Книга_5382_Библиотеки_им_академика_М_И_Перельмана

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NH2·HCl

69%

(a)

(b)

COCl

NH2·HCl

C]COCl

[

•

C CF

Figure 7.50 Synthesis of asymmetric 

Lemoucheux etal. demonstrated an alternative approach to the synthesis of unsymmetrical (Figure7.51). The intermediate tion with primary or secondary amines to aord unsymmetrical

C-ureas from [11C]COCl2 using the debenzylation of tertiary amines

C-carbamoyl chlorides could undergo further reac-

C-ureas in up to 76% RCY[441]. In addition to the formation of unsymmetrical ureas, the authors showed the further derivatization of the intermediate

C-amides upon reaction with NaOEt or Grignard reagents, respectively.

Carbonyl-

intermediate

C-Carbamates can be prepared from [11C]COCl2 by reaction of an

C-carbamoyl chloride or 11C-isocyanate with an excess of an alcohol in a

process analogous to the preparation of carbonyl-

C-carbamoyl chlorides to 11C-carbamates and

C-ureas. Carbon-11-labelled ligands for the central nicotinic acetylcholine receptor (nAchR) were prepared via treatment of an intermediate [ RCY and with 30% molar activity (Figure7.52a)[442]. Symmetrical [ prepared from Using this approach, Lidstrom etal. prepared phosphate for the imaging of prostate cancer. To accomplish this, [ with bis(2-chloroethyl)amine in THF to generate the symmetrical tively deprotonated estradiol was added to give the

C]isocyanate with an excess of alkoxide to give the 11C-carbamate in 7%

C-ureas, themselves

C-COCl2, have been subjected to alcoholysis to give the 11C-carbamates.

C-estramustine and [11C]estramustine

C]COCl2 was reacted

C-urea, before selec-

C-carbamate products, as shown in

(Figure7.52b)[443].

Carbonylexcess of an alcohol to give symmetrical metrical (Figure7.53a), [

C-Carbamates can also be prepared by rst reacting [11C]COCl2 with an

C-carbonates. Aminolysis of these sym-

C-carbonates gives the corresponding 11C-carbamates such as [11C]MTFC

C]TPZU (Figure7.53b), and [11C]SAR127303 (Figure7.53c), which have

found application in the imaging of serine proteases such as fatty acid amide hydrolase

33%

 205

(a)

(b)

Figure 7.51 The



use of



moyl chlorides generated from



[

2

their elabora tion to



and [









C]amides.

[11C]COCl

[

C]COCl

R3R4NH

H N

OMe

NaOEt

PhMgX

•

BuLi

OEt

H N

(ClH

CH2C)

N(CH

2CH2

Cl)

(ClH

2CH2C)2

[11C]estramustine: R = H

C]estramustine phosphate R = PO(OH)

[

Figure 7.52 C]phosgene.

and monoacylglycerol hydrolase[444–446]. Two structurally isomeric 11C-carbamates for imaging of TSPO, [ via an intermediate

C]PK13162 and [11C]PK13168 (Figure7.53d), were radiolabelled

C-chloroformate in 33% and 66% RCYs, respectively, and with molar activity ranging from 50 to 140 GBq·μmol nolic groups are suciently reactive toward [

C-chloroformates, which were further treated with diethylamine and heated to 110 °C

for three minutes to give the desired

[

C]COCl2 is often used in cyclization reactions, incorporating carbon-11 into the

C-carbamate products.

rings of various heterocycles, as shown in Figure7.54[448, 449]. [ ciently with 1,3- and 1,2-diamines, and 1-amino-2-hydroxyphenyls upon heating, to aord cyclized products in high RCY. Perimidinone analogue [ radiotracer for imaging the serotonin reuptake system[450], and [ prepared using this method[451]. [

C]COCl2 has also been applied to the synthesis of

−1

[447]. It was postulated that the phe-

C]COCl2 at −10 °C to aord corresponding

C]RPR72840A, a potential PET

C]COCl2 reacts e-

C]uric acid have been

206 Handbook of Radiopharmaceuticals

[

C]PK13168

(a)

O O

NEt,

NH·HCl

DMF

120 °C

H N

[

C]MFTC

[

C]COCl

(c)

(d)

(b)

C]COCl

N N

THF, 30 °C

H N

THF, 30 °C

Et2NH[

H N

[

C]TZPU

H N

[

C]SAR127303

Figure 7.53 Synthesis of 

Figure 7.54 Com

pounds prepared by cyclization reac tion with [

HN N

N H



2.

