A method for the synthesis of 2‐amino‐4‐fluoro‐bicyclo[3.1.0]hexane‐2,6‐dicarboxylic acid‐[3H2]

A process for double deuterium labeling of an alcohol was developed. The process was utilized in the subsequent tritium labeling of a secondary alcohol with high specific activity (24 Ci/mmol) by reduction of the corresponding ketone using sodium borotritide. The starting ketone was first brominated with pyridinium tribromide; the resulting alpha bromoketone was then reduced in THF/alcohol in the presence of Ni(OAc)₂. The alcohol was then converted to 2‐amino‐4‐fluorobicyclo[3.1.0]hexane‐2,6‐dicarboxylic acid‐[³H₂], an mGluR agonist. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis of [3‐3H]20(S)‐protopanaxadiol

[3‐³H]20(S)‐Protopanaxadiol (PPD) was prepared via selective reduction of PPD dioxide with sodium borotritide in N,N‐dimethyl acetamide. A radiochemical yield of 22% was obtained. The radiochemical purity of the final product was 99% and the ratio of C‐3/C‐12 tritium labeling was 97:3. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis of [3H]‐ABP688 using [3H]‐methyl nosylate: a non‐volatile alternative methylating agent

Tritiated ABP688 was synthesized from desmethyl ABP688 with [³H]‐methyl nosylate in high radiochemical yield. The results demonstrate that [³H]‐methyl nosylate is a good alternative methylating agent for radiosynthesis. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of [3H] vardenafil,Levitra®, using a new labeling technique

Tritium was introduced into the new orally active, selective phosphodiesterase type V (PDE V) inhibitor vardenafil (Levitra^®), by reduction of a suitable amide precursor with freshly prepared lithium aluminum tritide. A specific activity of 52.7 Ci/mmol (1.95 TBq/mmol) was achieved. In order to overcome the usual technical difficulties during the preparation of complex tritides a new and easy labeling technique which has considerable potential for various tritia‐tion procedures, was developed. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of 2H‐ and 3H‐labeled N‐cyclopropylmethyl‐7α‐[(R)‐1‐hydroxy‐1‐methyl‐3‐(2thienyl)‐propyl]‐6,14‐endoethano‐6,7,8,14‐tetrahydro nororipavine

A procedure for deuterium and tritium labeling of the titled compound, an analgesic agent, was developed. A secondary amine intermediate was acylated to an acylamide, then the carbonyl function was reduced by LiAlD₄ to yield the tertiary amine. In the tritium‐labeled synthesis, the process utilized a bromo‐substituted precursor, which was subsequently reduced with ³H₂ in the presence of a Pd/C catalyst. The labeled compounds were successfully applied in pharmacokinetic and pharmacological studies. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of [3α‐3H] 17α‐Hydroxy pregnenolone and [3α‐3H] Pregnenolone

For the first time, [3α‐³H] 17α‐hydroxy pregnenolone (1) was synthesized through a multiple step sequence. The presence of [3β‐³H] isomer in RP‐HPLC purified product was identified by tritium NMR. The [3β‐³H] isomer was then separated from [3α‐³H] 17α‐hydroxy pregnenolone with chiralPAK AD‐H column. [3α‐³H] pregnenolone (2) was synthesized from commercial available 5‐pregnen‐3,20‐dione in one step with an improved procedure.     

Facile synthesis of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB) for protein labeling

An efficient preparation of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) based on a convenient three‐step, one‐pot procedure is described. [¹⁸F]Fluorination of the precursor ethyl 4‐(trimethylammonium triflate)benzoate gave ethyl 4‐[¹⁸F]fluorobenzoate. Saponification of the ethyl 4‐[¹⁸F]fluorobenzoate with aqueous tetrapropylammonium hydroxide yielded the corresponding 4‐[¹⁸F]fluorobenzoate salt ([¹⁸F]FBA), which was then treated with N,N,N,N′‐tetramethyl‐O‐(N‐succinimidyl)uronium hexafluorophosphate. The purified [¹⁸F]SFB was used for the labeling of Avastin^? (Bevacizumab) through [¹⁸F]fluorobenzoylation of the Avastin's α‐amino groups. The decay‐corrected radiochemical yields of [¹⁸F]SFB were as high as 44% (based on [¹⁸F]fluoride (n=10) with a synthesis time of less than 60 min. [¹⁸F]Avastin was produced in decay‐corrected radiochemical yields of up to 42% (n=5) within 30 min (based on [¹⁸F]SFB). The radiochemical purities of [¹⁸F]SFB and [¹⁸F]Avastin were greater than 95%. Copyright © 2008 John Wiley & Sons, Ltd.     

