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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5903_Библиотеки_им_академика_М_И_Перельмана.pdf
(a)
(b)
3
(+)-[11C]PHNO
Boc
Ph
*
O
NPh
OEt
KOH, Bu4NHSO
DCM, 10 min, RT
I
4
Ph
O
NPh
OEt
aq. HCl
15 min, 100 °C
*
H2N
O
OH
*
DL-[3-11C]phenylalanine
1. BuLi, TMP
THF, –72 °C,
N
N
O
2. [11C]CH3I,
5–8 min, RT
Boc
N
N
O
11
CH
3
aq. HCl
8–10 min, 200 °C
H2N
L-[3-
O
11
CH
3
11
C]alanine
OH
(c)
(d)
(e)
O
TIPSO
Ph
Ph
N
Ni
N
N
Ph
O
NPh
OtBu
1. NaOH, acetone
2. [11C]CH3I,
5 min, 80 °C
R
N
R
[11C]CH3I, CsOH.xH2O,
Br
O
O
toluene/DCM,
5 min, 5 °C
O
N
1. LHMDS
THF, –78 °C,
2. [11C]CH3I,
O
TIPSO
Ph
O
O
N
Ni
N
N
Ph
11
CH
3
O
NPh
OEt
11
Ph
CH
3
N
5 min, 130 °C
1.5 min, 150 °C
O
11
CH
aq. HCl
aq. HCl
3
H2N
L-[3-
THF
BH
1.
3
7 min, 60 °C
2.
HCl
11
CH
11
C]alanine
H2N
L-[3-
O
OH
3
O
11
CH
3
11
C]alanine
HO
OH
11
CH
N
3–7 min, RT
Figure 7.41
thesis of a propyl group from a N
Filp, Pekošak, and Windhorst described the stereoselective 11C-alkylation of achiral
N-diphenylmethyleneimine glycinate precursors employing chiral phase-transfer catalysis (PTC). The combination of chiral cinchonium alkaloid or chiral ammonium bis-naphthyl derivatives with an excess of solid CsOH was found to induce stereoselectivity during
11
the
C-alkylation reaction of glycinate Schi base derivatives with [11C]CH3I or [α -11C]BnI
in toluene or toluene/dichloromethane mixtures.
11
l-[3-
C]Alanine was synthesised using
an automated method in 20% RCY and >90% ee (Figure7.41d)[348]. Similar RCY and stereoselectively were observed for the radiosynthesis of
the pseudoenantiomer of the catalyst, the
d-enantiomers of the
11
l-[3-
C]phenylalanine[349]. Using
11
C-labelled amino acids
could be accessed, albeit in lower RCY and enantiomeric excesses. Di- and tetrapeptides
195
were radiolabelled using this method, including the pharmacophore of somatostatin
2
(a)
(b)
2
receptor-targeting peptides, which were obtained in >90% ee[350, 351].
Takashima-Hirano etal.[352] and Kato etal.[353] reported the
enolates generated from arylacetates to give 3-
11
C-arylpropionates in 26–76% RCY. A
11
C-methylation of
similar reaction using the amide enolate generated in a reaction of N-acetyl amide with
n-BuLi gave the N -3Garcia-Arguello etal. used similar
receptor agonist (+)-[3amide derivative could be deprotonated by LiHMDS at −78 °C and reacted with [
at room temperature to give the N -3acidic deprotection gave (+)-[3-
11
C-propionyl derivative, albeit in low RCY due to side reactions[354].
11
C-methylation for the synthesis of dopamine D2/3
11
C]PHNO[489]. The authors showed that a protected N-acetyl
11
C]CH3I
11
C-propionyl derivative. Reduction by BH3•THF and
11
C]PHNO in 9% RCY in 60 minutes using an automated
synthesiser (Figure7.41e).
7.4.4 Reactions with [11C]Cyanide
[11C]Cyanide ([11C]CN−) is a reactive nucleophile that undergoes substitution reactions
with alkyl halides to produce organic nitriles, which may be further derivatized to obtain
11
C-labelled carboxylic acids[355–359], amides[360, 361], or amines[362] (Figure7.42a).
The wide reactivity of the nitrile group allows for more complex transformations: for
example,
lecular cyclisation has been used to radiolabel [2tionally, [
aziridine derivatives to produce
11
C-cyanoalanine could be converted in one step to the formamide (asparagine), the acid
(aspartic acid), or the amine (2,4-diamino-butyric acid) (Figure7.42c)[364].