[

C]RPR72840A

R = Me, 2-[

C]thymidine

R = F, 5-fluoro-[

C]uracil

[

C]uric acid

[

C]dantrolene

X = NH, O

R = H, F

N H

B-selective NMDA receptor antagonists

 207

[CH

-11C]Temozolomide

[

C-hydantoins. [11C]Dantrolene, a ligand for breast cancer resistance protein, was radiolabeled with [ and with 47 GBq·μmol and 5-uoro-[ β-aminoacrylamide salts[453]. 456], also prepared from [

C]COCl2 in a multi-step one-pot sequence by Takada etal. in 34% RCY

−1

molar activity[452]. 11C-Pyrimidines, including [11C]thymidine

C]uracil, have also been prepared from [11C]COCl2, from the appropriate

C-Benzoxazolones[454] and 11C-benzoimidazolones[455,

C]COCl2, have been explored as potential PET radiotracers for

imaging the NR2B subunit of the NMDA receptor.

Methyl isocyanate labelled at two dierent positions has been used to prepare Temo-

zolomide labelled at two dierent positions (e.g. 3-N-[

C]methyl or 4-[11C]carbonyl) depending on the method used to prepare carbon-11-labelled methyl isocyanate, as shown in Figure7.55[457]. For example, reaction of [ vides [methyl-

C]methyl isocyanate, whereas using [11C]COCl2 yields [carbonyl-11C]methyl

C]CH3I with silver cyanate pro-

isocyanate, in 20% and 15% RCYs, respectively. Cyclization of each agent with the appropriate diazoimidazole provided dierentially labelled [

C]temozolamide for the elucida-

tion of the mechanism of action of this anticancer drug.

7.4.7 Reactions with [11

It was not until 2012, when the Miller group disclosed their facile production of [11C]CS2, that the reagent received much attention in the radiochemistry literature[97]. [

and [

C]CO2 are similar in that they are both electrophilic at the central carbon atom and

undergo reaction with nucleophiles at this position. [

than [

C]CO2, due to the weaker C═S double bonds. In their seminal report, the Miller group showed the reaction of [ the corresponding

C-dithiocarbamate salts in only ve minutes (Figure7.56a)[97]. The

C]CS2 with a range of amines in acetonitrile, giving rise to

C]CS2 is, however, more reactive

only observed side product was carbon-11 labelled quaternary ammonium salt in under 5%. The resultant POCl

to give potently electrophilic substituted 11C-isothiocyanates. [11C]CS2 has been

used for the synthesis of acetonitrile or DMSO, as shown in Figure7.56b[98]. The resultant also be alkylated to give synthesis of

C-dithiocarbamates undergo alkylation with alkyl halides or react with

C-thioureas upon reaction with an excess of amine in either

C-thioureas could

C-isothioureas. [11C]Carbon disulde has also been used for the

C-thiocarbamates, exemplied by the synthesis of [11C]Tanaproget, a potential PET radiotracer for quantication of levels of the progesterone receptor in breast cancer. The acyclic precursor, shown in Figure7.56c, was labelled using [

DMSO[98].

C]CS2

C]CS2 at 150 °C in

Figure 7.55 

aration of



[

C]temozolamide labelled at different positions.

H2N

C(O)-11C]Temozolomide

•

from

[

C]COCl

H2N

from [

N CH

•

C]CH

H2N

208 Handbook of Radiopharmaceuticals

POCl

min

[

(a)

Oxathiolium salt

(b)

C]CS

(a)

H N

R-X

(b)

BnBr

SBn

Figure 7.56 

cation of the [ to the synthesis of





















C]CS2





(c)

DMSO

[

C]Tanaproget

As an alternative to the preparation of [11C]thiocyanate from [11C]cyanide, [11C]thio-

cyanate can be prepared from [

C]CS2 by trapping in acetonitrile before the addition of

an ammonia solution and heating to 90 °C, as shown in Figure7.57a[422]. The reaction of

MeCN

[

C]CS

90 °C

S11CN

95%

Cl, CN, OCH

95%

[

C]NH4SCN

then

S11CN

[

C]NH4SCN

MeCN 90 °C

S11CN

95%

HSO

75%

AcO

AcOH

90 °C

OAc

S11CN

82%

N H

Figure 7.57 Reac

tion of [



C]CS2 for

the preparation of





 209

[11C]NH4SCN with benzyl bromide aorded quantitative conversion to benzyl [11C]thiocyanate. Several dierent α-ketobromides and alkyl bromides were subjected to the same reaction conditions to give alkyl further converted to

C-thiazolones by treatment with sulfuric acid (Figure7.57b).

