Synthesis of C‐14 and C‐13, H‐2‐labeled IKK inhibitor: [14C] and [13C4,D3]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido[3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide

[¹⁴C]‐N‐(6‐Chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5B ), an IKK inhibitor, was synthesized from [¹⁴C]‐barium carbonate in two steps in an overall radiochemical yield of 41%. The intermediate, [carboxyl‐¹⁴C]‐2‐methylnicotinic acid, was prepared by the lithiation and carbonation of 3‐bromo‐2‐methylpyridine. [¹³C₄,D₃]‐N‐(6‐chloro‐7‐methoxy‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐2‐methyl‐3‐pyridinecarboxamide (5C ) was synthesized from [1,2,3,4‐¹³C₄]‐ethyl acetoacetate and [D₄]‐methanol in six steps in an overall yield of 2%. [¹³C₄]‐2‐methylnicotic acid, was prepared by condensation of [¹³C₄]‐ethyl 3‐aminocrotonate and acrolein, followed by hydrolysis with lithium hydroxide. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of C‐14‐labeled novel IKK inhibitor: 2‐[14C]‐N‐(6‐chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide

2‐[¹⁴C]‐N‐(6‐Chloro‐9H‐pyrido [3,4‐b]indol‐8‐yl)‐3‐pyridinecarboxamide (9A , also referred to as [¹⁴C]‐PS‐1145) was synthesized from [¹⁴C]‐paraformaldehyde in five steps in an overall radiochemical yield of 15%. The key intermediate 1‐[¹⁴C]‐6‐chloro‐1,2,3,4‐tetrahydro‐β‐carboline was obtained by Pictet–Spengler cyclization of chlorotryptamine with [¹⁴C]‐paraformaldehyde. Similar reactions were conducted with tryptamine to address the generality of the methodology. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of the carbon‐14 labeled isotopomers of (R)‐N‐methyl‐3‐[2‐methylphenoxyl]‐benzenepropanamine hydrochloride (atomoxetine hydrochloride,LY139603), and two of its metabolites

Carbon‐14 labeled Straterra^TM (Atomoxetine HCl, LY139603, (‐)‐N‐methyl‐3‐(2‐methylphenoxy)‐benzenepropanamine hydrochloride), a potent inhibitor of the presynaptic norepinephrine transporter, and two of its major metabolites were synthesized. The key component, S‐(+)‐3‐chloro‐l‐phenyl‐l‐propanol‐[1‐¹⁴C] was synthesized by Stille coupling of benzoyl chloride‐[carbonyl‐¹⁴C] with vinyl tri‐n‐butylstannane, followed by HCl addition to the vinyl ketone, and asymmetric reduction of the ketone by Corey's CBS reagent. Mitsunobu reaction of this S‐(+)‐3‐chloro‐l‐phenyl‐l‐propanol‐[1‐¹⁴C] with various phenol derivatives, followed by converting the chloride to amines, gave desired products. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐ 3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate‐1‐14C

γ‐Cyhalothrin ( 1a ), (S)‐cyano(3‐phenoxyphenyl)methyl (1R,3R)‐3‐[(1Z)‐2‐chloro‐3,3,3‐trifluoro‐1‐propenyl]‐2,2‐dimethylcyclopropanecarboxylate, is a single‐isomer, synthetic pyrethroid insecticide marketed by Pytech Chemicals GmbH, a joint venture between Dow AgroSciences and Cheminova A/S. As a part of the registration process there was a need to incorporate a carbon‐14 label into the cyclopropyl ring of this molecule. A high yielding radiochemical synthesis of γ‐cyhalothrin was developed from readily available carbon‐14 labeled N‐t‐Boc protected glycine. This seven step synthesis, followed by a preparative normal phase HPLC separation of diastereomers, provided 21.8 mCi of γ‐cyhalothrin‐1‐¹⁴C ( 1b ) with >98% radiochemical purity. Copyright © 2007 John Wiley & Sons, Ltd.     