11
C-cyanation of 2-nitrobenzyl bromide followed by nickel-catalyzed intramo-
11
C]indole (Figure7.42b)[363]. Addi-
11
C]CN− participates in ring-opening reactions, as exemplied by the reaction of
11
C-labelled amino acids. In this process, the intermediate
Figure 7.42
cations of
[
C]cyanide as a
nucleophile to
give [
R X
11
[
C]CN
–
which may be
further hydro
lysed or reduced
to give other
functional groups.
(c)
NH
H
N
CO
2
H
11
Br
[
C]CN
2
11
[
C]CN
i
Pr
196 Handbook of Radiopharmaceuticals
hydrolysis
*
R
CN
partial hydrolysis
reduction
OH
*
R
O
NH
2
*
R
O
NH
R
2
*
–
–
11
N
11
NH
2
O
C
NH
2
CN
i
O
Raney Ni
N
2
hydrolysis
Pr
or reduction
*
H
H
HCO
4.
2
N
H
21% RCY
176 GBq/μmol
O
R
OH
NH
11
=
R
[
C]CONH
C]CO
C]CH
2
H
2
NH
2
11
=
[
11
=
[
11
(a) Bucherer-Bergs
C-Amino acids may be synthesised by the Bucherer-Bergs reaction (often referred
to as the Bucherer-Strecker method). This multicomponent reaction combines an
aldehyde or ketone with ammonium carbonate and carrier-added [
typically performed at high temperature and pressure. The resultant
intermediate is subsequently hydrolysed to yield the corresponding carbonyl-
11
C]cyanide and is
11
C-hydantoin
11
C-amino
acid (Figure7.43a). This approach has been used to access a range of radiolabelled aromatic (e.g. tyrosine[365], trytophan[366], phenylglycine[367], and
l-DOPA[368]) and ali-
phatic amino acids (e.g. leucine[369], glycine[370], α-aminoisobutyric acid[371, 372], and
1-aminocyclopentanecarboxylic acid [ACPC][373–375]). An automated apparatus for the
production of a range of amino acids has been described[376].
The Strecker reaction allows carbonyl-
addition, via reaction of [
11
C]CN− with an aldehyde or ketone in the presence of ammonia,
followed by hydrolysis of the intermediate α-amino-
11
C-amino acids to be synthesised without carrier
11
C-nitrile (Figure7.43b). This was
originally performed using aldehyde-bisulte adducts in place of the parent aldehydes to
generate
11
C-labelled amino acids such as ACPC[76], alanine[377, 378], phenylalanine, and
tyrosine[379]. The analogous reaction of aldehyde-bisulte adducts in the absence of
ammonia generates
the synthesis of
11
C-cyanohydrins, which may be further derivatized, as exemplied by
11
C-labelled lactic acid[380, 381], dopamine[382], and octopamines[383].
(b) Strecker
Na
11
[
C]CN
R H
R
SO
2
OH
R
R
–
O
O
3
SO
OH
*
H
3
CN
11
[
(NH4)2CO
Na
C]CN
11
[
NH
NaOH
–
C]CN
NH
3
3
Figure 7.43 Reac
tion of [
containing
compounds.
NH
11
C]Leucine
O
OH
*
2
H2N
O
OH
*
R
[
O
HN
*
O
3
NH
NaOH
R
25% RCY
O
H
N
11
[
C]Sarcosine
3% RCY
O
NH
11
[
C]ACPC
60%
*
*
RCY
OH
OH
2
–
NH
2
*
R
NaOH
CN
H2N
O
OH
*
R
–
11
[
C]CN
NH
2
Na
SO
R
3
OH
OH
*
O
11
C]Lactic acid
HO
O
OH
*
R
[
C]cyanide
197
A direct Strecker approach, starting from the parent aldehyde, has been used to generate
(a)
(b)
an α-amino-[
In this process, [
11
C]nitrile as an intermediate in the synthesis of [11C]levetiracetam[384].
11
C]CN− reacts with an imine generated in situ from reaction of an aldehyde with ammonia. This approach has been used by Xing etal. to synthesise a series of
carbonyland [
11
C-amino acids, including [11C]sarcosine, [11C]methionine, N-phenyl- [11C]glycine,
11
C]glycine in moderate to good RCY via 11C-cyanation of mixtures of aldehydes and
simple amines[385].
