Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0909 110

17. Syntheses and uses of isotopically labelled compounds

969

10. New synthesis of [ 11C]propyl ketene (201) and its reactivity with alcohols

The total yield of 201 was increased and the synthesis time reduced by extracting [11C]butyric acid from its lithium salt by dry 0.1% HCl/He gas mixture and carrying out its pyrolysis at 530 °C over glass beads (equation 104). The relative reactivity of 201 to primary, secondary and tertiary alcohols (equation 105a, b, c) has been found to be as 1:0.4:0.1, respectively. Several bioactive compounds have been labelled with

[11C]propyl ketene, such as carbohydrate compounds193 and N-butyl compounds, for instance N-[11C]butyryl THPO, 202, and some phorbol esters192, 203, 204 and 205.

11CO2

P rLi

Pr11COOLi

HCl / He

Pr11COOH

PhCH2 CH2 OH

201

PhCH2 CH2 O11

CPr

O

PhCH2 CHCH3

201

PhCH2 CHCH3

O

OH

11C

O

Pr

PhCH2 C(Me2 )OH

201

PhCH2 C(Me2 )O11

CPr

O

HO

N

OH

O

O11COPr

HO

Pr11C

N

O

O

HO

O

OH

(202)

(203)

O

O

HO

HO

O 11CPr

O

(205)

Pyrolysis	EtCH	11C O

530 °C

(201) (104)

(105a)

(105b)

(105c)

OCOPr

O11COPr

HO

HO

OH

(204)

970 Mieczysław Ziełinski´ and Marianna Kanska´

11. Synthesis of [˛-11C]amphetamine, 206, and [˛-11C]phenethylamine, 207

206 and 207, increasing the synaptic levels of major neurotransmitters in the mammalians brain, noradrenaline or dopamine via stimulation of their release, have been synthesized194 (equations 106 and 107).

11

+ PhCHO

A c OH, A c ONH4

PhCH

11CNO2

LiA lH4

PhCH2 11CHNH2

CH3

CH2 NO2

104 °C, 10 min, separations

Me

Me

(206)

(106)

11CH NO + PhCHO

1. NaOH

11

LiA I H4

11

PhCH

CHNO2

PhCH2

CH2 NH2

3 2

2. HCl

(207)

(107)

12. Synthesis of [11C]methylenetriphenylphosphorane and [ˇ-11C]styrene (208)

The original Wittig synthesis195,196 of 208, shown in equation 108 involving synthesis of [11C]methyltriphenylphosphonium iodide, [11C]methylenetriphenylphosphorane and the 11C-Wittig type reaction used for preparation of the 11C-labelled methylene group, has been largely improved196 [11C]methyl iodide and benzaldehyde have been easily converted in high yield to 208 as shown in equation 109.

THF

−

+

11CH3 I + Ph3 P

I + Ph3 P11CH3

°C, 6 min

90

THF

BuLi

(108)

PhCH

11CH

P hCH

O

Ph3 P

11

CH2

2

(208)

+

Ph3 P11CH3 + PhCHO

epichlorhydrin			11CH2
	PhCH			(109)
1, 2-dibromobenzene

80 − 90% r. yield

13. Synthesis of [11C]cyanoalkyltriphenylphosphoranes

The 11C-labelled bifunctional precursors 3-[11C]cyanoethyltriphenylphosphonium bromide, 209, 4-[11C]cyanopropyltriphenylphosphonium bromide, 210, 5-[11C]cyanobu- tyltriphenylphosphonium bromide, 211, 4-[11C]cyanopropyltriphenylphosphonium iodide, 212 and 5-[11C]cyanobutyltriphenylphosphonium iodide, 213 have been obtained197. The intermediates 209 213 were treated in one-pot reactions with epichlorhydrin (generating the base in situ196,198) and aldehyde (Wittig reaction) providing the 11C-labelled olefins (equation 110). The aromatic olefins have been obtained from 209 213 in 85 96% radiochemical yield; the aliphatic olefins have been obtained in 60 78% radiochemical yield from 212 and 213. No change in the stereochemical outcome (Z/E ratios) was

17. Syntheses and uses of isotopically labelled compounds

971

observed when using the bromide or iodide salt.