C-thiocyanates. The 11C-thiocyanatophenones could be

 

 C]Fluoroform

The prevalence of the CF3 group in pharmaceuticals has led to signicant eorts to develop a method for incorporating a radionuclide with high molar activity into this motif. Much of this eort has focused on the use of uorine-18; however, existing methods all give radiolabelled products with low molar activity (30 GBq· μmol monly below 10 GBq· μmol

−1

). Haskali and Pike developed the synthesis of [11C]CF3H, which proved a versatile synthon for incorporating a radiolabelled CF PET probes using methods developed for [ addition of a solution of [

BuOK aorded [11C]triuoromethylbenzhydrol quantitatively (Figure7.58a). Simi-

larly, [

C]CF3H undergoes reaction with disuldes to give 11C-triuoromethyl suldes,

as shown in Figure7.58b. [

C]CF3H in DMF to a solution of benzophenone in the presence

C]CF3H could also be converted to [11C]CuCF3 (Figure7.58c),

F]CF3H and [18F]CuCF3[99]. For example, the

which reacts with aryl iodides (Figure7.58d) and aryl boronic acids (Figure7.58e) via a Cu-mediated process. Reaction of with 4-nitrophenylboronic acid gave 99% RCY of the coupled product, with a molar activity of >500 GBq·μmol reaction with [

C]CuCF3 in good RCY, as shown in (Figure7.58e). Three known PET

−1

. Diazonium salts also undergo

radiotracers were prepared in excellent RCYs of up to 93%, with molar activity of up to 40 0 GBq ·μmol

−1

, using this newly developed precursor[99].

−1

for the best case, com-

group into candidate

 

Deprotonation of [11C]CH3NO2 provides a nucleophilic [11C]nitronate anion, which undergoes facile addition to carbonyl compounds (the nitroaldol reaction), as well as to other electrophiles. The dehydrated in situ to give α,β -unsaturated-γthesis of β-[ Figure7.59a[100]. A moderately selective asymmetric variant of the nitroaldol reaction with [ binaphthyl (BINAP) bimetallic catalyst, providing enantioenriched shown in Figure7.59b[458]. The satility of the nitroaldol reaction with [ group in the product into other functional groups, including amines (via reduction) and aldehydes (via the Nef reaction). A number of bioactive molecules including [ (Figure7.59c)[459], [1- 2-nitro-[

210 Handbook of Radiopharmaceuticals

C]nitrostyrene is achieved from [11C]CH3NO2 in up to 85% RCY, as shown in

C]CH3NO2 has also been developed using a La-Li-2,2′-bis(diphenylphosphino)-1,1′-

C]glucose and [1-11C]mannose[460], and 2-(hydroxymethyl)-

C]propane-1,3-diol ([11C]TRIS)[461] have been prepared in this way.

C-nitroalcohols obtained from the nitroaldol reaction can be

C-alkylnitrates. For example, the radiosyn-

C-nitroalcohols, as

C-alkylnitrates may themselves be useful, but the ver-

C]CH3NO2 lies in the ability to convert the nitro

C]indole

99%

88%

Ph Ph

(a)

[

C]CF

100%

(c)

CuBr

[

C]CuCF

(d)

B(OH)

(e)

(b)

29%

–

(f)

MeCN

90 °C

S11CF

= CO2Et,

= CN, 90%

4-NO

3-F, 98%

88%

H N

[

C]Flutamide

76%

[

C]Fluoxetine

45%

from iodo precursor

[

C]Leflunomide

93%

from boronic acid precursor

Figure 7.58 C]CF33 group.

[11C]CH3NO2 has also been used in additional reactions. Maeding etal. employed

[

C]CH3NO2 in a reaction with various pyrylium salts to obtain 11C-nitrobenezenes, as shown in Figure7.59d[462]. Addition of [ was employed for the synthesis of ethyl [ ethyl glycinate (Figure7.59e)[463]. [

C]CH3NO2 to activated carbonyl compounds

C]nitroacetate, which was converted to [11C]

C]CH3NO2 has also been exploited for Michael additions with α,β -unsaturated compounds, including methyl p-chlorocinnamate for the synthesis of [4-

C]baclofen[464].

 

[11C]Diazomethane is an alternative agent for the transfer of a 11C-radiolabelled methyl group to suitable nucleophiles. The ubiquitous use of [ challenging multistep synthesis of [

C]diazomethane, means this reagent is rarely used.

C]CH3I and [11C]CH3OTf, and the

 211

OH OH

(a)

(c)

(b)

30 °C

(d)

(e)

[

C]CH3NO

140 °C

C]Nitrostyrene

β-[

[

C]CH3NO

Cat.,

THF

–10 °C

[

C]CH

3NO2

AcOH

HCO

2NH4

145 °C

C]CH3NO

HMPA, TBAF

BuOK,

[

–

BuOH

12 41%

RCY

Cat.