Novel methodologies for metal-catalyzed
to the radiochemistry laboratory to provide new radiolabeling strategies with [
cyanide[386]. Aryl
11
C-nitriles may be accessed via metal-catalysed coupling of [11C]CN−
12/13
C-cyanations may be translated
11
C]
and aryl halides, an early example being the reaction of uoroaryl chromium complexes
11
with [
C]KCN[387]. In 1994, Andersson and Långström explored Pd-mediated 11C-cyanation reactions with a range of aromatic electrophiles (Figure7.44a), achieving excellent
RCYs of aryl
of radioligands have been synthesised using this approach, including mGluR
nists [
loid imaging[391], and the aromatase inhibitor [
11
C-nitriles (e.g. [11C]nicotinamide) within ve minutes[388]. A diverse array
antago-
11
C]AZD9272 (Figure7.44)[389] and [11C]SP203[390], 11C-oligothiophenes for amy-
11
C]letrozole[392]. 11C-Nitriles prepared
5
by Pd-mediated reactions can also be further derivatized, illustrated by the synthesis
Figure 7.44
reactions.
R
R
(c)
I
doubly
electrophilic
organometallic
entity
O
*
N
11
[
C]Nicotinamide
45% RCY
70–100 GBq/mmol
X
NH
X
L
Pd
2
[11C]CN
PdL
n
11
[
C]CN
PdL
n
HS
I
L = BrettPhos
F
N
–
R
–
11
R
DMSO
N
O
N
[11C]AZD9272
50% RCY
47 GBq/mmol
11
CN
CN
MeO
NaH, DMSO
F
11
C CO
2
S
CN
Me
2
L
Pd
Me2N
[11C]Citalopram
MeO
C
2
11
[
I
O
85% RCY
CO
R
C]HCN
F
Me
2
11
CN
11
CN
S
11
11
CN
CN
O
OH
S
CO
H
2
HN
HN
HO
N
H
2
NH
GRGDSPC
33% RCY
2
198 Handbook of Radiopharmaceuticals
of carbonyl-11C-enzamides targeting poly(ADP-ribose) (PARP) synthetase[393], and
tuberculosis chemotherapeutics [
11
C]isonicotinohydrazide and [11C]pyrazine-2-carbox-
amide[394].
In an eort to improve yields, Buchwald, Hooker, and coworkers explored the
11
C-cyanation of aryl halides using biaryl phosphine Pd(0) catalysts (Figure7.44a)[395].
They postulated that performing oxidative addition before [
11
C]CN− delivery could
reduce reaction times and that biaryl phosphine ligands would obviate the need for
harsh reaction conditions. By mixing the Pd-ligand complex and aryl halide 30 minutes prior to [
11
C]CN− delivery, 11C-cyanation reactions were found to proceed rapidly
at ambient temperature with excellent functional group tolerance. This process was
used for radiolabelling a range of pharmacologically active compounds, e.g. [
lopram (Figure7.44). Vinyl bromides are similarly converted to vinyl
11
C-nitriles, which
11
C]cita-
may participate in subsequent Michael addition reactions with suitable nucleophiles
(Figure7.44b)[396]. Buchwald and Hooker further extended Pd-mediated
11
C-cyana-
tion chemistry to radiolabel the cysteine residue of unprotected peptides with aryl
11
C-nitriles (Figure7.44c) using a doubly reactive electrophile precursor[397]. This reaction demonstrated good chemoselectivity over other functional groups present on the
peptide, providing
11
C-labelled peptides such as the integrin-targeting RGD peptide
shown in Figure7.44 in good RCY.
Unlike most Pd(0)-mediated reactions, Cu-mediated reactions do not require stringent
air- and moisture-free conditions. Ponchant etal. explored the Rosenmund-von Braun
11
C-cyanation reaction between [11C]CuCN and aryl halides (Figure7.45a)[398], which was
found to proceed in good RCYs with aryl iodide substrates. In some cases, yields were
lower than those obtained under Pd-mediation[399]; however, the Cu-mediated reaction requires no special handling of reagents.
11
C-Cyanations with [11C]CuCN have been
used to prepare a library of potential PET imaging agents for the AMPA receptor[400,
401] and the orexin-2 receptor[401, 402] and employed in the multistep synthesis of the
11
C-tetrazoles, LY202157[403], and irbesartan[404], where the resultant nitrile participates in a subsequent [1 + 3] cycloaddition reaction with NaN
this methodology has been extended to enable copper-mediated
(Figure7.45b). Recently,
3
11
C-cyanation of aryl
boronic acids[405, 406] and aryl stannanes[406] (Figure7.45c). These reactions are compatible with a variety of substituted aryl and heteroaryl substrates and have been applied
to the synthesis of the κ-opioid receptor ligand [
11
drug [
C]perampanel[406].