+

XX−

+ 11CN−

K − 2.2.2 / K

+

+

−

−

Ph P(CH )

11

3

2

n

1, 2-C6 H4 Cl2

Ph3 P(CH2 )n

CNX

+ X

n = 2, 3 and 4

90 °C, 5 − 10 min

(209) n = 2, X = Br

(210) n = 3, X = Br,

X = Br, I

(211) n = 4, X = Br

(110)

(212) n = 3, X = I

(213) n = 4, X = I

1-chloro -2,3 -epoxypropane

R1CHO, 140−150 °C, 10 min

+ −

11

R1CHO

1

11

+ Ph3 P

Ph3 PCH(CH2 )n-1 CN

R CH

CH(CH2 )n-1

CN

O

14. Synthesis of 11C-labelled 5-hydroxytryptamine, [ 11C]5-HT (214)

[11C]serotonin (214) has been sythesized199 as outlined in equation 111 and was ready for injection to study the transport of [11C]5-HT across the pulmonary endothelial cell membrane and to make external non-invasive measurements of uptake of amines by the lung with standard nuclear medicine imaging equipment199. [14C]5-HT has been used before as a marker of lung damage200.

MeO	N				+
			Me2 SO4		N
			THF, glacial A c OH, < 10 °C		−OSO3 Me
NH
			K222 / MeCN, 110 ° C, 5 min
HO	11CN				K11CN
			BBr3
					11CN
			CH2 Cl2 , 110 °C, 5 min
NH			separation		(111)
	LiA lH4 , A I Cl3 , Et2 O
RT, 5 min, HPLC separations
	HO				NH2
					11CH2

NH

(214)

15. Synthesis of [ 11C]melatonin (215)

This hormone of the pineal gland, 215, has been labelled201 with carbon-11 to study its role in health, depressive illness and internal clock disorders (cyclic events of life in mammals). The new labelling reagent [11C]acetyl chloride has been used as shown

972	Mieczysław Ziełinski´ and Marianna Kanska´

in equation 112. Using 13C-enriched CO2, 13C-melatonin has been synthesized also and examined by 13C-NMR spectroscopy and mass spectrometry. The melatonin had 13C- enriched carboxamido carbon202.

MeBr Mg

MeMgBr	11CO		[ Me11COOMgBr ]	C H (COCI) -o					Me11COCl
		2		6	4	2
			p-MeOC6 H4 NHCH					CH(CH2 )2 NH2

MeO

(112)

NH11COMe

NH

(215)13% r. yield

16.Synthesis of [carbonyl-11C]6-fluoromelatonin (216)

This indoleamine-type neurohormone201, 216 secreted by the pineal gland203, has been prepared204 as shown in equation 113 with a 200-fold greater specific activity than the 6- [18F]fluoromelatonin synthesized by Chirakal and coworkers205. 216 permits one to study low populations of high-affinity binding sites or receptors of melatonine with PET206,207.

			Phthaloyl dichloride
11CO2	MeMgBr / Et2 O		2,6-di-t-butylpyridine
		[Me11COOMgBr]			Me11COCl
	under N2 , 2 min			8 min
				CH2 Cl2 , 0 °C
					6 -fluoro -
					5 -methoxytryptamine
				(113)
				CH3
	MeO	NH		11C

O

FNH

(216)35% r. yield from cyclotron produced [11C]CO2

17.Synthesis of 11C-labelled citalopram (217)

This prototype drug208, 217, has been 11C-labelled209 for assessment of serotonin uptake sites in depressed patients by reaction of [11C]iodomethane with desmethylcitalopram, 218, in 18 66% radiochemical yield (equation 114). 217 has been obtained also by Dannals and coworkers210 by reacting freshly prepared desmethylcitalopram dissolved in DMF with [11C]methyl iodide. The radiochemical yield based on [11C]CH3I was about 20%; the overall radiochemical yield was about 9% based on the initial activity of [11C]CO2 produced by 16 MeV proton irradiation of nitrogen gas in biomedical cyclotron.