Enantiospecific tritium labeling of 28‐homocastasterone

A regiospecific and enantiospecific synthesis of tritium‐labeled 28‐homocastasterone is reported. Appropriate chlorocarbonate, efficiently synthesized from the starting 28‐homocastasterone in an overall yield of 46%, undergoes catalytic tritium dechlorination by the T₂/Pd[0]/Et₃N system, providing 28‐[3β‐³H]homocastasterone, in a good yield, radiochemical purity (>97%), and with a high specific activity (5.8 Ci/mmol).     

Synthesis of [1,2‐3H]ethylamine hydrochloride and [3H]‐labeled apadenoson for a human ADME study

Tritium‐labeled [1,2‐³H]ethylamine hydrochloride was prepared through a multiple‐step sequence in high radioactive specificity. The labeled amine was isolated in high purity following cartridge filtration and used subsequently in the synthesis of [N‐ethyl‐1,2‐³H]apadenoson, an adenosine A_2a receptor agonist. The overall yield for this transformation was 56% and the radiochemical purity of the final product was greater than 99%. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of tracer labelled [11,12‐3H]‐β‐carotene

The synthesis of tracer labelled [11,12‐³H]‐β‐carotene is described. The procedure uses Wittig condensation of tracer labelled ³H‐retinal (retinal spiked with [11,12‐³H]‐retinal) with retinyl triphenylphosphonium bromide. The preparation of tracer labelled[³H]‐β‐carotene is suitable for studies involving bioavailability and bioconversion of β‐carotene to vitamin A. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and characterization of the potent cannabinoid agonist [naphthyl‐3H] WIN 55212‐2 at high specific activity

[Naphthyl‐³H] WIN 55212‐2 was prepared at high specific activity by the catalytic tritiation of dibromo precursor 3 . Product 4 was characterized by chromatography as well as tritium NMR and proven to be a useful radioligand. Copyright © 2002 John Wiley & Sons, Ltd.     

A simple and efficient synthesis of [3α‐3H]5α‐androst‐16‐en‐3β‐ol

An efficient one step synthesis of [3α‐³H]5α‐androst‐16‐en‐3β‐ol by NaBT₄ reduction of a ketone precursor is described. The specific activity of the product was 21.6 Ci/mmol with a radiochemical purity >99%. Synthesis of the precursor, 5α‐androst‐16‐en‐3‐one, from commercially available 5α‐androst‐16‐en‐3α‐ol is also presented. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis and characterization of [N‐methyl‐3H]loperamide

Loperamide is a piperidine butyramide mu‐opiate receptor agonist and currently employed to treat diarrhea. Because a single past report of tritiating loperamide was limited to only a very low specific activity product without technical details or extensive analysis, the synthesis of [N‐methyl‐³H]loperamide at high specific activity is now described in detail. An imine precursor was alkylated with [³H]methyl iodide to obtain a quaternary intermediate, which was then reacted with 4‐(4‐chlorophenyl)‐4‐hydroxypiperidine to afford the desired product [N‐methyl‐³H]loperamide, characterized by thin layer chromatography (TLC), HPLC, MS, UV, and proton‐decoupled tritium NMR.     