Li Li

O O

LiOH

HO OH =

TiCl

AcOH

N H

OEt

[11C]CH3NO

NaH, DMF or DMSO

EtO

HCl, EtOH

EtO

Figure 7.59 C]CH32 for nitroaldol reactions and addition reactions.

Some examples of compounds prepared by reaction with [11C]diazomethane include the

C-methyl ester of N-nitro-l-arginine, a nitric oxide synthase inhibitor[465], and the cal-

cium-channel antagonist [

C]S12968 (Figure7.60a) and its enantiomer [11C]S12967[466].

 

[11C]CH3N3 has been employed as a reagent for the Cu-catalyzed alkyne-azide cycloaddition (CuAAC) as a rapid, biorthogonal approach to labelling both peptides and nucleotides with carbon-11. Schirrmacher and coworkers[103] reported the radiolabeling of an alkyne-modied peptide with [ of 25 GBq·μmol

[

C]CH3N3 from [11C]CH3I and NaN3; however, this method was unreliable due to the var-

iable trapping of [

212 Handbook of Radiopharmaceuticals

−1

(Figure7.60b). The authors also explored the in situ generation of

C]CH3I, and more reliable production of the product was observed

C]CH3N3 in up to 55% RCY and with molar activity

(b)

(a)

(c)

EtO

(d)

Figure 7.60



N H

[

C]CH2N

MeOH, DME

EtO

[

C]S12968

N H

labelling using



[





[





and [

C]trimethylsi

lyl ynolates.

C]CH

[

3N3

CuI, CH3CN

R = D-Glu-D-Tyr-[Cys-Tyr-Tr p-Lys-Thr-Cys]-Thr

•

[11C]CH3N

CuI, 60 °C

N H

SiMe

when [11C]CH3N3 was prepared in a separate step. Similarly, Bordenave etal. explored the CuAAC reaction between [ as PET radiotracers to image cell proliferation, as shown in Figure7.60c. A

C]CH3N3 and alkyne-bearing nucleosides and oligonucleosides

C-radiola-

beled thymidine analogue was prepared in this way in 48% RCY.

 C]Lithium Trimethylsilylynolate

[11C]Lithium trimethylsilylynolate (Figure7.60d) has been prepared as a novel reagent for the incorporation of carbon-11 into heteroaromatic rings. The reaction of [ methylsilylynolate with the diazopyrazole derivative gave the bicyclic product in 40% RCY, but with poor molar activity (0.006 GBq·μmol

−1

)[105].

 213

C]lithium tri-

C-pyrazolotriazine

 

35%

(b)

The 1,4-addition of organocuprates to α,β-unsaturated carbonyls is a well-established synthetic method, but it has seen limited application to radiochemistry. The Långström group rst explored 1,4-conjugate addition of lithium [

C]methyl(2-thienyl) cuprate to α ,β-unsaturated ketones, aording the addition products in 35–50% RCY (Figure7.61a)[467]. Lithium [

[

C]CH3Li to lithium (2-thienyl)cyanocuprate or lithium (2-thienyl)iodocuprate. [11C]CH3Li

was produced by lithium-halogen exchange between [

[

C]methyl(2-thienyl)cuprate was used for the radiosynthesis of [11C]mesterolone

C]methyl(2-thienyl)cuprate was prepared by addition of

C]CH3I and nBuLi. Lithium

(Figure7.61b), a PET radiotracer for imaging the androgen receptor in prostate cancer, in 31% RCY and with molar activity of 40 GBq·μmol group also reported the radiosynthesis of [ (Figure7.61a) by reaction of lithium [

C]methyl(2-thienyl)cuprate with the corresponding

acid chloride, in 35% RCY and with molar activity of 14 GBqμmol

−1

after deprotection. The Långström

C]progesterone labeled in the C21-position

−1

[468].

 

Enzymes are attractive catalysts for the incorporation of carbon-11 into biomolecules as they can perform complex reactions under mild conditions to give highly functionalized radiolabelled products, which may be hard to access through chemical routes[469]. Additionally, enzymes usually operate under conditions where substrate concentrations

Figure 7.61 

of lithium



[



cuprate for addition reactions.

(a)

OAc

[

C]CH

BuLi

[

C]CH3Li

then HCl

LiCN

TMSCl,

50 °C

O, THF

[

LiCN

C]Mesterolone

[

C]Progesterone

OAc

TMSCl

214 Handbook of Radiopharmaceuticals

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