17. Syntheses and uses of isotopically labelled compounds			973
NC		NC
O	11CH3 I	O
			11CH3

(CH2 )3 NHCH3 C6 H4 F-p

(218)

(CH2 )3 N

C6 H4 F-p CH3

(217) r. purity > 95%,

sp. act. (2.52 − 16.06).103 GBq / mmol

(68 − 434) Ci / mmol at the end of synthesis

(114)

18. Synthesis of N-[methyl-11C]hydromorphone (219)

219 has been obtained211 in the direct alkylation of desmethyl hydromorphone, 220, with 11CH3I using a remote-controlled synthetic system212 (equation 115). Compound 219, an opiate receptor ligand, has been used211 to study the distribution and kinetics in brain of macaque monkeys213 by PET. The 11C-labelled alkaloids such as morphine, heroin, codeine, nicotine and bromocryptine have also been prepared by N-alkylation of the corresponding desmethyl compounds with 11CH3I in DMF or in acetonitrile214.

HO

HO

	O	11CH3 I, DMSO / DMF (1 : 1) O
	NH	107 °C, 5 min
	O	O
	(220)	(219) r. purity > 99.5%
		after semipreparative HPLC

19. Synthesis of (N-[ 11C]methyl)doxepin (221)

N 11CH3

(115)

Doxepin, 221, a tricyclic antidepressant, one of the most potent histamine H1 antagonists215, has been labelled216 with carbon-11 by N-alkylation of normethyldoxepin (equation 116).

20. Synthesis of (N-[ 11C]methyl)Y-29794 (222)

The title compound, 2-(8-dimethylaminooctylthio)-6-isopropyl-3-pirydyl-2-thienyl ketone (222), a potent competitive reversible inhibitor of the enzyme PEP (prolyl endopeptidase which cleaves a variety of oligopeptides in brain and peripheral tissues217), has been synthesized218 by [11C]alkylation of the N-desmethyl precursor 223 (equation 117). 222 crosses the BBB and inhibits brain PEP in rodents219. It is used in the study of biodistribution and activity of brain proteases by PET to evaluate the roles

974	Mieczysław Ziełinski´ and Marianna Kanska´

of peptides and protein degradative processes in normal and diseased human brain218.

O

O

1.11CH3 I / DMF, −78 °C

2.80 °C, 3 min

3.Work-up, HP LC

CH3

NH

S

	NCA 11CH3 I , Et3 N
	1. DMF, 85 °C, 5 min
O	2. Silica gel chromatography

N S (CH2 )8 NHCH3

. tosylate

CH3

N

11 CH3

(221) sp. ct. 1.63 Ci / mol (EOS) 15% r. yield based on 11CH3 I (116)

S

O

11CH3

N S (CH2 )8 N

CH3

(223)	(222) 10 − 17% (EOB)	(117)

21. Synthesis of D-[1-11C]glucopyranose (224) and D-[1-11C]galactopyranose (225) using diborane

224and 225 have been obtained220 from D-arabinopyranose (226) and D-lyxopyranose,

(227)respectively (equation 118). In the previous synthesis of 224 from D-gluconolactone

the reaction time at room temperature was 3.5 hours for optimal yield221.

22. Synthesis of DL-[1-11C]alanine (228) from [11C]HCN

228 has been synthesized222 in high radiochemical yield and purity (equation 119) by introducing [11C]HCN into a solution of sodium 1-hydroxyethanesulphite in 8% ammonium hydroxide and subsequent hydrolysis of [1-11C]2-aminopropanenitrile to DL-[1- 11C]alanine. The above reaction conditions have been selected from extensive investigation of the effects of [11C]HCN trapping temperature, reaction temperatures, volume and concentration of precursor. [1-11C]Pyruvic acid ready for use in PET studies has been prepared subsequently from crude 228 in an enzymatic synthesis222 224.