11
[
C]CN− is readily converted into other reactive labelling precursors, including cya-
11
nate ([
[
C]NCO−), thiocyanate ([11C]NCS−), and cyanogen bromide ([11C]CNBr) (Figure7.46).
11
C]CNBr is prepared by solution-phase reaction of [11C]HCN with bromine[408] or
by gas-phase reaction with pyridinium tribromide[409]. [
umpolung reactivity, providing an electrophilic source of [
11
C]LY2795050[407] and the epilepsy
11
C]CNBr is notable for its
11
C]cyanide and allowing an
opportunity for reaction with nucleophiles such as amines (including proteins)[410] to
11
give
C-cyanamides or 11C-guanidine derivatives[411–414], alcohols (including polysaccharides)[415] to give
pared by oxidation of [
11
C-cyanates, or thiols to give 11C-thiocyanates. [11C]NCO− is pre-
11
C]CN− with KMnO4[380, 416, 417]. Aminolysis of [11C]NCO− with
199
11
CN
X
(a)
(b)
Figure 7.45
mediated
nation reactions.
11
[
C]CuCN
R
11
X
[
C]CuCN
R
11
R
CN
NaN
R
N
N
3
N
N
*
R
SnMe
HCl
3
N
N
N
N
*
H
R
(c)
Ph
11
[
C]LY2232645
50
[M]
R
N
2.5% RCY
GBq/mmol
11
[
C]CN
[M] = B(X)3or SnR
11
CN
11
[
C]Irbersatan
25
–
O
N
N
3% RCY
GBq/mmol
11
CN
R
3
N
N
N
NH
*
10% RCY vs 12% via Pd
N
N
11
[
C]LY 2795050
GBq/mmol
24
O
NH
*
O
Cl
N
2
11
[
N
N
11
C
C]Perampanel
30% RCY
70
GBq/mmol
Ph
O
ammonium sulfate at 185 °C gives [11C]urea[416, 417], which can be used for the synthesis of
[2Emran etal. in the radiosynthesis of 5,5-diphenyl-[2-
be prepared from [
421]. [
11
C-labelled heterocycles such as 2-11C-pyrimidines, including [2-11C]thymine and
11
C]thymidine[418]. 11C-Ureas can also be used to prepare 11C-hydantoins, as shown by
11
C]hydantoin[419]. [11C]SCN− can
11
C]NaCN or [11C]CNBr by reaction with S8 or Na2S, respectively[420,
11
C]SCN− is particularly useful as an intermediate and can be converted to a range of
other functional groups, including thialozones, thiocyanates, isothiocyanates, and sulfenyl-tetrazoles[422], and incorporated into heterocycles such as the myeloperoxidase
(MPO) inhibitor [
11
C]AZD3241[423].
7.4.5 Reactions with [11C]Formaldehyde
[11C]HCHO is not widely used as a precursor for radiolabelling with carbon-11, but the
intermediate oxidation state of this reagent has allowed for its use in a wide range of
reactions for incorporating a one-carbon unit into complex scaolds. [
found application in the synthesis of saturated and unsaturated heterocycles labelled
with carbon-11. Saeed etal. prepared [
radiotracer for imaging proliferating cells, by cyclization of enzymatically produced tetrahydrofolate with [
11
C]HCHO, as shown in Figure7.47a[424]. [11C]Methylenetetrahydrofolate has also previously been prepared from [
system for the synthesis of
the radiosynthesis of two selective 5HT
200 Handbook of Radiopharmaceuticals
11
C]HCHO has
11
C]methylenetetrahydrofolate, a candidate PET
11
C]HCHO in situ in a multistep bioreactor
11
C-labelled nucleosides[425]. [11C]HCHO has been used in
agonists: [11C]WAY163909 and [11C]vabicaserin
2C
KMnO
KOH
O
NH
OH
4
11
N
C
O
4
(NH4)
2SO4
H2N
11
C
NH
2
Figure 7.46
Further derivatiza
tion of [
C]cyanide
to other useful
ROH
Br
11
N
C
2
Br
Na
11
N
C
S
2
RNH
RSH
2
R
11
O
N
C
R
11
HN
C
R
11
C
S
RNH
N
2
N
NH
11
C
N
N
H
H
radiolabelling pre
tracers prepared
from [
RR
derived precur
[
C]
C]
thiocyanate.
