Preparation of carbon‐14 labeled (3R)‐7‐hydroxy‐N‐(1S)‐1‐{[(3R,4R)‐4‐(3‐hydroxyphenyl)‐3,4‐dimethyl‐1‐piperidinyl]methyl}‐2‐methylpropyl‐1,2,3,4‐tetrahydroisoquinolinecarboxamide (JDTic)

Starting with [¹⁴C]‐D‐tyrosine, carbon‐14 labeled JDTic dihydrochloride with specific activity 15 mCi/mol was prepared in 5% radiochemical yield. Separation of the (3R)‐ and (3S)‐diastereomers was carried out via the 3‐phenyl‐2,3,10,10a‐tetrahydro‐5H‐imidazo[1,5‐b]isoquinolin‐1‐ones formed by reaction with benzaldehyde. Copyright © 2008 John Wiley & Sons, Ltd.     

A novel and efficient asymmetric synthesis of carbon‐14 labeled (S,S)‐2,7‐di‐boc‐diamino[1,8‐14C2]suberic acid

Five hundred mCi of Potassium [¹⁴C]cyanide at a specific activity of 51 mCi/mmol was used to diastereoselectively introduce the carbon‐14 label into 1,6‐hexanedial via a thermodynamically controlled asymmetric Strecker reaction using (R)‐(‐)‐2‐phenylglycinol as the chiral auxiliary. The expected and predominant (R,S/S,R) diastereomer ( 2 ) was separated by preparative normal phase HPLC. The chiral auxiliary was removed by oxidation with lead tetraacetate and the resulting benzylimino nitrile exhaustively hydrolyzed in hydrochloric acid to give (S,S)‐2,7‐diamino[1,8‐¹⁴C₂]suberic acid ( 6 ). Subsequent acylation with di‐tert‐butyldicarbonate gave the title compound ( 1 ) with a radiochemical purity of 95.5%, a specific activity of 113 mCi/mmol, and an enantiomeric purity of 95.5% e.e. To our knowledge this is the first report of the asymmetric Strecker methodology being applied to the synthesis of a carbon‐14 labeled amino acid. Copyright © 2002 John Wiley & Sons, Ltd.     

The synthesis of [1‐14C]2‐(1H‐tetrazol‐5‐yl)acetic acid

Tetrazoles are a common heterocyclic functionality in many biologically active molecules. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was required as an intermediate in the synthesis of a development candidate as part of a discovery phase program to complete metabolic profiling studies. [1‐¹⁴C]2‐(1H‐Tetrazol‐5‐yl)acetic acid was prepared in 4 steps overall and in 3 radiochemical steps from K¹⁴CN in an overall 32% radiochemical yield.     

Synthesis of [2‐13C, 4‐13C]‐(2R,3S)‐catechin and [2‐13C, 4‐13C]‐(2R,3R)‐epicatechin

The first synthesis of doubly labeled, [2‐¹³C, 4‐¹³C]‐(2R,3S)‐catechin 15 and [2‐¹³C, 4‐¹³C]‐(2R,3R)‐epicatechin 18 starting from labeled 2‐hydroxy‐4, 6‐bis(benzyloxy)acetophenone 3 and labeled 3, 4‐bis(benzyloxy)‐benzaldehyde 7 are described. Copyright © 2010 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.     

Synthesis of empagliflozin,a novel and selective sodium‐glucose co‐transporter‐2 inhibitor,labeled with carbon‐14 and carbon‐13

Empagliflozin, (2S,3R,4R,5S,6R)‐2‐[4‐chloro‐3‐[[4‐[(3S)‐oxolan‐3‐yl]oxyphenyl]methyl]phenyl]‐6‐(hydroxymethyl)oxane‐3,4,5‐triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon‐13 and carbon‐14 labeled empagliflozin. Carbon‐13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α‐D‐glucose‐[¹³C₆]. For the radiosynthesis, the carbon‐14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon‐14 D‐(+)‐gluconic acid δ‐lactone was used to prepare specifically labeled empagliflozin in carbon‐1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon‐14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon‐14 uniformly labeled phenol was used to give [¹⁴C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.     

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.     