23. Synthesis of [11C]dexetimide and [11C]levetimide

In vitro225 and in vivo226 studies with [3H]dexetimide and [3H]levetimide showed that dexetimide, 229, binds to m-AChR (‘muscarinic cholinergic receptors’) while levetimide,

17. Syntheses and uses of isotopically labelled compounds

975

230, is a pharmacologically inactive enantiomer and did not show preferential uptake in regions of human brain known to have high concentration of m-AChR. 229 and 230 have therefore been 11C-labelled for non-invasive in vivo investigation of m-AChR by PET, by alkylation of the appropriate norbenzylamine substrate, 231, with [˛-11C]benzyl iodide

(equation 120)227.
				HOCH2
	O
		OH		R2
	HO		11
R2			H CN	OH
HO				R1

R1

(226) R1 = OH, R2 = H

(227) R1 = H, R2 = OH

HOCH2				HOCH2
R2	O			R2
			1 M diborane in THF
	11C	OH
OH			10 min reflux, work-up	OH
R1				R1

OH

(224)R1 = OH, R2 = H

(225)R1 = H, R2 = OH

	OH				NH2			NH2
			H11CN			HCl
	CH3 CHSO3 Na			CH3 CH11CN			CH3 CH11COOH
			NH4 OH
							(228)

OH

11CN

OH

(118)

O

11C O

OH

(119)

	1. 1 1 CO2		1. HI
PhMgBr	2. LiA lH4	Ph1 1 CH2 OH	2. CH2 Cl2	Ph1 1 CH2 I
	THF / Et2 O
				(231) HN

MeCN, 80 ° C, HPLC

O (120)

O

1 1 CH2	NH
Ph	N
	Ph
	[1 1 C]dexetimide / levetimide
	sp. act. 905 mCi/ mol

976	Mieczysław Ziełinski´ and Marianna Kanska´
	O	N		O	O
			Ph
					NH
O	NH		Ph	N
	Ph				Ph
	(229)			(230)
	Dexetimide			Levetimide

24. Synthesis of 3-N-[11C]methylspiperone, 11CNMS (232) with high specific activity

232 has been produced automatically228 with high specific activity at EOB by reaction of [11C]CH3I with spiperone (equation 121), for measurement of dopamine D2 receptors in the human brain with a positron camera.

	O	O
		11CH3
	NH	N
F	N	+ 11CH3 I
O	N	(121)
		N
	Ph	Ph
		(232) 85− 95% labelling yield
		from 11CH3 I

The yield of 232 decreased228,229 to <50% at higher reaction temperatures and longer reaction time. The observed fast self-radiolysis of 11C-NMS has been suppressed remarkably by addition of hydroxyl radical scavengers230 such as potassium iodide (rate constant 1.0 ð 1010 M 1 s 1 at pH 7) and accelerated slightly by hydrated electron scavengers such as sodium nitrate (1.1 ð 1010 M 1 s 1 at pH 10 in aqueous solutions). The carrier methylspiperone (NMS) decomposed on 60Co irradiation gave the same compound with a molecular weight of 425 as the 11C-NMS gave upon self-radiolysis. The G-value of NMS decomposition by 60Co irradiation was about two in aqueous solution. Polysolvate80 (emulsifier, with three alcoholic OH groups in one molecule) and EtOH have been used228 as i.v. injectable additives to protect 11C-NMs against decomposition.

25. The synthesis of [3-11C]pyruvic acid (233)

233, a normal metabolite in the myocardium, applied in in vivo metabolic studies, has been obtained233 from racemic DL-[3-11C]alanine, 234, in turn obtained from N- (diphenylmethylene)glycine t-butyl ester, 235, as shown in equation 122, and subsequent enzymatic synthesis232,233 of 233 using D-amino acid oxydase (D-AAO)/catalase and glutamic-pyruvic transaminase (GPT) in a coupled, one-pot reaction presented in equations 123a and 123b.

26. Microwave method of radiolabelling with [11C]cyanide

The use of the microwave cavity in the typical syntheses involving NCA and carrier added [11C]cyanide234, such as cyano-de-halogenation with subsequent hydrolysis

17. Syntheses and uses of isotopically labelled compounds

977

of the nitrile (equation 124), or Bucher Strecker synthesis of aromatic amino acids235 (equation 125) instead of

11CH3

KOH, 11CH3 I

Ph2 C NCH2 COO-But-t Ph2 C NCHCOOBut-t

DMF / DMSO, 80˚C, 2 min

(235)

CH2 Cl2

, 150 ˚C, 5 min

(122)

6M HCl

11CH3

+

H3 NCHCOOH

(234)