Synthesis of N‐(2‐chloro‐5‐methylthiophenyl)‐ N′‐(3‐methyl‐thiophenyl)‐ N′‐[3H3]methylguanidine, {[3H3]CNS‐5161}

The preparation of the title compound, [³H₃]CNS‐5161, was accomplished in three steps starting with the production of [³H₃]iodomethane (CT₃I). The intermediate N‐[³H₃]methyl‐3‐(thiomethylphenyl)cyanamide was prepared in 77% yield by the addition of CT₃I to 3‐(thiomethylphenyl)cyanamide, previously treated with sodium hydride. Reaction of this tritiated intermediate with 2‐chloro‐5‐thiomethylaniline hydrochloride formed the guanidine compound [³H₃]CNS‐5161. Purification by HPLC gave the desired labeled product in an overall yield of 9% with >96% radiochemical purity and a final specific activity of 66 Ci mmol^?1. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and characterization of [vinylidene‐3H] (−)‐α‐kainic acid at high specific activity

[Vinylidene‐³H] (?)‐α‐Kainic acid was prepared by means of a Wittig reaction with a protected ketone precursor and has proved useful as a tool to study neuroexcitatory amino acid receptors. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of [3‐13C]‐, [4‐13C]‐ and [11‐13C]‐porphobilinogen

[4‐¹³C]‐porphobilinogen 1a, [3‐¹³C]‐porphobilinogen 1b and [11‐¹³C]‐porphobilinogen 1c are prepared from [1‐¹³C]‐3‐(tetrahydropyran‐2′‐yloxy)‐propionaldehyde 2a, methyl [4‐¹³C]‐4‐nitrobutyrate 3b and [1‐¹³C]‐isocyanoacetonitrile 5c, respectively. The building blocks 2, 3 and 5 can be prepared efficiently in any isotopomeric form. Via base‐catalyzed condensation of these building blocks porphobilinogen can be enriched with ¹³C and ¹⁵N stable isotopes at any position and combination of positions. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis of N-acetyl-l-aspartyl-l-glutamic acid; [3H]NAAG

[³H]NAAG, N-acetyl-l -aspartyl-l -glutamic acid, has been widely used as a substrate in glutamate carboxypeptidase II (GCPII) reactions, either to determine the inhibitory constants at 50% inhibition (IC₅₀) of novel compounds or to measure GCPII activities in different tissues harvested from various disease models. The importance of [³H]NAAG, combined with its current commercial unavailability, prompted the development of a reliable eight-step synthetic procedure towards [³H₂]NAAG starting from commercially available pyroglutamate. Pure [³H]NAAG of high molar activity (49.8 Ci/mmol) and desired stereochemistry was isolated in high radiochemical yield (67 mCi) and radiochemical purity (>99%). The identity was confirmed by mass spectrometry and co-injection with unlabeled reference.     

Synthesis of [3H]‐labelled 4‐[Ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]‐2,3‐[3H]‐butan‐1‐ol: a high affinity radioligand for the corticotropin‐releasing hormone type 1 receptor

[³H]‐Labelled 4‐[ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]‐2,3‐[³H]‐butan‐1‐ol ( 3b ) was prepared as a novel non‐peptidic radiolabelled high affinity antagonist of the corticotropin‐releasing hormone type 1 receptor (CRHR₁) that could be useful as a more stable and receptor‐selective alternative to the radiolabelled peptides now used to label the CRHR₁ receptor for displacement studies in cell‐based binding assays. The precursor (Z)‐4‐[ethyl[2,5,6‐trimethyl‐7‐(2,4,6‐trimethylphenyl)pyrrolo[2,3‐d]pyrimidin‐4‐yl]amino]but‐2‐en‐1‐ol ( 2 ) was reduced with tritium gas using palladium as the catalyst. After HPLC purification 3b was obtained with a specific activity of 35 Ci/mmol in high radiochemical purity (>97%). Copyright © 2006 John Wiley & Sons, Ltd.     

Preparation of high specific activity tritium labeled 6α,9,‐difluoro‐11β,21‐dihydroxy‐16α,17‐[(1‐methylethylidene)bis(oxy)]pregna‐1,4‐diene‐3,20‐one,fluocinolone acetonide

Fluocinolone acetonide was tritiated by selective reduction of the 1,2‐double bond of the O‐protected analog under tritium, followed by re‐establishment of the 1,2‐double bond and deprotection. Protection of both hydroxyl functionalities was required. The product was obtained with specific activity 36.8 Ci/mmol. Copyright © 2009 John Wiley & Sons, Ltd.