Synthesis of lead LFA‐1 antagonist [14C]spyrocyclic hydantoin

Radiolabelled drug lead candidate leukocyte function‐associated antigen 1 antagonist [¹⁴C]spyrocyclic hydantoin: 5‐(((5S,9R)‐9‐(4‐[¹⁴C]‐cyanophenyl)‐3‐(3,5‐dichlorophenyl)‐1‐methyl‐2,4‐dioxo‐1,3,7‐triazaspiro[4.4]nonan‐7‐yl)methyl)thiophene‐3‐carboxylic acid, 12 , was conveniently prepared in three radiochemical steps from (5S,9R)‐tert‐butyl 9‐(4‐bromophenyl)‐3‐(3,5‐dichlorophenyl)‐1‐methyl‐2,4‐dioxo‐1,3,7‐triazaspiro[4.4]nonane‐7‐carboxylate 9 . The radiochemical yield of 12 was 28.5% from the resolved bromide 9 . The preparation of the racemic spyrocyclic hydantoin 3 was obtained via a [3+2]dipolar cycloaddition reaction between 2 and N‐benzyl‐N‐(methoxymethyl)trimethylsilylmethylamine. The introduction of [¹⁴C] cyanide was completed via a palladium (0) catalyzed reaction by the addition of Zn(¹⁴CN)₂ to aryl bromide 9 . The radiochemical and chiral purities of 12 determined by high‐performance liquid chromatography were 98.7 and 99.7%, respectively. The specific activity of 12 was 87.5 µCi/mg (48.6 mCi/mmol). Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of potent lymphocyte function‐associated antigen‐1 inhibitors labeled with carbon‐14 and deuterium,part 1

The lymphocyte function‐associated antigen‐1 (LFA‐1) is an essential component in normal immune system function and is a target for drug discovery for its broad therapeutic potential in treating inflammatory diseases. Here, we report the synthesis of three potent antagonists of LFA‐1 labeled with carbon‐14 and deuterium to support drug metabolism and pharmacokinetics studies. Carbon‐14 labeled (R)‐1‐acetyl‐5‐(4‐bromobenzyl)‐3‐(3,5‐dichlorophenyl)‐5‐methyl‐imidazolidine‐2,4‐dione (1) was prepared in 27% radiochemical yield in two steps and with a specific activity of 2.1 GBq/mmol by using [¹⁴C]‐phosgene. Carbon‐14 labeled 5‐bromopyrimidine was used to prepare (R)‐5‐(1‐piperazinylsulfonyl)‐1‐(3,5‐dichlorophenyl)‐3‐[4‐(5‐pyrimidinyl)benzyl]‐3‐methyl‐1‐H‐imidazo[1,2a]imidazol‐2‐one (2) and (R)‐1‐[7‐(3,5‐dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐pyrimidin‐5‐yl‐benzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonyl]piperidin‐4‐carboxylic acid amide (3) via a Suzuki reaction with the corresponding boronic acid esters in 42% and 67% radiochemical yield and specific activities of 1.85 GBq/mmol and 1.95 GBq/mmol, respectively. Deuterium labeled piperazine was reacted with the sulfonyl chloride derivative (7), followed by a Suzuki coupling to the pyrimidine boronic ester to give deuterium labeled (2) in 47% yield. Deuterium labeled isonipecotamide was reacted in a similar way with the sulfonyl chloride derivative (14) to furnish deuterium labeled (3) in one step and in 94% yield. Copyright © 2011 John Wiley & Sons, Ltd.     

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 and stability of a carbon‐14‐labeled 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase inhibitor

Inhibition of 3‐hydroxy‐3‐methylglutaryl coenzyme‐A reductase (HMGR) is an effective method of lowering plasma low‐density lipoprotein cholesterol levels. Hemi‐calcium (3R,5S,E)‐7‐(4‐(4‐fluorophenyl)‐6‐isopropyl‐2‐(methyl(1‐methyl‐1H‐1,2,4‐triazol‐5‐yl)amino)pyrimidin‐5‐yl)‐3,5‐dihydroxyhept‐6‐enoate (1) is a cholesterol‐lowering statin drug that effectively inhibits HMGR. An important step in the development of this compound was the synthesis of a carbon‐14‐labeled analog for use in preclinical absorption, distribution, metabolism and excretion studies. The synthesis of a carbon‐14‐labeled analog of the cholesterol‐lowering statin drug 1 is described. The carbon‐14‐labeled compound [¹⁴C]‐1 was prepared in 11 steps from [¹⁴C]‐labeled urea. The overall radiochemical yield for the synthesis was 22% and the radiochemical purity of [¹⁴C]‐1 was 99.9% immediately after synthesis. It was found that [¹⁴C]‐1 with a specific activity of 43.2 µCi/mg decomposed at a rate of about 1.9%/month when stored at ?78°C under argon. Three samples of [¹⁴C]‐1 were prepared to study the chemical stability of the molecule. One sample had a specific activity of 3.8 µCi/mg and the other two contained radical inhibitors, L ‐ascorbic acid (1% by weight, specific activity of 10.5 µCi/mg) or BHT (1% by weight, specific activity of 9.8 µCi/mg). For these samples the decomposition rates were decreased to 0.5%/month, 0.2%/month and 0.1%/month, respectively. Copyright © 2010 John Wiley & Sons, Ltd.     