Syntheses of carbon‐14 labelled AJ‐9677, a specific β3‐adrenoceptor agonist

Two ¹⁴C‐labelled versions of AJ‐9677, a novel anti‐diabetic drug candidate, have been synthesized. The first, [acetic acid‐2‐¹⁴C]AJ‐9677, was synthesized via a four‐step process starting from 2‐chloro‐N,N‐diethyl[2‐¹⁴C]acetamide ( 3 ), and the second, [hydroxymethine‐¹⁴C]AJ‐9677, by a two step process from (R)‐3‐chloro[7‐¹⁴C]styrene oxide ( 8 ). When stored in the solid state both compounds undergo radiolytic decomposition in a similar manner, despite the labelled position being different, to give the dechlorinated derivative ( 12a, 12b ). Purification of the required product was achieved after derivatization to the methyl esters. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of 3,7,8‐15N3‐N1‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin

3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was synthesized from the oxidation of 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine with 2 equivalents of Ir(IV) in pH 4.5 potassium phosphate buffer. The synthesis of 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine started with bromination of 1,7,NH₂‐¹⁵N₃‐2′‐deoxyguanosine. The resulting 1,7,NH₂‐¹⁵N₃‐8‐bromo‐7,8‐dihydro‐2′‐deoxyguanosine reacted with sodium benzyloxide to afford 1,7,NH₂‐¹⁵N₃‐8‐benzyloxy‐7,8‐dihydro‐2′‐deoxyguanosine. Subsequent catalytic transfer hydrogenation of 1,7,NH₂‐¹⁵N₃‐8‐benzyloxy‐7,8‐dihydro‐2′‐deoxyguanosine with cyclohexene and 10% Pd/C yielded 1,7,NH₂‐¹⁵N₃‐8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine. Purification of 3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was first carried out on a C18 column and the product was further purified on a graphite column. ESI‐MS was used to confirm the identity and to determine the isotopic purity of all the labeled compounds. The isotopic purity of 3,7,8‐¹⁵N₃‐N¹‐(β‐D‐erythro‐pentofuranosyl)‐5‐guanidinohydantoin was 99.4 atom% based on LC‐MS measurements. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

Sodium ring‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from [¹⁴C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, [¹⁴C]‐4‐guanidinobenzoic acid, was prepared by coupling [¹⁴C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐[¹⁴C]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐[¹⁴C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. [D₄,¹⁵N]‐4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from [¹⁵N₂]‐cyanamide and [D₄]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐[[9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido[5,4‐d][2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of 3H and 14C labeled (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐indol‐2‐one,maxipost™. An agent for post‐stroke neuroprotection

The syntheses of tritium labeled (S)‐3‐(5‐chloro‐2‐[OC³H₃]methoxyphenyl‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐1H‐indol‐2‐one, and carbon‐14 (S)‐3‐(5‐chloro‐2‐methoxyphenyl)‐1,3‐dihydro‐3‐fluoro‐6‐(trifluoromethyl)‐2H‐[2,3‐¹⁴C₂] indol‐2‐one are reported. The ³H‐labeled compound was prepared in a two‐step synthesis from C³H₃I. The final product was purified via chiral HPLC to yield the desired enantiomer in a 4% radiochemical yield and a specific activity of 60 Ci/mmol. The ¹⁴C‐labeled compound was prepared in a four‐step synthesis from diethyl [carboxylate‐¹⁴C₁,₂] oxalate. The final product was purified via chiral HPLC to yield the desired enantiomer in a 20% radiochemical yield and a specific activity of 28.4 μCi/mg. Copyright © 2002 John Wiley & Sons, Ltd.     

13C‐ and 14C‐labelling of N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐methyleneamino] guanidinium acetate

N‐[1‐(4‐chlorophenyl)‐1H‐pyrrol‐2‐yl‐¹³C₄‐methyleneamino]guanidinium acetate has been synthesized by a four‐step procedure. This involved reduction of the Weinreb amide N,N′‐dimethyl‐N,N′‐dimethyloxybutane‐1,4‐diamide‐1,2,3,4‐¹³C₄ by Dibal‐H to give the corresponding unstable dialdehyde which is reacted in situ with 4‐chloroaniline to form 1‐(4‐chlorophenyl)‐1H‐pyrrole‐¹³C₄. This pyrrole analogue underwent a Vilsmeyer acylation with POCl₃/DMF followed by final reaction with aminoguanidine bicarbonate to produce the desired labelled compound with 99% atom ¹³C. By using DMF [α‐¹⁴C] a radio‐labelled analogue was synthesized with a specific activity of 60 mCi/mmol. Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of 2‐exo‐(2′‐[18F]Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent epibatidine‐based radioligand for nicotinic acetylcholine receptor PET imaging