NH2

O

11CH3 CHCOOH

D-A A O / catalase

11CH3

CCOOH

(123a)

D-alanine

(233) pyruvic acid

COOH

COOH

NH2

O

(123b)

11CH3

O CCOOH

GPT

11CH3

CHCOOH +

CCOOH +

H2 NCHCOOH

L-alanine

α-ketoglutarate

(233)

pyruvic acid

O

11C

(124)

HO(CH2 )3 X

HO(CH2 )3 11CN

O

X = Br, Cl

2 steps

p-HOC6H4CH2CH(OH)SO3Na ! p-HOC6H4CH2CH(NH2)11COOH 125

thermal treatment reduces the reaction time in the case of short-lived radionuclide, 11C, by about one half-life of the radionuclide and provides nearly 100% more radioactive product (at EOS). Thus less starting radioactivity is required to produce the given amount of radiotracer and the previously rejected radiolabelling routes because a small half-life of radioisotope may now be possible.

27. Synthesis and uses of [11C]thiocyanate

[11C]Thiocyanate has been obtained236 in 94% radiochemical yield under anhydrous conditions237 and used for preparation of ethyl- i-propyl- and benzyl[11C]thiocyanates in 78%, 71% and 88% radiochemical yields within 27 min, 28 min and 25 min synthesis time, respectively (equation 126). The organic [11C]thiocyanates will be converted to [11C]thiocarbamates236. They might be potentially useful also in the study of the tubular

978

Mieczysław Ziełinski´ and Marianna Kanska´

transport of anions in the kidneys.

11CNBr

Na2S

K[2.2.2]

S11CN

RX, DMSO

RS11CN

126

C

!

!

DMSO, 80

°C, 1 min

80

120 °C, 2

5 min

separations

R D ethyl-, 2-propyl-, benzyl-

28. Synthesis of [1-11C]putrescine (236)

The radiosynthesis of 236 has been significantly improved238 by near-quantitative trapping of the [11C]HCN in anhydrous silica gel coated with potassium hydroxide, Michael addition reaction to acrylonitrile under anhydrous conditions on the same solid support medium and reduction of the [1-11C]succinonitrile obtained in anhydrous form with BMS (borane methyl sulphide complex) (equation 127). The absence of water during the addition reaction eliminated the formation of by-products and decreased the total synthesis time. The biochemical tumor masker239 241 236 has been obtained also previously242,243

but with lower radiochemical yields using BrCH2CH2CN/Na11CN/NaOH reagent242 or CH2DCHCN/Na11CN/NaOH243.

	CH2		CHCN	[11C]HCN		N11CCH2 CH2 CN
				KOH / silica gel
				75 °C, 5 min
			2. A nhydr. HCl / MeOH, RT
			3. 0.03M NaOH, HP LC			(127)
						1. BH3 :SMe2, dry THF, 140 °C, 10 min reflux

11CH2 (NH2 )CH2 CH2 CH2 NH2

(236)[1-11C]-1, 4-diaminobutane.

29.Synthesis of [11C]octopamine (237a,b)

[11C]-p- and m-Octopamine, 237a,b, have been synthesized244 from [11C]HCN through the [11C]cyanohydrin intermediates 238 (equation 128). The radiochemical yield of 237 at the end of 40 60 min synthesis time was 0.7 2.3%; the (S)-enantiometric purity of the

[11C]octopamine obtained through the enzymatic process was 92%, the (R)-enantiomatic purity of [11C]-m-octopamine was 42%244,245. Studies with [3H]-p- and m-octopamine246

suggested its role in emotional and neurovegatative responses to stress247. The 11C- labelled compounds 237 in enantiomeric pure or enriched forms were needed to study the activities of the stereoisomers of p- and m-octopamine on ˛-adrenoceptors248.

30. One-line synthesis of [11C]cyanide from cyclotron-produced [11C]carbon dioxide

(a) H[11C]CN, 240, was recently produced249 in essentially quantitative yield by passing an [11C]CH4 ammonia mixture over a platinum catalyst in a furnace held at 1000 °C. The yield of 240 obtainable by this method highly depends on the proton energy and current impinging on the target and the compact cyclotrons providing 9.4 MeV proton