A potent IκB kinase‐β inhibitor labeled with carbon‐14 and deuterium

3‐Amino‐4‐(1,1‐difluoro‐propyl)‐6‐(4‐methanesulfonyl‐piperidin‐1‐yl)‐thieno[2,3‐b]pyridine‐2‐carboxylic acid amide (1) is a potent IκB Kinase‐β (IKK‐β) inhibitor. The efficient preparations of this compound labeled with carbon‐14 and deuterium are described. The carbon‐14 synthesis was accomplished in six radiochemical steps in 25% overall yield. The key transformations were the modified Guareschi–Thorpe condensation of 2‐cyano‐¹⁴C‐acetamide and a keto‐ester followed by chlorination to 2,6‐dichloropyridine derivative in one pot. The isolated dichloropyridine was then converted in three steps in one pot to [¹⁴C]‐ (1) . The carbon‐14 labeled (1) was isolated with a specific activity of 54.3 mCi/mmol and radiochemical purity of 99.8%. The deuterium labeled (1) was obtained in eight steps and in 57% overall chemical yield using 4‐hydroxypiperidine‐2,2,3,3,4,5,5,6,6‐²H₉. The final three steps of this synthesis were run in one pot.     

(R)‐N‐Methyl‐3‐(3′‐[18F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (18F‐MFP3) as a potential PET imaging agent for norepinephrine transporter

A decline of norepinephrine transporter (NET) level is associated with several psychiatric and neurological disorders. Therefore positron emission tomography (PET) imaging agents are greatly desired to study the NET pathway. We have developed a C‐fluoropropyl analog of nisoxetine: (R)‐N‐methyl‐3‐(3′‐[¹⁸F]fluoropropyl)phenoxy)‐3‐phenylpropanamine (¹⁸F‐MFP3) as a new potential PET radiotracer for NET with the advantage of the longer half‐life of fluorine‐18 (110 min compared with carbon‐11 (20 min). Synthesis of (R)‐N‐methyl‐3‐(3′‐fluoropropyl)phenoxy)‐3‐phenylpropanamine (MFP3) was achieved in five steps starting from (S)‐N‐methyl‐3‐ol‐3‐phenylpropanamine in approx. 3–5% overall yields. In vitro binding affinity of nisoxetine and MFP3 in rat brain homogenates labeled with ³H‐nisoxetine gave Ki values of 8.02 nM and 23 nM, respectively. For radiosynthesis of ¹⁸F‐MFP3, fluorine‐18 was incorporated into a tosylate precursor, followed by the deprotection of the N‐BOC‐protected amine group with a 15% decay corrected yield in 2.5 h. Reverse‐phase chromatographic purification provided ¹⁸F‐MFP3 in specific activities of >2000 Ci/mmol. Fluorine‐18 labeled ¹⁸F‐MFP3 has been produced in modest radiochemical yields and in high specific activities. Evaluation of ¹⁸F‐MFP3 in animal imaging studies is in progress in order to validate this new fluorine‐18 radiotracer for PET imaging of NET. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of 6β‐([1‐14C]propoxy)celangulin V

Chinese bittersweet, Celastrus angulatus Max., is a widely distributed plant and is used as a traditional insecticide in China. Celangulin V (CA‐V), one of the main insecticidal ingredients from the plant, has special insecticidal mechanism. A synthesized compound, 6β‐propoxycelangulin V, exhibits more remarkable insecticidal activity against insect pests. In this study, the synthesis of a labeled version of a CA‐V analog, 6β‐([1‐¹⁴C]propoxy)celangulin V, was accomplished from 1‐[1‐¹⁴C]propanol and CA‐V in two steps with the chemical and radiochemical purities of 98.7 and 99.9%, respectively. The labeled compound can be used as a radiotracer to study the mechanism of action of CA‐V analogs. Copyright © 2008 John Wiley & Sons, Ltd.     