2‐exo‐(2′‐Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane (F₂PhEP), a novel, epibatidine‐based, α4β2‐selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N‐Boc‐protected chloro‐ and bromo derivatives as precursors for labelling with fluorine‐18 were synthesized from 7‐tert‐butoxycarbonyl‐7‐azabicyclo[2.2.1]hept‐2‐ene in 13, 19 and 8% overall yield, respectively. [¹⁸F]F₂PhEP was prepared in 8–9% overall yield (non‐decay‐corrected) using 1 mg of the bromo derivative in the following two‐step radiochemical process: (1) no‐carrier‐added nucleophilic heteroaromatic ortho‐radiofluorination with the activated K[¹⁸F]F‐Kryptofix^®₂₂₂ complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA‐induced removal of the N‐Boc protective group. Radiochemically pure (>95%) [¹⁸F]F₂PhEP (1.48–1.66 GBq, 74–148 GBq/µmol) was obtained after semi‐preparative HPLC (Symmetry^® C18, eluent aqueous 0.05 M NaH₂PO₄ CH₃CN: 78/22 (v:v)) in 75–80 min starting from an 18.5 GBq aliquot of a cyclotron‐produced [¹⁸F]fluoride production batch. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of 14C‐labelled myosmine, [2′‐14C] ‐3‐(1‐pyrrolin‐2‐yl)pyridine

¹⁴C‐Labelled myosmine ([2′‐¹⁴C]‐3‐(1‐pyrrolin‐2‐yl)pyridine) was synthesized for autoradiography studies starting from [carboxyl‐¹⁴C]‐nicotinic acid by initial esterification of the latter in the presence of 1,1,1‐triethoxyethane. Without any purification the ethyl nicotinate formed was directly reacted with N‐vinyl‐2‐pyrrolidinone in the presence of sodium hydride, yielding ¹⁴C‐labelled myosmine. The product was purified by silica gel column chromatography. The radiochemical yield was 15% and the specific activity 55.2 mCi/mmol. Copyright © 2003 John Wiley & Sons, Ltd.     

Caution in the use of 2‐iminothiolane (Traut's reagent) as a cross‐linking agent for peptides. The formation of N‐peptidyl‐2‐iminothiolanes with bombesin (BN) antagonist (d‐Trp6,Leu13‐ψ[CH2NH]‐Phe14)BN6−14 and d‐Trp‐Gln‐Trp‐NH2

Abstract: During a study aimed at generating a bispecific molecule between BN antagonist (d ‐Trp⁶,Leu¹³‐ψ[CH₂NH]‐Phe¹⁴)BN_6‐14 (Antag1) and mAb22 (anti‐FcγRI), we attempted to cross‐link the two molecules by introducing a thiol group into Antag1 via 2‐iminothiolane (2‐IT, Traut's reagent). We found that reaction of Antag1 with 2‐IT, when observed using HPLC, affords two products, but that the later eluting peptide is rapidly transformed into the earlier eluting peptide. To understand what was occurring we synthesized a model peptide, d ‐Trp‐Gln‐Trp‐NH₂ (TP1), the N‐terminal tripeptide of Antag1. Reaction of TP1 with 2‐IT for 5 min gave products 1a and 3a ; the concentration of 1a decreased with reaction time, whereas that of 3a increased. Thiol 1a , the expected Traut product, was identified by collecting it in a vial containing N‐methylmaleimide and then isolating the resultant Michael addition product 2a , which was confirmed by mass spectrometry. Thiol 1a is stable at acidic pH, but is unstable at pH 7.8, cyclizes and loses NH₃ to give N‐TP1‐2‐iminothiolane ( 3a ), ES‐MS (m/z) [602.1 (M+H)⁺], as well as regenerating TP1. Repeat reaction with Antag1 and 2‐IT allowed us to isolate N‐Antag1–2‐iminothiolane ( 3b ), FAB‐MS (m/z) [1212.8 (M+H)⁺] and trap the normal Traut product 1b as its N‐methylmaleimide Michael addition product 2b , ES‐MS (m/z) [1340.8 (M+H)⁺]. Thiol 1b is also stable at acidic pH, but when neutralized is unstable and cyclizes, forming 3b and Antag1.     

