OH
73% RCY
O
O OH
188 GBq/µmol
*
O
O
*
61% RCY
158 GBq/µmol
Figure 7.25
reactions to form
[
C]carbonyl
compounds.
O
N
*
N
Ph
54% RCY
192 GBq/µmol
R′-NH
2
O
R N
*
R′
H
(b)
Se
11
[
C]CO
Se
R-NH
– SeH2
O
2
R
N
O
[11C]SBox-13
44% RCY
O
*
C
N
N
*
O
O
*
C
Ph
R-XH
CN
R
O
NHX
corresponding 11C-carbamoyl product. This method was used to synthesise the oxazolidinone MAO-B radioligand [
11
C]SBox-13, previously accessed via [11C]COCl2.
Despite the success of high-pressure 11C-carbonylation, its technical complexity and lack
of commercial availability have prompted researchers to explore alternative approaches.
In 2004, Audrain etal. reported on the use of BH
enhance [
11
C]CO solubility at atmospheric pressure via coordination of BH3 to the lone
electron pair of CO[240]. This process was used to synthesise a model carbonyland model carbonyl-
11
C-lactone in moderate RCY via Pd(0)-catalysed 11C-carbonylation. In
2009, Kealey etal. used a copper(I) tris(pyrazolyl)borate (CuTp*) complex to coordinate
11
[
C]CO, observing near-quantitative [11C]CO trapping at room temperature without the
need for a preconcentration step[241]. [
11
C]CO was released by addition of a competing
phosphine ligand and used directly in a one-pot Pd(0)-catalysed
form model carbonylNPY-Y5 radioligand [
11
C-amides and carbonyl-11C-carboxylic acids[241–243], including the
11
C]MK-0233 (Figure7.26)[244].
•THF as a complexation agent to
3
11
C-carbonylation to
11
C-amide
R
173
O
O
48% RCY
N
*
H
N–benzyl[carbonyl-11C]benzamide
: 47% RCY
via BH
3
via Cu(I): 67% RCY
via xenon: 71% RCY
via Pd-xantphos: 98% RCY
Ph
N
O
N
*
H
VAChT ligand
via xenon
9% RCY
55–78 GBq/µmol
N
OH
NH
N
O
*
O
[11C]MK-0233
via Cu(I)
7% RCY
100 GBq/µmol
H
Ph
Ph
11
[
C]N-tritylacrylamide
via xenon/Pd-xantphos
86–170 GBq/µmol
N
*
Ph
O
22% RCY
N
F
i
Bu
S
S
O
[11C]C21
via xenon
24% RCY
34–51 GBq/µmol
O
N
N
H
receptor ligand
3
via Pd-xantphos
88% RCY
121 GBq/µmol
N
N
O
O
N
OBu
*
H
O
*
NH
O
Ph
Cl
O
N
*
H
N
N
N
H
TG2 inhibitor
via xenon
38–45% RCY
220 GBq/µmol
O
O
N
*
H
OH
Cl
[11C]raclopride
via Pd-xantphos
50% RCY
34 GBq/µmol
N
N
O
N
N
N
cyclo-RGD
[11C]lactone-cycloRGD
bioconjugate
via Pd-xantphos
O
*
O
N
O
*
H
11
[
C]JNJ-31020028
via Ar-Pd-xantphos
25% RCY
N
FN
O
N
Ph
N
Figure 7.26
ation methods.
During these experiments, it was observed that replacing the Pd(0) with a Pd(II)
species led to the formation of homocoupled N,N′-[carbonylside product. This reaction was further developed for the synthesis of
11
C]dibenzylurea as a major
11
C-labelled symmetrical and unsymmetrical ureas (Figure7.27a). Urea formation is thought to proceed
via a Pd(II)-mediated oxidative carbonylation process, as previously reported using
174 Handbook of Radiopharmaceuticals