The synthesis of carbon‐14 labeled (R)‐4‐(dipropylamino)‐1,3,4,5‐tetrahydrobenz[cd]indole‐6‐carboxamide hippurate. A partial ergoline with 5‐HT1A agonist activity and an 125I‐labeled analog

Partial ergoline agonists such as (R)‐4‐(dipropylamino)‐1,3,4,5‐tetrahydrobenz[cd]‐indole‐6‐carboxamide ( LY228729, 1a ) mimic a locked conformational analog of serotonin and in fact possess potent in vitro activity as agonists of the 5‐HT_1A receptor. In the course of pre‐clinical investigation of 1a for potential use as an anxiolytic agent, 1b was prepared in a five step synthesis from K¹⁴CN. In addition, an ¹²⁵I‐analog of 1a was prepared for aid in the development of a radioimmunoassay (RIA). Copyright © 2005 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 a highly potent leukocyte function‐associated antigen‐1 antagonist and its metabolite labeled with stable isotopes and carbon‐14, part 2

(S)‐2‐[(R)‐7‐(3,5‐Dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐trifluoromethoxybenzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonylamino]‐proprionamide (1), a potent lymphocyte function‐associated antigen‐1 antagonist and its sulfonamide metabolite (2) labeled with stable isotopes and carbon‐14 were prepared for Drug Metabolism and PharmacoKinetics and other studies. A long linear route was used to prepare [¹³C₂, ²H₃]‐(1) using [3,3,3‐²H]‐D‐alanine and [¹³C₂]‐glycine in 15 steps and 2.5% overall yield. With the availability of [¹³C₆]‐3,5‐dichloroaniline, the sulfonamide [¹³C₆]‐(2) was prepared in 12 steps and in 5.6% overall yield. For the carbon‐14 synthesis, a six‐step synthesis gave both compounds [¹⁴C]‐(1) and [¹⁴C]‐(2) from the common sulfonyl chloride intermediate [¹⁴C]‐(15) in 18% and 4% radiochemical yields and specific activities of 44 and 40.5 mCi/mmol, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Radiosynthesis of the α4β2 nicotinic acetylcholine receptor ligand: 5‐((1‐[11C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)vinyl)pyridine

5‐((1‐[¹¹C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)‐vinyl)pyridine ([¹¹C]‐FPVC) was synthesized from [¹¹C]‐methyl iodide and the corresponding normethyl precursor. The average time of synthesis, purification, and formulation was 42 min with an average non‐decay‐corrected radiochemical yield of 19%. The average specific radioactivity was 359 GBq/µmol (9691 mCi/µmole) at end of synthesis (EOS). Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of 1‐[4‐(m‐tolyl)amino‐6‐quinazolinyl]‐3‐[14C]‐methyl triazene: a radiolabeled probe for the combi‐targeting concept

The synthesis of 1‐[4‐(m‐tolyl)amino‐6‐quinazolinyl]‐3‐[¹⁴C]‐methyl triazene (SMA41) is described. This triazene was designed to be hydrolyzed under physiological conditions to N⁴‐m‐tolyl‐quinazoline‐4,6‐diamine (SMA52), a moderate inhibitor of the epidermal growth factor receptor (EGFR) and the DNA alkylating species [¹⁴C]‐methyldiazonium. A radiolabeled probe was needed to test the hypothesis that in situ hydrolysis of SMA41 may induce alkylation of the ATP binding site of EGFR. ¹⁴C‐SMA41 was obtained with a radiochemical yield of 21% and a specific activity of 54.6 mCi/mmol, as determined by HPLC quantitation and scintillation counting. Radio‐TLC analyses showed 98% radiochemical purity. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [3H]ABT‐518, a matrix metalloproteinase inhibitor (MMPI) labeled in the phenyl rings

A novel matrix metalloproteinase inhibitor, ABT‐518, [S‐(R^*, R^*)]‐N‐[1‐(2, 2‐dimethyl‐1,3‐dioxol‐4‐yl)‐2‐[[4‐[4‐(trifluoromethoxy)‐phenoxy]phenyl]sulfonyl]ethyl]‐N‐hydroxyformamide, was labeled with tritium in two phenyl rings in a seven‐step synthesis. The overall radiochemical yield of [³H]ABT‐518 in seven steps starting from 1‐(methylsulfonyl)‐4‐[4‐(trifluoromethoxy)phenoxy]benzene was 6.2% with the radiochemical purity of 99.4%. Copyright © 2009 John Wiley & Sons, Ltd.