Application of the Bischler–Napieralski–Pschorr radiosynthesis of (R)‐(‐)‐[6a‐14C]apomorphine,a non‐selective D1/D2 dopamine receptor agonist

A method has been developed for the carbon‐14 radiosynthesis of non‐narcotic morphine derivative (R)‐(‐)‐[6a‐¹⁴C]apomorphine ( 1 ) from the starting material 3,4‐dimethoxy‐2‐nitrophenyl‐N‐phenethyl[carboxyl‐¹⁴C]acetamide ( 5 ). The key to this synthesis was the application of the Bischler–Napieralski cyclodehydration to 1‐(3,4‐dimethoxy‐2‐nitrobenzyl)dihydro[1‐¹⁴C]isoquinoline ( 4 ), followed by N‐methylation and reduction to 1‐(3,4‐dimethoxy‐2‐nitrobenzyl)‐2‐methyl‐1,2,3,4‐tetrahydro[1‐¹⁴C]isoquinoline ( 3 ). A final Pschorr reductive ring closure followed by chiral separation to give (R)‐(‐)‐[6a‐¹⁴C]apomorphine dimethyl ether ( 2 ) and O‐demethylation led to (R)‐(‐)‐[6a‐¹⁴C]apomorphine ( 1 ) with a specific activity of 55 mCi/mmol, radiochemical purity of >98% and chiral purity of >99%. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [18F] 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression

To synthesize ¹⁸F‐labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting ¹⁸F into a target molecule are necessary. The ¹⁸F‐fluorobenzene moiety has been widely utilized in the synthesis of ¹⁸F‐labeled compounds. The present study utilized [¹⁸F]‐labeled aniline as intermediate in [¹⁸F]‐radiolabeling chemistry for the facile radiosynthesis of 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide ([¹⁸F]IDO5L) as indoleamine 2,3‐dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC₅₀. [¹⁸F]IDO5L was synthesized via coupling [¹⁸F]3‐chloro‐4‐fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [¹⁸F]IDO5L was obtained with specific radioactivity ranging from 11 to 15 GBq/µmol at the end of synthesis within ~90 min, and the decay‐corrected radiochemical yield was 18.2 ± 2.1% (n = 4).     

Synthesis and in vivo evaluation of [O‐methyl‐11C] 2‐(4‐methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methyl‐ piperidin‐4‐yl)acetamide as an imaging probe for 5‐HT2A receptors

2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT_2A antagonist, was labeled by [¹¹C]‐methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C] 4 cannot be used as PET ligand for imaging 5‐HT_2A receptors. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of (R)‐ and (S)‐[O‐methyl‐11C]N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐methoxy‐phenyl)‐urea as candidate high affinity β1‐adrenoceptor PET radioligands

Molecular imaging and quantification of myocardial β₁‐adrenoceptor (AR) rather than total β‐AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial β₁‐AR density is reduced in patients with chronic heart failure whereas cardiac β₂‐AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess β‐AR density non‐invasively in humans. However, no PET radioligand for the selective imaging of cardiac β₁‐ARs is clinically available. Here some derivatives of the well characterized β₁‐AR selective antagonist, ICI 89,406, namely the enantiomers of N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐hydroxy‐phenyl)‐urea ( 5a and 5b ) were synthesized and evaluated in vitro. The (R)‐isomer 5a was more β₁‐selective but has lower affinity than its (S)‐enantiomer 5b (β₁‐AR selectivity: 6100 vs 1240; β₁‐affinity: K₁ = 0.288 nM vs K₁ = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f , respectively, with [¹¹C]iodomethane gave ¹¹C‐labelled versions of 5a and 5b , namely 5g and 5h , in 44 ± 5% radiochemical yield (decay‐corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial β₁‐ARs. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of labelled N‐(4‐hydroxy‐[14C(U)]phenyl)‐2‐[2,3‐dihydro‐3‐oxo‐l,2‐benzisothiazol‐2‐yl‐1,1‐dioxide]acetamide

The amidation of 2‐[1,1‐dioxide‐3‐oxo‐1,2‐benzisothiazole‐2(3H)‐yl] acetyl chloride with carbon‐14‐labelled 4‐amino‐[¹⁴C(U)]phenol in NaOAc‐HOAc buffer solution at ?10°C gave N‐(4‐hydroxy‐[¹⁴C(U)]phenyl)‐2‐[2,3‐dihydro‐3‐oxo‐1,2‐benziso‐thiazol‐2‐yl‐1,1‐dioxide]acetamide in 82% yield. Subsequent hydrolysis with aqueous 0.5 N NaOH solution afforded the ring opened product N‐(4‐hydroxy‐[¹⁴C(U)]‐phenyl)‐2‐[2‐carboxy‐phenylsulfonamido]acetamide in 80% yield. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of morphine‐[N‐methyl‐14C]‐6‐β‐D‐glucuronide