S
8
11
N
C
S
RX
11
O
dextran
11
[
C]Dextran, 76 kDa
from
[11C]BrCN via [11C]CN
31% RCY
GBq/mmol
48
CN
O
HN
*
N
O
HO
O
HO
11
[
C]Thymidine
–
from
[11C]Urea via [11C]CN
35% RCY
–
from
O
H
HN
S
N
*
N
O
[11C]AZD3241
[11C]SCN–via [11C]CN
9 GBq/mmol
(Figure7.47b)[426]. These compounds were prepared via a Pictet-Spengler cyclization
11
with [
C]HCHO in modest RCYs of 1.5% and 1.3%, and products had 43 or 31 GBq·μmol−1
molar activity, respectively. Under the acidic reaction conditions required for the cycliza-
12/13
tion, [
C]HCHO is released from the reaction solvent DMF, necessitating substitution
of the solvent for N,N-diethylformamide (DEF ) to achieve acceptable molar activities of
the desired products. The Pictet-Spengler reaction with [
11
C]HCHO has also been used for
radiolabelling cyclic RGD peptides (Figure7.47c) with carbon-11 at a tryptophan residue
in only 35 minutes[427]. Mathews and co-workers prepared [
phate ([
with [
of 90 GBq·μmol
etaldehyde derivative to aord [
NH
and had been prepared by
11
C]AMP) by cyclisation of the carboxamidine phosphate precursor (Figure7.47d)
11
C]HCHO in the presence of palladium on carbon in 2% RCY and with molar activity
−1
in 35 minutes[428]. [11C]HCHO has also been used to cyclize a 2-oxoac-
11
C]atipamezole in 24% RCY in the presence of ZnO and
OH[429].
4
d-Serine is an important co-transmitter of N -methyl-d -aspartate (NMDA) receptors
11
C-hydroxymethylation of chiral nickel(II) complex using
11
C]adenosine 5′-monophos-
–
201
n
OH
[11C]AMP
H
[
N
*
HN
n = 0, [11C]WAY163909, 1.5%
11
n = 1, [
C]Vabicaserin, 1.3%
HN
N
N
N
2
H
11
C]CH2H2folate
DEF, TFA
H
n
N
HN
NH
N
H2N
N
N
R
N
*
O
O
H
SAX
purification
H2N
R
N
H
(a)
(b)
[11C]HCHO
(d)
NH
2
N
NH
N
NH
2
R
HO
O
P
HO
O
2
Pd/C, EtOH
80 °C
NH
N
N
N
O
HN
NH
2
N
H
(c)
HN
R
O
H2N
N
H
DMF, H2O
100 °C
HN
*
N
H
2
N
*
NH
O
N
O
H
CO
H
HN
NH
O
NH
HN
2
O
O
O
O
OH
HO
Figure 7.47
[11C]HCHO, as illustrated in Figure7.48a, in 80% diastereomeric excess and RCY 50%
(based on starting [
11
C]CH3I)[430]. [11C]HCHO has also been used to prepare 1,1′-[11C]
methylene-di-(2-naphthol), a candidate PET tracer for Alzheimer’s disease, and was prepared in an automated synthesizer from [
tions in 48% RCY and with molar activity of 32 GBqμmol
The reactivity of [
11
C]HCHO has facilitated its use for radiolabelling proteins by reduc-
tive amination[431]. Non-selectively N-
11
C]HCHO and 2-naphthol under acidic condi-
−1
(Figure7.48b)[430].
11
C-methylated human serum albumin, brinogen,
and luteinizing hormone were produced in good RCYs of up to 40%, as illustrated in
Figure7.48c. More recently, small-molecule amines have been radiolabelled by reductive
amination in phosphate-buered saline with [
an alternative to radiolabelling amines with [
11
C]HCHO and NaBH3CN (Figure7.48d), as
11
C]CH3I or [11C]CH3OTf[432].
7.4.6 Reactions with [11C]Phosgene
Despite its challenging synthesis, gaseous [11C]COCl2 is a simple reagent to use under
the automated paradigm used for the preparation of carbon-11 radiotracers. [
202 Handbook of Radiopharmaceuticals
11
C]COCl2
HO
Ph
2
*
OH
H
NH
C
HN
2
11
CH
3
= albumin/fibrinogen/
luteinizing hormone
O
N
Ni
N
N
O
Ph
1. NaOMe, MeOH
2. Hydrolysis
NH
2
c.
NaBH
4
O
a.
[
11
C]HCHO
[11C]HCHO
b.
R
N
d.
H
PBS, NaCNBH
70–90 °C
H
HCl/EtOH
110 °C
R
3
OH
HO
HO
*
11
CH
3
NH
HO
24–33%
11
CH
N
H
HO
3
NH
11
CH
N
H
3
27%
HO
S
N
11
NH
CH
3
[11C]PIB, 8%
Figure 7.48
is soluble in various organic solvents, including acetonitrile and toluene, and it is typically trapped from a gas stream at ambient or below ambient temperatures in a solution
already containing precursor[433]. With the rise of applications of [
chemistries for the radiosynthesis of
11
C-carbonyl compounds, the use of [11C]COCl2 is
11
C]CO2 and [11C]CO
likely to see decline in usage due to its dicult radiosynthesis and diculties in obtaining asymmetrically substituted products.
Radiolabelling of candidate PET tracers with [
11
C]COCl2 is challenging as it is reac-
tive toward two equivalents of a nucleophile. Preparation of symmetrically substituted
11
C-carbonyl-labelled-agents is, therefore, fairly straightforward and involves heating
a solution containing both [
11
C]COCl2 and the amine (or alcohol) of interest. Such sym-
metrical molecules are, however, rarely of interest, and often the challenge in using
11
[
C]COCl2 lies in the preparation of asymmetrically substituted 11C-ureas and 11C-carbon-
ates, or in the preparation of
11
C-carbamates. Without selective means for their prepara-
tion, the synthesis of asymmetrically substituted carbonyl compounds relies on the use
203
of precursors with signicant dierences in reactivity and their stepwise reaction with
H
[11C]DPFC
(a)
(b)
11
[
C]COCl2.
11
C-Isocyanates prepared by reaction of [11C]COCl2 with a primary amine in the presence
of a tertiary amine is one strategy used to prepare asymmetrically substituted
11
C-carbonyl-radiolabelled products; however, extensive optimization of the reaction conditions is often required.
11
C-Isocyanates can also be prepared from N,N-bis(trimethylsilyl)
alkylamines[434], from N-alkyl-sulnylamines, or directly from N,N′-organoureas[435].
Dolle etal. performed a detailed optimization of reaction conditions leading to a two-step
one-pot radiosynthesis of [
nist[436]. The intermediate
11
C]GI181771 (Figure7.49a), a cholecystokinin-A (CCK-A) ago-
11
C-isocyanate derivative was formed at room temperature,
followed by reaction with an aniline derivative at 70 °C to aord the desired asymmetric
carbonylmoda etal. described that the coupling of [
eort to minimize symmetrical
11
C-urea in up to 10% RCY and with molar activity of 55 GBq·μmol−1. Similarly, Shi-
11
C]COCl2 and an aminoisoxazole at −15 °C in an
11
C-urea formation during the synthesis of [11C]DPFC for
PET imaging of fatty acid amide hydrolase, as shown in Figure7.49b[437].
Asakawa etal. developed the radiosynthesis of a glycyrrhetinic acid derivative with
the aim of establishing a PET radiotracer for double imaging of kinases and proteasomes
in tumors[438]. To avoid symmetrical
11
C-urea formation, [11C]COCl2 was reacted with
the hydrochloride salts of the corresponding amines, as shown in Figure7.50. The amine
hydrochlorides retained sucient nucleophilicity to react with [
suciently reactive to add to the intermediate
11
C-isocyanate. The second, free amine
coupling partner was then added and underwent rapid reaction with the
to give the desired asymmetric [
11
C]urea in 33% (Figure7.50a) or 69% (Figure7.50b) RCY
11
C]COCl2 but were not
11
C-isocyanate
depending on the sequence of reactions. The automation of the process aorded the
11
C-glycyrrhetinic acid derivative in 5% RCY and with a molar activity of 48 GBq·μmol−1
molar activity. The use of amine hydrochlorides for the synthesis of asymmetric
11
C-ureas via intermediary 11C-isocyanates was also demonstrated in the radiosynthesis
11
of [
C]Sorafenib[439] and for the preparation of three potential 11C-labelled PET radio-
tracer candidates for imaging carbonic anhydrase IX in tumors[440].
Figure 7.49
Formation of asym
metric
using [
2.
N
O
N
NH
O
O
NH
N
2
O
1. [11C]COCl
2.
HN
N
2
204 Handbook of Radiopharmaceuticals
2.
N
S
1. [11C]COCl
2
N
O
N
O
H
2
HH2N
CO
2
N
N
O
H
F
N
N
O
N
*
N
S
N
O
N
H
N
*
O
[11C]GI181771
CO
2
F