Protected morphine‐6‐glucuronide was converted into morphine‐[N‐methyl‐¹⁴C]‐6‐glucuronide by a three‐step procedure. Methyl (3‐pivaloylmorphin‐6‐yl 2,3,4‐tri‐O‐isobutyryl‐β‐D‐glucopyranosid)uronate was N‐demethylated by treatment with 1‐chloroethyl chloroformate to afford protected normorphine‐6‐glucuronide as its hydrochloride salt. The normorphine‐6‐glucuronide derivative was alkylated with iodomethane‐[¹⁴C] in the presence of potassium carbonate to produce C‐14 labelled protected morphine‐6‐glucuronide. Finally, hydrolysis of the protecting groups using 5% sodium hydroxide solution gave morphine‐[N‐methyl‐¹⁴C]‐6‐β‐D‐glucuronide with a specific activity of 41.8 mCi mmol^?1 and radiochemical purity of 99.2% (HPLC). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [15N4] purine labeled cytokinin glycosides derived from zeatins and topolins with 9‐β‐d, 7‐β‐d‐glucopyranosyl,or 9‐β‐d‐ribofuranosyl group

Synthesis of [¹⁵N₄] purine labeled cytokinine glycosides derived from zeatins and topolins containing a 9‐β‐d , 7‐β‐d ‐glucopyranosyl, or 9‐β‐d ‐ribofuranosyl group is described. These N⁶‐substituted adenine derivatives are intended as internal analytic standards for phytohormone analysis. All labeled compounds were prepared from 6‐chloro[¹⁵N₄]purine ( 1 ). The equilibrium reaction of 1 with acetobromo‐α‐d ‐glucose gave isomeric 7‐β‐d ( 3 ) and 9‐β‐d ( 4 ) chloro glucosyl precursors, which were treated with the corresponding amines to get desired labeled cytokinin 7‐β‐d ( 6 ) and 9‐β‐d ( 5 ) glucopyranosides. Cytokinins containing 9‐β‐d ‐ribofuranosyl group ( 8 ) were obtained by direct enzymatic transglycosylation reaction of cytokinins ( 7 ) prepared from 6‐chloro[¹⁵N₄] purine ( 1 ).     

Radiosynthesis of 7‐chloro‐N,N‐dimethyl‐5‐[11C]methyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide, [11C]SSR180575, a novel radioligand for imaging the TSPO (peripheral benzodiazepine receptor) with PET

SSR180575 (7‐chloro‐N,N,5‐trimethyl‐4‐oxo‐3‐phenyl‐3,5‐dihydro‐4H‐pyridazino[4,5‐b]indole‐1‐acetamide) is the lead compound of an original pyridazinoindole series of potent and highly selective TSPO (peripheral benzodiazepine receptor) ligands. Isotopic labeling of SSR180575 with the short‐lived positron‐emitter carbon‐11 (T_1/2: 20.38 min) at its 5‐methylpyridazino[4,5‐b]indole moiety as well as at its N,N‐dimethylacetamide function by methylation of the corresponding nor‐analogues was investigated. Best results in terms of radiochemical yields and purities were obtained for the preparation of [indole‐N‐methyl‐¹¹C]SSR180575, where routine production batches of 4.5–5.0 GBq of radiochemically pure (>99%) i.v. injectable solutions (specific radioactivities: 50–90 GBq/ µ mol) could be prepared within a total synthesis time of 25 min (HPLC purification included) starting from a 55 GBq [¹¹C]CO₂ cyclotron production batch (non‐decay‐corrected overall radiochemical yields: 8–9%). The process comprises (1) trapping at ?10°C of [¹¹C]methyl triflate in DMF (300 µ l) containing 0.2–0.3 mg of the indole precursor for labeling and 4 mg of K₂CO₃ (excess); (2) heating at 120°C for 3 min; (3) dilution of the residue with 0.5 ml of the HPLC mobile phase and (4) purification using semi‐preparative reversed‐phase HPLC (Zorbax^® SB‐C‐18). In vivo pharmacological properties of [indole‐N‐methyl‐¹¹C]SSR180575 as a candidate for imaging neuroinflammation with positron emission tomography are currently evaluated. Copyright © 2010 John Wiley & Sons, Ltd.